Biological chemistry {biochemistry}| is about carbohydrates, proteins, nucleic acids, and lipids.
Molecules {carbohydrate}| can have only carbons, oxygens, and hydrogens, with one oxygen atom attached to each carbon. Carbohydrates have alcohol side chains, except for one carbonyl side chain.
Pancreatic amylase in small intestine digests polysaccharides. Polysaccharides are 98% absorbed. Intestine absorbs fructose passively but transports glucose and galactose across membrane actively {absorption, food} {food absorption}.
If carbohydrate in diet is low, fats provide energy, and acetyl-CoA builds up in cells.
Alpha and beta rings are equivalent {anomer}.
Sugars can link by ether bonds {glycosidic bond}. In glycosidic bonds, carbonyl-carbon hydroxyl leaves with hydrogen atom from other-sugar hydroxyl, forming water. Then other-sugar hydroxyl oxygen binds to carbonyl carbon. First-sugar carbonyl is on either first or second carbon. Other-sugar carbon is fourth or sixth carbon. Glycosidic bonds break by hydrolysis.
Sugar substitutes {artificial sweetener} include saccharin, cyclamate, aspartame, and mannitol.
Connective tissue, skin, cornea, and bone have saccharides {chondroitin sulfate}. Chondroitinase cleaves and dissolves extracellular-matrix chondroitin.
Plants have molecules {fiber, nutrition}| that people cannot digest into smaller molecules and/or absorb across intestinal wall into blood.
solubility
Some fiber {insoluble fiber} {crude fiber} does not absorb water. Other fiber {soluble fiber} {dietary fiber} can absorb water.
bond
Cellulose is crude fiber. Lignin, hemicellulose, and pectin are dietary fiber. Cellulose, lignin, hemicellulose, pectin, and inulin have glycosidic bonds that are not the same as for starch and glycogen. Human intestine cannot break them down.
sources
Soluble fiber is in fruit, oats, barley, beans, peas, lentils, peanuts, and some vegetables. Insoluble fiber is in fruits, grains, nuts, and vegetables. Starchy vegetables have low fiber.
functions
Insoluble fiber adds bulk and maintains regular bowel movements. Soluble fiber increases bile-acid secretion. Soluble fiber absorbs water. Soluble fiber affects blood sugar and cholesterol levels.
Three-carbon monosaccharides {glycerol, saccharide} can have alcohol group at each carbon.
Extracellular proteins {glycoprotein}| have saccharides bound to asparagine, serine, threonine, and lysine. Egg-white ovalbumin, egg-white avidin, mucoprotein, collagen, eye-lens protein, basement-membrane protein, ribonuclease, pepsin, cholinesterase, chorionic gonadotropin, follicle-stimulating hormone, thyroid-stimulating hormone, fibrinogen, gamma-globulin, blood-group proteins, and fish-blood antifreeze protein are glycoproteins.
Animal-cell coats and ground substance have glycosphingolipids, acid mucopolysaccharide, and glycoprotein, which are soft, flexible, and adhesive and are for cell recognition and growth inhibition.
Arterial wall has carbohydrate blood-coagulation blocker {heparin}.
Acid mucopolysaccharides, mucins, and mucoprotein make fluid {mucus}|. Mucus keeps inner body surfaces slippery or sticky. Mouth mucus is antibacterial.
Seeds and fruit have chemicals {psoralen} sensitive to light. Light makes them react with DNA.
To enter TCA cycle, pyruvate {pyruvate} first converts to acetyl-CoA. NAD+ attaches acetyl to CoA by thioester bond and makes carbon dioxide and two NADH, in irreversible reaction. Process uses free enzymes in inner mitochondria. ATP inhibition regulates reaction. Arsenate can poison reaction.
Pigments {pigment compounds} are chlorophyll, carotenoid, xanthophyll, and physobilin. Light oxidizes pigments. Donated electron adds to NADP+. Electron-transport chain and oxidative phosphorylation make ATP and oxygen.
Chlorophyll a {chlorophyll}| absorbs orange light, and chlorophyll b absorbs red light, making plants green.
Yellow, red, or purple pigments {carotenoid} absorb at different wavelengths.
Carotenoid {physobilin} absorbs blue or red.
Carotenoid {xanthophyll} absorbs yellow.
Monosaccharides can form polymers {polysaccharide}|, with glycosidic bonds between units. Polysaccharides are not water-soluble and are not sweet.
Seaweed carbohydrate can make gel {agar}|.
Unbranched polysaccharides {cellulose}| in plant cell walls have linked glucose molecules.
Short polysaccharides {dextran} {dextrin}| of 5 to 15 carbons are for energy.
Short polysaccharides {dextrose}| of 5 to 15 carbons are for energy.
Branched polysaccharides {glycogen}| in animals link glucoses and store energy.
Carbohydrates {gum arabic} can be gum.
Polysaccharides {hemicellulose} can link pentose molecules and be in gum.
Linear soluble polymers {hyaluronic acid} can surround egg cell and have disaccharide units.
Carbohydrates {inulin} can be fructose polymers.
Carbohydrates {lignin} can be in tree and grass cell walls. Lignin is hard and woody. It remains when enzymes turn cellulose into sugar.
Two-carbon to ten-carbon polysaccharides {oligosaccharide} can be for energy.
Glucose chains {pectin, polymer}| can be in unripe fruit and be thickeners or gels.
Mouth amylases {ptyalin} can make polysaccharides into dextrin.
In plants, polysaccharides {starch, plant}| can link glucose molecules and store energy. Starches can be unbranched and helical {amylose} or branched {amylopectin}.
Two delta-aminolevulinic acids make porphobilinogen ring, which becomes tetrapyrrole, which makes molecules {porphyrin}|. Porphyrin can make heme. Chlorophyll has porphyrin ring, as does cytochrome oxidase. If bad metabolism causes porphyrin to have no metal inside, porphyrin goes to skin, bones, and teeth, where light makes free radicals {porphyria}.
Iron-containing ring structure {heme} can derive from succinyl-CoA of TCA cycle. Two delta-aminolevulinic acids make porphobilinogen ring, which becomes tetrapyrrole, which makes porphyrin. Porphyrin can make heme. Heme breakdown product is bilirubin, excreted in urine.
Glucose and galactose {hexose} have six carbons. One amino group can bind at glucose second carbon {glucosamine}. Glucosamine is in insect chitin. One amino group can bind to galactose {galactosamine}. Galactosamine is in glycolipids and chondroitin sulfate. One amino group can bind to aldehyde sugars at first carbon {muramic acid} {neuraminic acid}. Muramic acid and neuraminic acid make cell walls.
Sucrose has one glycosidic bond between fructose and glucose, from second carbon to first carbon {invert sugar}|, to make acetal or ketal.
Carbohydrates {monosaccharide}| can have three to seven carbons and one carbonyl group, as in glucose, fructose, mannose, maltose, and galactose. Monosaccharides {triose} can have three carbons, such as glyceraldehyde. Monosaccharides {tetrose} can have four carbons. Monosaccharides {pentose} can have five carbons, such as ribose. Monosaccharides (hexose) can have six carbons. Aldehyde hexoses are glucose, mannose, and galactose. Ketone hexoses include fructose, in honey and fruit. Monosaccharides {heptose} can have seven carbons.
Sugar aldehyde or ketone group can reduce to alcohol group {reduced sugar}|, to make glycerol, inositol, sorbital, and mannitol.
Carbohydrates {sugar}| can be disaccharides. Glycosidic bonds link two monosaccharides. Sucrose, in sugar cane, sugar beets, and corn syrup, has fructose and glucose. Maltose, in malt, has two glucoses.
Lactose, in milk, has galactose and glucose. Lactase gene, for lactose digestion, can stay active after infancy. Regulatory-region mutations happened in Funnel Beaker culture of Sweden and Holland [-4000 to -3000], in Nilo-Saharan peoples of Kenya and Tanzania [-4800 to -700], in Beja people of northeast Sudan [-4800 to -700], and in Afro-Asiatic peoples of north Kenya [-4800 to -700].
Carbohydrates have reactions {carbohydrate reactions}. Mitochondria have citric acid cycle (Krebs cycle). Cytoplasm and mitochondria have gluconeogenesis. Cytoplasm has glycolysis. Mitochondria have oxidative phosphorylation. Cytoplasm has pentose phosphate pathway. Mitochondria have respiratory chain.
organs
Brains use glucose and do not store fat or glycogen. Muscle stores glycogen and uses glucose when active. Heart muscle uses ketone bodies. Liver puts glucose into blood and regulates glucose blood level.
Reactions {anaerobic} can require no oxygen.
TCA cycle uses oxygen {aerobic respiration} to make carbon dioxide.
Acetyl-CoA reactions {Claissen condensation} can lengthen carbon chains by branching. Acetyl-CoA ketone, CH3-CO-S-CoA [3 is subscript], can lose hydrogen when CoA leaves, CH3-CO-, and separate charges to make (C-H2)-(C+O) [2 is subscript and - and + are superscripts]. Ketone carbon is positive, and methyl carbon is negative. Separated charges attack dicarboxylic acid, HOOC-CH2-COOH [2 is subscript], to add ketone, HOOC-(CH2C-H2C+O)-COOH [2 is subscript and + and - are superscripts]. Adding water molecule neutralizes carbon and makes branched carbon chain, HOOC-CHCH2COOH-COOH [2 is subscript], as hydrogen gas leaves.
Reactions {reverse aldol condensation} {condensation reaction, carbohydrate} can lengthen carbon chains by two carbons.
ketol-enol
Proton can transfer from -CO-CH2OH ketol last carbon to next-to-last carbon, to make enol double bond between carbons and alcohol on next-to-last carbon: -COH=CHOH. Enol can add water molecule to make separated charges: -(H2OC+OH)-(C-HOH) [2 is subscript and + and - are superscripts]. Last carbon becomes negative, and next-to-last carbon becomes positive.
aldol
Enol with separated charges can attack aldol, -CHOH-CHO, carbonyl double bond to single-bond carbonyl carbon and carbanion: -CHOH-(C-OH)-CHOH-(H2OC+OH)- [2 is subscript and + and - are superscripts]. Positive charge is still on next-to-last enol carbon, and negative charge is on last aldol carbon.
proton transfer
Water leaves, and proton transfers from positive charge to carbanion and makes atoms neutral: -CHOH-CHOH-CHOH-CHOH-.
Glucose can convert to ethanol and carbon dioxide, using no oxygen {fermentation}|. Glucose converts to pyruvate. Pyruvate converts to acetaldehyde by losing carbon dioxide. Acetaldehyde reduces to ethanol using NADH. Berzelius described fermentation [1837].
Glucose can convert to pyruvate and then to lactic acid {glycolysis}| {Embden-Meyerhof pathway}. Glycolysis makes more ATP than it uses and is anaerobic, requiring no oxygen. Glycolysis enzymes float free in cytoplasm. In first part, glucose becomes glyceraldehyde-3-phosphate by adding two ATPs to ends and splitting into two molecules. In second part, glyceraldehyde-3-phosphate becomes pyruvate and makes four ATPs. Pyruvate makes lactic acid by adding NADH.
Isocitrate makes glyoxalate, and glyoxalate makes malate {glyoxalate cycle}, if acetyl-CoA is present. Glyoxysomes make succinate, which is precursor for fatty-acid synthesis.
Glucose-6-phosphate becomes 6-phosphogluconate by oxidation {phosphogluconate pathway} {pentose phosphate pathway} {hexose monophosphate shunt}. Aldehyde becomes carboxyl. NAD+ becomes NADPH. 6-phosphogluconate makes pentoses, such as ribose-5-phosphate, for nucleotides. Hexose monophosphate shunt in reverse makes hexoses from pentoses for extra energy. Pentose phosphate pathway is in photosynthesis dark reaction.
Sugars can isomerize by keto-enol tautomerism at carbonyl {isomerization}|.
By isomerization {keto-enol isomerization}, enol can become ketol, and ketol can become enol. Keto-enol isomerization must polarize, with lysine, cysteine, or serine.
At cysteine, aldehyde can oxidize to carboxylic acid using two NAD+ {oxidation, carbohydrate}. R-CHO -> R-CHOH-S-cys + 2 NAD+ -> R-CO-S-cys + 2 NADH -> R-COOH. Sugars can oxidize to makes acids: ascorbic acid, gluconic acid, uronic acid, and phytic acid {oxidized sugar}. Sugar aldehyde or ketone group can reduce to alcohol group to make glycerol, inositol, sorbital, and mannitol reduced sugars. Glycerol and inositol bind fatty acids. Sorbital and mannitol are food additives.
Hydrogen-ion transfer provides energy to convert ADP to ATP {phosphorylation}. ADP makes ATP {oxidative phosphorylation}, using hydrogen-ion gradient set up by respiratory chain in mitochondria inner membrane. Channels through membrane allow hydrogen ions to flow past ATPase, which uses electric and flow energy to phosphorylate ADP. ADP controls process by controlling coupling between FAD+ to FADH2 [2 is subscript] and NAD+ to NADH, by folding inner membrane more or less. Arsenate or dinitrophenol destroys pH gradient. Oligomycin binds to ATPase.
Carbon dioxide, water, and sunlight can make oxygen and glucose {photosynthesis}|.
process
First, light reacts with water, NADP+, and ADP to make oxygen, NADPH, H+, and ATP {light phase}. Light oxidizes pigments, to release electron. Donated electron adds to NADP+. Electron transport chain and oxidative phosphorylation make ATP and oxygen. Then carbon dioxide, NADPH, H+, and ATP make glucose, NADP+, and ADP {dark phase}, with no light required.
pigments
Chlorophyll a absorbs orange light, and chlorophyll b absorbs red light, making plant green. Yellow, red, or purple carotenoid pigments absorb at different wavelengths. Xanthophyll carotenoid absorbs yellow. Physobilin carotenoid absorbs blue or red.
Older system absorbs light at 710 nanometers and makes ATP but no oxygen. Newer system absorbs light at 680 nanometers and makes oxygen.
bacteria
Nitrogen-fixing bacteria use photosynthesis to make nitrogen into ammonia. Nitrate-fixing bacteria use photosynthesis to make ammonia. Sulfur bacteria use photosynthesis to make sulfates.
NADH and NADPH from glycolysis, TCA cycle, and other oxidations reduce oxygen to water in mitochondria {respiration, metabolism}. Hydrogen ions increase inside mitochondria and make pH gradient across mitochondrial membrane.
respiratory chain
Aerobic reduction reactions {respiratory chain} make the following compounds: FMNH2 [2 is subscript], ferrous iron, coenzyme Q, cytochrome b, iron-sulfur bond, cytochrome c, cytochrome c1, cytochrome a, cytochrome a3, and water from oxygen.
phosphorylation
Oxidative phosphorylation links to respiratory chain at three places: coenzyme Q reduction, cytochrome c reduction to cytochrome c1, and oxygen reduction to water. At the three steps, respiratory chain places hydrogen ions on mitochondria inner-membrane outside.
poisons
Hydrogen cyanide, carbon monoxide, and hydrogen sulfide inhibit oxygen reduction to water.
Fruit can increase sugar and decrease complex carbohydrates {ripening}|. After picking, starch builds up, and sugar breaks down. Ethylene can ripen fruit.
Citrate and ATP can make acetyl-CoA. Acetyl-CoA enters cycles {TCA cycle} {tricarboxylic acid cycle} {citric acid cycle} {Krebs cycle} and becomes two carbon dioxides and four NADH hydrogens. TCA cycle makes citrate, isocitrate, alpha-ketoglutarate, succinyl-CoA, succinate, fumarate, malate, oxaloacetate, and citrate again. These are mostly three-carbon carboxylic acids. Pyruvate, carbon dioxide, and ATP can make oxaloacetate and malate, which can enter cycle.
purpose
NADH hydrogens are for reduction reactions.
aerobic
TCA cycle uses oxygen to make carbon dioxide.
Acetyl compounds {acetyl-CoA} can enter lipid chain, go to TCA cycle, or become pyruvate. Acetyl-CoA breaks down to water and carbon dioxide. Pyruvate can become acetyl-CoA. Amino acids can make acetyl-CoA. Fatty acids can become acetyl-CoA.
Last carbon can have aldehyde functional group and next-to-last carbon can have alcohol functional group, -CHOH-CHO {aldol}. Aldol and ketol have tautomerism. Aldol can transfer two protons to last carbon to make ketol, -CHO-CHOH. Ketol can transfer two protons to next-to-last carbon to make aldol.
Carbohydrates have carbonyl group {carbonyl group}. First carbon can have aldehyde group {aldose}. Second carbon can have ketone group {ketose}. In water, ketone oxygen can substitute for hydroxyl on next-to-last carbon, to make five-carbon ring {furanose}. Furanose is hemiketal. In water, aldehyde oxygen can substitute for hydroxyl on next-to-last carbon to make six-carbon ring {pyranose}. Pyranose is hemiacetal.
anomer
Carbonyl carbon can be axial {alpha-glycosidic bond} or equatorial {beta-glycosidic bond} to sugar ring. Oxygen can be on right {alpha ring} or left {beta ring}. Alpha and beta rings have similar properties.
Proton can transfer from ketol last carbon to next-to-last carbon to make alkene double bond between carbons and alcohol on next-to-last carbon, -COH=CHOH {enol}. Enol can add water molecule to make separated charges, -(H2OC+OH)-(C-HOH) [2 is subscript and + and - are superscripts].
Ketone can be at next-to-last carbon and alcohol on last carbon, -CO-CH2OH [2 is subscript] {ketol}. Aldol and ketol exhibit tautomerism. Ketol can transfer two protons to next-to-last carbon to make aldol, -CHOH-CHO. Aldol can transfer two protons to last carbon to make ketol.
Fats, oils, fatty acids, steroids, and terpenes {lipid}| are complex hydrocarbons. Terpenes and steroids are simple lipids. Fatty-acid-based lipids are complex lipids. Lipids are for insulation and energy storage. Cell membranes and hormones have lipids. Most lipids are insoluble in water. Lipids can have polar ends and be soluble in water. Lipids contain 2.25 times more energy, by mass, than do carbohydrates or proteins, because they can oxidize more.
lipid disease
Lipids can make gall bladder contract {gall bladder disease}. Gallstones can block bile-salt flow. Cystic fibrosis is inherited low ability to digest fat.
Fatty acids can break down {fatty-acid oxidation} {beta-oxidation} in mitochondria.
functions
Fat tissue hydrolyzes and esterifies fat and oil if body needs energy. Muscle uses fatty acids when resting.
process
In fat cells, lipase binds to triglyceride to split glycerol from fatty acid. Blood serum albumin carries fatty acids to tissues. In tissues, ATP adds CoA to fatty-acid carboxyl end to make acetyl group. Process repeatedly removes acetyl group, with two carbons, from fatty-acid end. Unsaturated bonds become trans, not cis, isomers.
products
Fatty-acid oxidation makes ATP, NADH, acetyl-CoA, and water. Camels store fat in humps, not water.
factors
B vitamins and pantothenic acid affect fat breakdown and synthesis.
Enzymes {lipase} can catabolize triglycerides.
Molecules {emulsifier}, with polar and non-polar ends, can bind non-polar end to fat molecule and dissolve polar end in water {emulsification}|, to make micelles.
Acetyl-CoA added to another acetyl-CoA makes carboxylic acid, and then fatty-acid chain adds two-carbon acetyl-CoA {fatty-acid synthesis}. Cytoplasm has fatty-acid synthesis.
Air oxidizes fats {rancid}|.
Strong hydroxide can break triglyceride into glycerol and fatty-acid salts, both of which can dissolve in water {saponification}|.
If carbohydrate level is too low, cell makes acetyl-CoA. Acetone, acetoacetate, and beta-hydroxybutyrate {ketone body} accumulate.
Carboxylic acids {fatty acid}| can have long hydrocarbon chains. Fatty acids have even numbers of carbons, from 12 to 20. Liver regulates fatty acids in blood.
Sphingosine, ceramide, sphingomyelin, and cerebroside {cell-surface lipid} determine blood group, direct development, make organ structures, confer immunity, and signal cancer.
Blood has triglyceride globular micelles {chylomicron}. Non-polar ends are inside, and polar ends, which dissolve in water, are on surface. Lipids digest slowest. Intestine absorbs 95% of lipids.
Triglycerides {phosphoglyceride} can have fatty acids replaced by phosphates. Cell-membrane phosphatidic acid, lecithin or phosphatidyl choline, and cephalin or phosphatidyl ethanolamine are phosphoglycerides.
Ether group can replace triglyceride fatty acid {plasmalogen}.
CDP, serine, ethanolamine, or choline can replace phosphatidic-acid phosphate group to make other lipids {sphingolipid}. Palmitic acid, in CoA form, adds serine to replace CoA and then reduces to sphingosine. Acyl CoA can bind to sphingosine to make ceramide. CDP-choline can bind to ceramide to make sphingomyelin. UDP-sugar can bind to ceramide to make cerebroside. Sialic acid can bind to cerebroside to make ganglioside. Ganglioside is in synapses and nerve receptors.
Cell-surface lipids {sulfatide} can determine blood group, direct development, structure organs, confer immunity, and signal cancer.
Lipids {triglyceride}| {triacylglycerol} can combine three fatty acids and one glycerol. Glycerol can attach fatty acid at each alcohol. Triglycerides {fat, biochemistry} can have three saturated fatty acids. Triglycerides {oil, biochemistry} can have three unsaturated fatty acids.
synthesis
Dihydroxyacetone phosphate reduces to glycerol-3-phosphate, in glycolysis pathway. Acetyl-CoA binds to two glycerol-3-phosphate hydroxyls, to make phosphatidic acid. Replacing phosphatidic acid phosphate group with fatty acid makes triglyceride.
Fatty-acid esters {wax, lipid} can have long chain alcohols or sterols. Carnauba wax is hard and lustrous and is for floor, car, and furniture. Candelilla wax is brown and is for records, floor, and candles. Bayberry wax is for candles. Beeswax is for cosmetics, candles, polishes, crayons, and artificial flowers. Wool wax is purified lanolin for ointments, cosmetics, and soaps.
Petroleum wax is odorless, tasteless, and inactive. Paraffin is hard petroleum wax for paper coatings. Petroleum jelly is soft petroleum wax for medicine.
Four-carbon alkenes {butadiene} can have two double bonds. Butadiene can single bond a side chain to second carbon. Butadiene can attach a methyl group to make isoprene. Butadiene can attach tertiary carbon to make neoprene.
Butadiene {isoprene}| can attach methyl-group side chain. Polymers can be isoprene chains, with fifth carbon attached to second carbon. Rubber is natural isoprene polymer.
Butadiene {neoprene} can single bond a tertiary-carbon side chain on second carbon.
Organic molecules {terpene}| can use isoprene structure. Monoterpenes are geranium, lemon, mint, turpentine, camphor, and caraway. Linear polyterpenes are rubber and gutta-percha. Fat-soluble terpenes are vitamin A, vitamin E, vitamin K, and carotene. Polyprenols are coenzyme Q, bactoprenol or dolichol hydrogen carrier, and phytol in chlorophyll. Squalene makes cholesterol. Rubber and gutta-percha are terpenes.
Proteins {lipoprotein}| can carry lipids in blood. Serum albumin carries short-chain fatty acids in blood.
Lipoproteins {high-density lipoprotein}| (HDL) can carry phospholipids.
Lipoproteins {low-density lipoprotein}| (LDL) can carry cholesterol.
Lipoproteins {very low-density lipoprotein}| (VLDL) can carry triglycerides.
Hydrocarbon chains {mono-unsaturated hydrocarbon}| {monounsaturated hydrocarbon} can have one double bond and no triple bonds.
Hydrocarbon chains {polyunsaturated hydrocarbon}| can have more than one double bond.
Hydrocarbon chains {saturated hydrocarbon}| can have no double or triple bonds between carbons and hold maximum hydrogens.
Cholesterol is the fundamental structure in many hormones {steroid hormone}|.
biology
Steroids induce enzymes to increase glucose usage and start stress response. Sex steroids and glucocorticoid hormones have neuron receptors.
types
Ergosterol makes vitamin D.
Bile acids emulsify and absorb lipids in small intestine.
Male sex-hormone androgens include testosterone and androstenol. Female sex-hormone estrogens include estrone, estradiol, and progesterone.
Adrenocorticosteroids, such as corticosterone and aldosterone, control body water amount. Cortisone reduces inflammation.
Digitoxin affects heart rate.
Lipids {cholesterol}| can have quadruple aromatic carbon rings. Cholesterol is the fundamental structure in steroid hormones. Plants have no cholesterol, which is only in animals.
process
Acetate becomes acetyl-CoA and acetoacetyl-CoA. Added water makes 3-hydroxy-3-methyl-glutaryl CoA, which reduces to mevalonate when CoA leaves. ATP adds three phosphates to alcohol oxygens to reduce mevalonate to activated isoprene isopentyl pyrophosphate. Isoprenes cyclically add to make squalene. Squalene epoxide makes cholesterol. Adding functional groups to ring carbons makes other steroids from cholesterol.
Lipids {sterol}| can have quadruple aromatic carbon rings. Plant sterols {phytosterol} include campesterol, sitosterol, and stigmasterol. Animal sterols {zoosterols} include cholesterol.
Lipids {stanol}| can be saturated sterols. Stanols can add fatty acids to make stanol esters.
Polymers {nucleic acid}| can have nucleotides connected by phosphodiester bonds. Nucleic acids are 10% of body dry weight.
structure
Phosphodiester-bond phosphate groups link pentose fifth carbon to next-pentose third carbon, called 5' to 3' linkage. Nucleotide nitrogenous bases are perpendicular to phosphodiester bond chain. Nucleotide ribose rings are parallel to phosphodiester bond chain. Phosphodiester bonds have no rotation. Nucleic acids have no branches.
information
Molecules encode genetic information in base sequences and replicate using strands as templates. DNA bases are adenine A, guanine G, cytosine C, and thymine T. DNA codes instructions for replication, transcription, and translation, to initiate and grow tissues and organs during development, to react to cell environment during development and in life, and to cycle over hours, days, months, and years.
Repressors typically form at constant rate {constitutive synthesis}.
If A hydrogen-bonds to T by conventional Watson-Crick pairing, another T can hydrogen-bond to A {Hoogsteen pairing}. If G hydrogen-bonds to C by conventional Watson-Crick pairing, another C can hydrogen-bond to G.
Bacteriophage, plasmids, and chromosomes have mobile genetic elements {replicon}.
Mutations {nonsense mutation} can make stop codons from non-stop codons.
Pyrimidine can substitute for pyrimidine, or purine can substitute for purine {transition, nucleotide}.
Pyrimidine can substitute for purine, or vice versa {transversion}.
DNA has two linear polynucleotide strands hydrogen-bonded together to form twisted ladder shape {double helix}|.
hydrogen bonds
Nitrogenous bases adenine and thymine in DNA or uracil in RNA can link by two hydrogen bonds, on aromatic-ring side away from pentose and phosphate, if aromatic-ring planes are parallel, with one inverted. Nitrogenous bases cytosine and guanine can link by three hydrogen bonds, on aromatic-ring side away from pentose and phosphate, if aromatic-ring planes are parallel, with one inverted.
ladder
Strands are pentose sugars and phosphodiester bonds and make ladder sides. Strand bonds have opposite direction. Nitrogenous-base and hydrogen-bond-link planar aromatic rings are ladder rungs. Because tetrahedral chemical bonds form at angle, ladder twists and is helical.
Ribose sugar (RNA) or deoxyribose sugar (DNA), phosphate group, and nitrogenous-base adenine, guanine, cytosine, and thymine in DNA or uracil in RNA can link to other bases with phosphodiester bonds to make sequences {base sequence} {DNA sequence}.
Two adjacent nucleic-acid polymers {anti-parallel strands} can have opposite bond direction.
Hydrogen bonding between adenine and thymine in DNA or uracil in RNA, or between guanine and cytosine {base pairing}, links two DNA strands or DNA and RNA strands.
Hydrogen bonds can form between adenines and thymines in DNA or uracils in RNA, and between cytosines and guanines {complementary bases}.
polymer chain {strand, DNA}.
Topoisomerase and gyrase affect DNA coiling and can add to or subtract from helix angle {supercoiling}. Circular DNA has negative supercoiling.
Molecules {effector} can help RNA polymerase bind to DNA or help DNA strands separate.
Histone H1 connects DNA beads {nucleosome}. Nucleosomes have 200 bases, two H2A histones, two H2B histones, two H3 histones, two H4 histones, and other regulatory proteins.
Proteins {catabolite activator protein} (CAP) can bind to cAMP to form cAMP-CAP complexes, which bind to promoter for gene that breaks down lactose and galactose. If glucose is low, cAMP builds up.
Enzymes {modification enzyme} can methylate DNA at special sites.
Enzymes {topoisomerase} {gyrase} can affect DNA coiling and can add to or subtract from helix angle for supercoiling.
Cells can copy DNA double helices {replication, DNA}| {DNA replication}.
separation
Replication protein uses ATP to separate DNA nucleotide chains, by breaking hydrogen bonds between nitrogenous bases, so DNA unwinds. Replication protein starts at one DNA location and separates chains in both directions simultaneously. Single-strand binding protein keeps DNA strands apart.
pairing
RNA primer binds to operon first part and provides starting molecule to which DNA polymerase can add paired deoxyribonucleotides. Free deoxyribonucleotides hydrogen-bond with DNA-strand deoxyribonucleotides: A and T, or C and G.
linking
DNA polymerase links deoxyribonucleotides by phosphodiester bonds between pentoses, at rate 10 nucleotides per second. Pyrophosphate leaves. Copying error rate is only 10^-9. Exonuclease checks new strand at new deoxyribonucleotide pairs to see if deoxyribonucleotides paired correctly. Exonuclease removes wrongly paired nucleotides. Second exonuclease checks if double helix is correct and unwinds DNA if DNA double helix is not correct.
ligating
DNA ligase joins DNA strand ends. Both new strands link from ribose fifth carbon to next-ribose third carbon. One strand is continuous. One strand has Okazeki fragments. DNA ligase connects Okazeki fragments.
result
Replication makes two double helices, each with one strand of old double helix and one new strand {semiconservative replication, DNA}.
Replication protein uses ATP to separate DNA nucleotide chains, by breaking hydrogen bonds between nitrogenous bases {replication fork}, and so unwinds DNA.
Enzymes {replication protein} can use ATP to separate DNA nucleotide chains, by breaking hydrogen bonds between nitrogenous bases, and so unwind DNA.
Enzyme {single-strand binding protein} keeps DNA strands apart.
RNA primer binds to operon first part and provides a starting molecule for enzymes {DNA polymerase} that synthesize DNA from existing nucleic acid. It adds paired deoxyribonucleotides to DNA template strand and links them to make new strand.
Enzymes {DNA ligase} can join DNA strand ends and can rejoin broken DNA.
One strand forms in 1000-nucleotide segments {Okazeki fragment}. DNA ligase connects Okazeki fragments.
DNA, enzymes, and energy can make RNA {transcription, DNA}| {DNA transcription}.
process: strand separation
RNA polymerase binds to DNA double helix locations {promoter, DNA}. RNA polymerase separates DNA strands for one complete double-helix turn, little more than three nucleotides. RNA polymerase separates two deoxyribonucleotide chains by breaking hydrogen bonds, starting at one double-helix point and going in one direction only. Transcription uses DNA strand lying in third carbon to fifth carbon direction. Direction that chains separate is opposite to chain phosphodiester-bond direction.
process: polymerase
Eukaryotic 5.8S, 18S, and 28S rRNA use RNA polymerase I. Eukaryotic mRNA and snRNA use RNA polymerase II. Eukaryotic 5S rRNA and tRNA use RNA polymerase III. RNA types have different promoters. RNA polymerase does not need primer.
process: matching
Free ribonucleotides in solution hydrogen-bond to matching chain deoxyribonucleotides. Adenine and thymine hydrogen-bond. Adenine and uracil hydrogen-bond. Guanine and cytosine hydrogen-bond. Error rate is 10^-4 to 10^-5.
process: linking
Using phosphodiester bonds, RNA polymerase links ribonucleotides to make RNA sequence. Phosphodiester bonds invert compared to original-DNA-strand phosphodiester bonds. Nucleotides link at rate 50 nucleotides per second.
process: termination
RNA transcription terminates just after poly-uracil region, using RNA chain-terminating proteins. Using rho protein, region near tRNA end curves around to hydrogen bond with itself using paired A and U or C and G ribonucleotides to make a hairpin loop.
process: separation
RNA polymerase leaves DNA, and RNA separates from DNA. Double helix reforms.
product
Transcription makes one rRNA, tRNA, or mRNA strand. In higher animals, mRNA intron regions can make protein, and exons do not. Introns can be separate or overlap.
blocking
Actinomycin can block transcription by sliding between and separating guanines and cytosines. Mushroom poisons block RNA polymerase from making histone protein.
DNA
DNA operons have gene for repressor, promoter where RNA polymerase binds, operator where repressor can bind and inducer can remove repressor, and one or more genes, typically in that order. RNA or protein binding at regulatory regions controls RNA amount.
DNA: repressor
Repressor prevents RNA polymerase from binding at promoter, because operator is next to promoter. Bacteriophage lambda has repressor-gene {cro gene} repressor. Cro and other repressors typically are dimers that have alpha-helix binding in DNA-helix major groove. Repressors can affect several transcriptions {trans-acting control}.
DNA: promoter
Promoters affect downstream transcription {cis-acting control}. Catabolite activator protein binds to cAMP to make cAMP-CAP complexes, which bind to promoter for lactose and galactose breakdown genes. If glucose is low, cAMP builds up.
Enzymes {RNA polymerase} can bind to DNA double-helix promoters.
Three nucleotides {termination sequence} end transcription.
Special enzymes {nuclease} can modify free-floating RNA. Nuclease adds methyl groups to nucleotides. Nucleases make other modified bases, such as inosine. In eukaryotes, nuclease adds adenines to mRNA 3' end to stabilize RNA and protect 3' end. In eukaryotes, nuclease adds nucleotides to mRNA to protect 5' end.
Endonuclease can split long RNA into functional pieces. For example, nuclease divides chain that contains all rRNA types into different ribosomal RNAs. Photolyase restores UV-induced dimers, using light.
Using enzymes {rho protein}, region near tRNA end curves around to hydrogen bond with itself, using paired A and U or C and G ribonucleotides.
Proteins induced from other sites control RNA transcription {transcriptional control}.
E. coli tryptophan operon (trp) has five genes, but, if tryptophan is at high levels, only short transcription {leader, DNA} can happen {attenuation}. Leader makes hairpin that stops transcription. If tryptophan is low, full operon transcribes, because different hairpin has few tryptophans.
mRNA, rRNA, and tRNA together can make protein {translation, RNA}| {RNA translation}.
template
mRNA nucleotide sequence codes for protein. mRNA is 2% of all RNA.
process
AUG or GUG codon, which codes for methionine, always starts mRNA. mRNA attaches to both smaller ribosome rRNA and larger ribosome rRNA. Ribosomes have two slots, one {peptidyl site} for current amino acid and one {aminoacyl site} for amino acid to add. Three mRNA nucleotides are in slots and lie in 5' carbon to 3' carbon direction.
process: tRNA
tRNA has amino acid on one side tip and three nucleotides on other side tip. Nucleotide tip can be complementary to three mRNA nucleotides in one slot. tRNA with complementary tip hydrogen-bonds its three tip nucleotides to the three slot nucleotides and brings one amino acid into ribosome slot. Streptomycin prevents tRNA attachment to first site.
process: peptide bonding
When amino acids are in both slots, ribosomal enzymes and GTP-protein complex join both amino acids by one peptide bond. Amino acid adds to protein chain in one second.
process: shift
Then ATP shifts both amino acids one slot. Messenger RNA also slides over one slot, leaving one slot empty. Diphtheria toxin inhibits translocation enzyme.
process: repeat
Empty slot fills with tRNA, amino acid comes in, and enzymes make peptide bond.
process: termination
The last three mRNA nucleotides are UAG, UAA, or UGA and do not pair with any tRNA tip, so slot stays empty and terminates mRNA coding. Puromycin terminates amino-acid chain early.
process: release
Enzyme releases protein and mRNA from ribosome.
modification
Enzymes can modify free-floating proteins after translation. Enzymes can remove formyl group from methionine. Enzymes can remove amino acids from amino end. Enzymes can form disulfide bonds. Enzymes can add hydroxyl to side chain. Enzymes can add sugar. Enzymes can add phosphate. Enzymes can split protein into functional parts.
Three DNA or RNA nucleotides {codon} can code for amino acids. Up to six codons can code for same amino acid. Codons coding for same amino acid have same first two bases. Coding redundancy can minimize errors. Codons are the same for all species, except for mitochondria. Mitochondrial DNA uses different genetic code for different groups.
Before initiation sites, mRNA has a purine-rich ribosome-binding site {Shine-Dalgarno sequence}, which matches rRNA molecule site. With extra ribosomal proteins, some bind to Shine-Dalgarno site and prevent or slow protein synthesis.
mRNA sites control translation rate and protein synthesis {translational control}.
Genes {suppressor gene} can make tRNA with an anticodon that matches stop codon but adds an amino acid. If DNA mutation makes a stop codon, such tRNAs allow cell to continue reading mRNA. Suppressor genes suppress such mutations.
Bases A, C, G, and T can attach to N-(2-aminoethyl)-glycine {peptide nucleic acid} (PNA). PNAs have no electric charge, are more stable, and bind better to DNA or RNA than oligonucleotides do.
triplex
If PNA is all C or T and so is homopyrimidine, PNA strand can lie in double-stranded-DNA major groove and bind to double-stranded DNA {PNA-DNA triplex}. Two PNA strands can push away a DNA strand, which forms a loop, and make a triple-strand {triplex invasion}. PNA strand can bind to DNA strand, displacing but not removing other DNA strand {duplex invasion}. Two PNA strands can bind to opposite DNA-strand regions, displacing but not removing DNA strands {double duplex invasion}.
DNA {TNA} can have different sugar than ribose.
DNA {xDNA} can be less likely to mutate.
Combining adenosine and three phosphate groups {adenosine triphosphate} (ATP) can carry energy in phosphate bonds. Magnesium or calcium ions attach to phosphate to make ATP have neutral charge. ATP decreases noradrenaline release from adrenergic nerves and acetycholine release from cholinergic nerves.
Combining guanine and three phosphate groups {guanidine triphosphate} (GTP) can carry energy in phosphate bonds. Magnesium or calcium ions attach to phosphate to make ATP have neutral charge.
Organic molecules {nucleotide}| can have a nitrogenous base and a phosphate group bound to a pentose sugar.
location
Mitochondria have nucleotide synthesis.
types
Nitrogenous base determines nucleotide type: purine or pyrimidine. Molecule can contain ribose sugar (RNA) or deoxyribose sugar (DNA). Nucleotides make RNA, DNA, ATP, NAD, FAD, CoA, and cyclic AMP.
nucleic acid
Nucleotides can link to other bases with phosphodiester bonds. Adenine, guanine, cytosine, and thymine are in DNA. Adenine, guanine, cytosine, and uracil are in RNA.
history
Levene and Bass isolated uridylic acid [1931].
Ribonucleotides make higher nucleotides by adding hydrogen atom using NADPH {deoxyribonucleotide} (DNA). Adenylate makes deoxyadenylate. Guanidylate makes deoxyguanidylate. Cytodylate makes deoxycytodylate. Uridylate makes deoxyuridylate. Deoxyuridylate methylation makes thymidylate. Thymine deoxyribonucleotide is stable and is in DNA, instead of uracil deoxyribonucleotide. Uracil ribonucleotide is in RNA, rather than thymine ribonucleotide, because thymine ribonucleotide easily changes into cytosine, but uracil ribonucleotide does not change.
Nucleotides {ribonucleotide} can have hydroxyl group at pentose-sugar second carbon.
Adenine and guanine {purine}| are double-ring nitrogenous bases synthesized from glycine, aspartate, glutamine, carbon dioxide, or methyl groups. Purine breaks down to urate.
Cytosine, thymine, and uracil {pyrimidine, nucleic acid}| are single-ring nitrogenous bases synthesized from carbamoyl phosphate and aspartate, which make carbamylaspartate, which becomes dihydroorotate, which NAD+ oxidizes to orotic acid, making pyrimidine ring. Orotic-acid nitrogen binds to ribose-ring first carbon by pyrophosphate, to make uridylate. Uridylate transamination can make cytidylate.
Nucleotides {nucleoside} can lose a phosphate group.
Nitrogen-containing molecules {base, nucleic acid} {nitrogenous base} can be purine or pyrimidine: adenine, guanine, cytosine, thymine in DNA, or uracil in RNA.
Rather than uracil, similar nucleotides {thymine} can be in DNA, because cytosine can deaminate to become uracil and so change DNA template too easily. If DNA cytosine deaminates, enzymes remove new uracils and replace with cytosine to repair chain.
Bonding uracil and three phosphate groups {uridine triphosphate} (UTP) can carry energy in phosphate bonds. Magnesium or calcium ions attach to phosphates, so ATPs have neutral charge.
Nucleic acids {ribonucleic acid}| (RNA) can have ribonuceotides. Hydroxyl groups at pentose-sugar second carbons make RNA chains unable to lie anti-parallel to each other for more than several bases, so RNA cannot make double helices. RNA can double back on itself to make hairpin loops, with short double strand at neck.
types
Ribose-nucleotide nucleic acid is for protein translation (mRNA), codon translation (tRNA), protein-synthesis sites (rRNA), and intron excision from RNA (snRNA). Specific 22-nucleotide fragments of RNA have regulatory activity.
genes
E. coli has 50 to 200 RNA genes, as do other organisms. Over 95 percent of eukaryotic RNA encodes rRNA, mRNA, and tRNA, not proteins.
RNA {messenger RNA}| (mRNA) can hold information for making proteins. mRNA is 5% of RNA and has short life. mRNA is ribonucleotide chain copied from gene.
Two or three globular RNAs {ribosomal RNA}| (rRNA) can make ribosomes for protein synthesis. rRNA is 80% of RNA. rRNA has three or four long-lived types. Ribosomes look like snowmen, with two main rRNA globules beside each other. Globular rRNAs have two adjacent binding sites for tRNAs and mRNA. Ribosomes use many proteins.
RNA {transfer RNA}| (tRNA) can transfer amino acids from cytoplasm to ribosomes, to make protein chains. tRNA is 15% of RNA.
structure
tRNA is 75 bases long and has three-leaf-clover shape. tRNA has modified bases in three locations to make tRNA hydrophobic and curve back on itself. Middle-clover-leaf tip has three ribonucleotides, which differ for different amino acids. Clover-stem tip has three ribonucleotides that bind an amino acid. Different tRNAs bind different amino acids. There are more than 40 different tRNAs.
number
Different tRNA amounts differ greatly. Low amounts can limit protein production.
codon
RNA has three-nucleotide codons. tRNA has three tip nucleotides {anticodon}. Anticodon binds to first two codon nucleotides exactly but can bind inexactly to third codon nucleotide {wobble}.
mitochondria
Mitochondria have only 22 tRNAs and use only first two codon bases.
Polypeptides {protein, peptide}| {polypeptide} are 50% of body solids. Polypeptide has 5 to 4000 amino acids.
nitrogen
Protein is the only nitrogen source in diet. Nitrogen leaves body as urea in urine.
metabolism
Conjugated protein can bind to another molecule. Peptide-bond breaking, phosphorylation, dephosphorylation, amidation, methylation, and glycosylation alter protein structure and function.
structure
Protein has four structure levels: primary, secondary, tertiary, and quaternary.
functions
Most proteins are enzymes. Proteins are also for transport, structure, storage, hormones, movement, toxins, protection, and clotting. Proteins maintain water balance, because soluble cell proteins cause higher water pressure inside cell, by osmosis. Proteins buffer water solution inside cells, because soluble proteins have weak acid and weak base groups.
functions: storage
Proteins {storage protein} can be for storage. Ferritin stores iron. Casein stores carbohydrate. Ovalbumin stores fat and carbohydrate.
functions: structures
Fibrous proteins {structural protein} are for body structure.
Alpha-keratin is in skin, hair, wool, horn, and nails. Alpha-keratin has three to seven amino acid chains in bundle, cross-linked by disulfide bonds, which then bundle again.
Scales, claws, beaks, silk, and feathers have beta-keratin. Beta-keratin is mostly glycine, alanine, and serine.
Collagen covers organs and bones. Collagen has three amino-acid chains twisted into left-handed helix. It is mostly glycine, alanine, proline, and hydroxyproline. It has lysine-bond cross-links. Boiled collagen is gelatin.
Elastin is in ligaments and stretchable connective tissue such as blood vessel walls.
Resilin is in flea-leg ligaments, fly-wing ligaments, and cicada-song vibrating tissue.
Glycoprotein is in membranes and cell walls.
Mucoprotein is in membranes and cell walls.
Wing joints have resilen, which is elastic.
Insect skeletons have sclerotin.
Viruses have protein coats.
functions: transport
Proteins {transport protein} can transport small molecules {protein transport}.
Ceruloplasmin carries copper.
Ferritin carries iron.
Hemoglobin carries oxygen and carbon dioxide.
Lipoprotein carries fats and cholesterol.
Myoglobin carries oxygen and carbon dioxide.
Serum albumin carries fatty acids and many other substances.
Proteins can also carry calcium and heavy metals.
Cell has 30,000 organelles {proteasome}| that are 100 times bigger than proteins, are tubes, and have proteases that fragment poorly folded or poorly working proteins. Cytoplasm free proteases split protein fragments into amino acids.
enzymes
E1 enzyme activates ubiquitin, which can bind to E2 enzyme, which can then bind to E3 enzyme. E3 enzyme has various possible F-box regions that recognize different protein-end regions. E2-E3 complex (SCF complex) can bind protein at F-box, attach ubiquitins to protein, and release.
proteasome
If several ubiquitins attach to protein, ubiquitin chain attaches to proteasome and activates enzymes that unfold protein and pull protein chain into proteasome tube.
First amino acids can make sequence {signal sequence} that lets protein go through membrane channels.
Amino-acid catabolysis makes energy {amino-acid oxidation}. Liver mitochondria have amino-acid oxidation. Protein-hormone, purine, pyrimidine, vitamin, and porphyrin metabolism involves amino-acid oxidation. Transamination, to make alpha-ketoacid, or deamination, through oxidation by NAD+ to make carbohydrate, removes amino group. Oxidation removes amino acid side chains. Oxidized amino acids become pyruvate, acetyl-CoA, alpha-ketoglutarate, succinyl-CoA, fumarate, or oxaloacetate, for use in TCA cycle.
After release through membranes, membrane-protein complex {calcium pump} restores calcium ions to inside membrane.
Protein chains can have cross connections {cross-linking, protein}|. Two nearby cysteines, which form a spontaneous disulfide bond, can have strong cross-linking. Protein side chains can form hydrogen bonds with oxygens on other amino acids, such as glycine, cysteine, tyrosine, serine, threonine, asparagine, and glutamine.
Proteins above 37 C can lose three-dimensional structure {denaturation, protein}|. If protein has less than 100 amino acids, folding is subcritical after denaturation. If protein has more than 100 amino acids, folding is critical after denaturation.
Proteins can catalyze reactions {enzymatic reaction}|.
types
Enzymes can catalyze hydrogen-ion interactions. They can catalyze anion and cation formation. They can catalyze chelation. They can catalyze charge-transfer coupling. They can catalyze organic-acid formation and breakdown. They can catalyze proton abstractions. They can catalyze Schiff-base reactions.
They can catalyze configuration inversion.
They can catalyze phosphate transfer. They can catalyze pyrophosphate incorporation. Adenylate cyclase can catalyze cAMP-mediated reactions. They {guanylate cyclase} can catalyze cGMP-mediated reactions. They can catalyze transfers.
They can catalyze oxidation. They can catalyze reduction.
They can catalyze metal-bridge formation. They can catalyze metal binding.
They can catalyze acetylation. They can catalyze acylation.
They can catalyze free-radical reactions.
They can catalyze ring breaking and forming.
They metabolize amines, amides, aldehydes, histidines, imidazoles, ketones, nitroxides, oxides, serines, thiols, and thiol esters. They metabolize lipoproteins, carbohydrates, membranes, ion channels, enzyme proteins, lipids, and nucleic acids.
process
Enzymatic reactions can involve active-site directed agents, induced fit, steric effects, and molecular vibrations.
process: reversible
In enzyme-catalyzed chemical reaction, substrate and enzyme quickly and reversibly bind together to make transition state {enzyme-substrate complex}. The reversible reaction has forward and backward reaction rates {Michaelis-Menten rate equation, enzymatic reaction}.
process: irreversible
Transition state slowly and irreversibly separates to reform enzyme and make product. The irreversible reaction has only forward reaction rate.
process: overall
Reaction first part reaches equilibrium quickly, and intermediate concentration quickly becomes constant {steady state, equilibrium}. At steady state, intermediate concentration change over time is zero, free-enzyme concentration is much less than substrate concentration, and intermediate concentration equals total enzyme concentration.
d[ES]/dt = 0 = f1*[E]*[S] - b1*[ES] - f2*[ES]. [E] = [ET] - [ES]. [E] << [S], so [ES] = [ET]. [ES] is enzyme-substrate-complex concentration. [ET] is total-enzyme concentration. [E] is enzyme concentration. f1 is reversible-reaction forward rate. b1 is reversible-reaction backward rate. f2 is irreversible-reaction forward rate.
process: rate
Substrate depletion rate equals product creation rate: product amount divided by time in seconds. Rate is reaction velocity. Rate depends on forward rate, of making product from intermediate, times intermediate concentration.
Reaction rate can be constant {constitutive reaction rate}. Reaction rate can depend on another-molecule concentration {induced reaction rate}.
Product formation rate depends on maximum possible rate, substrate concentration, and forward and back reaction rate constants.
Maximum velocity depends on enzyme concentration and rate constant. Maximum rate {maximum velocity} {Vmax} equals forward reaction rate times total enzyme concentration.
Rate constant for whole Michaelis-Menten equation depends on all three rates: Km = (b1 + f2) / f1. Reaction velocity v depends on rate constant Km, substrate concentration S, and maximum velocity Vmax: v = (Vmax * [S]) / (Km + [S]).
After formation, proteins spontaneously rotate around single bonds, under electric forces, to make three-dimensional structures {protein folding}|.
process: forces
Amino-acid side chains have polarity. Amino acids can be more polarized, dissolve in water, and tend to be at protein surface. Electric forces are greatest at protein surface, where water interacts with amino-acid side chains. Protein ends polarize and are always at protein surface.
Amino acids can be non-polar and tend to be in protein interior. Protein middle has no water, and side chains there interact among themselves.
process: time
It takes 0.2 second to fold protein.
process: misfolding
One-third of proteins misfold {misfolding, protein}. Rotenone pesticide increases misfolding.
structure
In protein structure, all torques equal zero, and all angular accelerations equal zero. Peptide bonds have no rotation. Typically, all amino acids contribute to structure.
structure: globular
Protein typically becomes globular, because amino-acid chain folds back on itself. Globular proteins have 3.5 to 7.5 loops, with 16 to 24 amino acids each. Loop almost touches ends. Loop goes in same direction as alpha helix coil. Loop follows right-hand rule, with loop going around fingers and thumb in forward-motion direction along sequence.
structure: peptide bond
Peptide bond has N[H2]-Calpha[HR]-Ccarboxy[O]-N[H]-Calpha[HR]-Ccarboxy[O] (2 is subscript).
Bond lengths are the following. C-C for sp^3 = 0.1524 nanometers. C-H for sp^3 = 0.1090 nanometers. C-S = 0.1810 nanometers. S-S = 0.2036 nanometers. C-O peptide bond = 0.123 nanometers. N-H peptide bond = 0.100 nm. Calpha-N = 0.146 nanometers. Calpha-Csidechain = 0.153 nanometers. Calpha-Hsidechain = 0.100 nanometers. Calpha-Ccarboxy = 0.152 nanometers. C-N peptide bond = 0.132 nanometers. Ccarboxy-Cnextalpha = 0.243 nanometers. N-Cnextcarboxy = 0.246 nanometers. Calpha-Nnext = 0.241 nanometers. Ccarboxy-Cnextcarboxy = 0.372 nanometers. N-Nnext = 0.368 nanometers. Calpha-Cnextalpha = 0.381 nanometer.
Bond angles in degrees are the following. C-C-C for sp^3 = 113.0, C-C-H for sp^3 = 109.3, H-C-H for sp^3 = 107.2, C-S-C = 100.4, and C-S-S = 104.5.
Distance between alpha carbons can be 0.381 nanometers {beta sheet, protein}, 0.250 nanometers {alpha helix, protein}, 0.090 nanometers {beta turn, protein}, or random {random coil, protein}.
Protein structure descriptions can use phi angle around N-Calpha axis and psi angle around Calpha-C axis, at all Calphas. One angle has highest probability.
Right-handed alpha helix has phi angle = -57 degrees and psi angle = -47 degrees. Range can be -180 to +180 degrees. Normal range is -180 to +60 degrees. -120 degrees is normal. For proline, angle is always 0 or 110 degrees.
Beta sheet has phi angle -120 and psi angle +120. Range can be -180 to +180 degrees. Normal range is -60 to +120 degrees. Normal is 0 degrees.
technique
To study protein folding, place start position for first amino acid nonexistent alpha carbon at 0,0,0. Pick phi angle. Make new k-axis vector be N-Calpha bond. New i-axis direction is from k-axis line to Ccarboxy. j axis is cross product of k with i. Pick psi angle. Make k-axis vector be Calpha-Ccarboxy bond. New i axis is direction from bond to previous N. j axis is cross product of k with i.
Translate polar coordinates to Cartesian coordinates as necessary. Use many known structures to get actual side-chain coordinates from actual values. Use these to find conditional probabilities for amino acids and nearest, second nearest, and so on, amino acid, to make large table. Do not use alpha helix, beta sheet, or beta turn for values. Just find best parameter set and number.
Transition state slowly and irreversibly separates to reform enzyme and make product {Michaelis-Menten rate equation, enzyme}. The irreversible reaction has only forward reaction rate.
Amide bonds {peptide bond}| can form between amino-acid carboxyl groups and amino-acid amino groups. Peptide bonds resonate, are planar, have no rotation, and have hydrogen in trans configuration to oxygen. Peptide bonds do not allow branching.
Trypsin in stomach acid normally cleaves proteins, using water. If body water is low, trypsin ligates amino acids, forming water {plastein reaction}.
Cell-membrane proteins {sodium-potassium pump} can use one-third of all ATP, keep cell volume constant, make membrane excitability possible, and drive amino-acid and sugar active transport. If sodium is present, ATPase phosphorylates. Conformational change carries sodium ion from cell inside to outside, and potassium ion from outside to cell inside, against concentration gradients. Digitalis affects sodium-potassium pumps.
In muscle and microtubule contraction {muscle contraction}|, protein slides along another protein by grabbing and pulling, using ATP.
process
Calcium ions are in muscle-cell sarcoplasmic reticulum. Calcium-ion release initiates sliding. If calcium ion is present, tropomyosin goes into actin helix groove, and calcium opens binding sites, so actin can bind. Then ATPase globule tilts 45 degrees, pulling actin along. Then actin releases. After contraction, tissue elasticity passively returns muscle to normal length.
myosin
Myosin has four light chains and two long alpha-helix chains, which make two beads at myosin end. Beads are ATPases, connect actin to myosin, and are where calcium ions act. Three thick myosins surround each thin actin.
actin
Actin is globular protein that polymerizes into globule helix. Six thin actin proteins surround each thick myosin protein.
tropomyosin
Tropomyosin molecule helically wraps around actin.
troponin
Troponin molecule has binding sites for calcium, tropomyosin, and actin.
Transverse tubules are adjacent to sarcoplasmic reticulum at structures {triad junction}.
Muscle fibers have fine-tube {tubule} networks on cell surfaces and insides.
Skeletal muscle has parallel protein filaments {myofibril} lined up along elongated muscle-cell axis. Dark A bands have overlapping actin and myosin. Light I bands have actin, tropomysin, and troponin.
Repeating units {sarcomere} can have alternating dark A bands and light I bands. Dark Z line is in light I-band middle, where actins connect. Light H zone is in dark A-band middle and has thick myosin. Light H zone has middle dark M line, where myosins meet.
Proteins can have hydrogen bonds between every fourth peptide bond, with hydrogen-bond plane parallel to helical axis and side chains perpendicular to helical axis {alpha helix, protein structure}. Big or charged amino acids disrupt alpha helix. Proline stops alpha helix, because it is imino acid and does not make regular peptide bond.
Proteins can have hydrogen bonds between amino-acid chains lying in opposite directions, with side chains perpendicular to hydrogen bonds {beta sheet, protein structure}. Large amino acids interfere with hydrogen bonding and disrupt beta sheets.
The charged amino acids serine, isoleucine, and proline can make amino-acid-chain turn {beta turn, protein structure}. Proline is imino acid and makes irregular peptide bond at different angle.
Proteins {fibrous protein} can be elongated amino-acid chains. Fibrous proteins are for structure.
Proteins {globular protein} can have polar side chains on surface and non-polar side chains inside, with sharp bends at proline, serine, or isoleucine. Most proteins, such as enzymes, are globular.
Proteins {oligomer} can have multiple amino-acid chains.
Amino acid sequence {primary structure} determines protein properties.
Amino-acid-sequence three-dimensional alignment can be irregular, alpha helix, beta sheet, or beta turn {secondary structure} {conformation, protein}. Heat or chemicals can disrupt secondary structure and change protein conformation {denaturation, protein structure}.
Overall amino-acid-chain shape can be globular or fibrous {tertiary structure}.
Protein oligomers can have multiple amino-acid chains {quaternary structure}. Hydrogen bonds hold chains together. Hemoglobin has two "alpha" chains and two "beta" chains.
Carbon atoms can attach to carboxyl group and amino group {amino acid}|. The carbon atom also attaches to hydrogen atom and functional group {side chain, amino acid}. Cells can have 150 different amino acids.
asymmetry
Central carbon is asymmetric, because it has four different groups. It can rotate light clockwise (R) or counterclockwise (L).
groups
Amino acids have groups. Alkyl amino acids are glycine, alanine, valine, leucine, and isoleucine. Aromatic amino acids are phenylalanine, tryptophan, and tyrosine. Sulfur amino acids are cysteine, which is thiol, and methionine, which is thioether. Hydroxyl amino acids are the alcohols serine and threonine and the phenol tyrosine. Acidic amino acids have charge -1 in solution: aspartic acid and glutamic acid. Amide amino acids are asparagine and glutamine.
Lysine and arginine, which have amino group, are basic amino acids and have charge +1 in solution. Histidine is basic amino acid, is secondary amine, has aryl ring with two nitrogens, has charge +0.5 in solution, and has smaller charge in solution because it is weak base.
Imino acid is proline, which is secondary amine. Non-polar amino acids are alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, and proline.
polymerization
Amino acids can polymerize to make protein. Twenty different amino acids are in protein. Proteins have only L-amino acids, not R-amino acids. Amino acids that are fewest in proteins are methionine, then histidine, and then tryptophan. Methionine is first amino acid in protein chain. Free amino acid to dipeptide ratio is 10:1.
absorption
Intestine absorbs 92% of amino acids.
types
Delta-aminolevulinic acid comes from glycine and succinyl-CoA. Epinephrine comes from tyrosine. Melanin comes from tyrosine. Phenylalanine makes tyrosine. Serotonin comes from tryptophan. Amino acids can make folic acid, S-adenosylmethionine, thyroxine, histamine, sphingosine, and NAD+. Amino acids can lose amino group to become carboxylic acids in TCA cycle. Carboxylic acids in TCA cycle can gain amino group to become amino acids. Amino acids can break down to ammonia and urea.
Fibrinogen, thrombin, and blood-factor proteins participate in blood clotting {blood clotting}|.
Proteins {conjugated protein} can bind to other molecules.
Cysteine can bind to another cysteine {cystine} by disulfide bond.
Glutamic acid {glutamate, protein} builds purines and pyrimidines.
Cell proteins {heat-shock protein} can increase during stress. HSP40 carries newly folded amino-acid chains. HSP60 chaperone covers proteins as they fold, to prevent partly folded proteins from hitting others, and binds to misfolded intermediates to restart folding. HSP70 holds ATP, but when ATP leaves, it binds peptide and so aids protein conformation and assembly. HSP90, such as gp96, organizes proteins from other chaperones into receptors and other multiprotein structures. HSP70 and HSP90 carry antigens to antigen-presenting-cell CD91 receptors.
Small proteins {interferon}| can bind to plasma membranes and can protect against viruses that degrade mRNA and block protein-synthesis initiation. After viral-gene expression starts, interferon can stop all viral-gene expression {interferon response}. In humans, viruses that make long double-stranded RNAs trigger PKR enzyme production, which stops mRNA translation to protein. RNAse L breaks down mRNA. Interferon cytokine secreted by virus-infected cells enhances both these responses.
Alpha-keratin {keratin}| is in skin, hair, wool, horn, and nails. Alpha-keratin has three to seven amino acid chains in bundle, cross-linked by disulfide bonds, which then bundle again. Scales, claws, beaks, silk, and feathers have beta-keratin. Beta-keratin is mostly glycine, alanine, and serine.
Amino acids can link by peptide bonds {peptide}|. Peptides do not branch. Peptides are transmitters and hormones.
Proteins {protein hormone}, such as insulin, growth hormone, and adrenocorticotropin, can be hormones.
Protofibrils {protofibril} are soluble, have 4 to 30 misfolded proteins that clump together, and do not break down quickly enough in disease, later forming fibrils and {amyloid} plaque.
Urea processing uses the following steps {urea cycle}. Ammonia builds up in cells from various deaminations. Ammonia is toxic, because it blocks TCA cycle. In mitochondria, ammonia reacts with two ATP, carbon dioxide, and water molecule to make one carbamyl phosphate. In cytoplasm, carbamyl phosphate reacts with ornithine to make citrulline. Citrulline diffuses to cytosol and reacts with aspartic acid, which splits to give arginine and fumarate. Water reacts with arginine to make nitrogen compounds {urea}| {ornithine}. Urea is not toxic, can cross membranes, and excretes in urine.
Proteins, such as snake venoms, can be poisons {toxin}|. Bacteria make diphtheria toxin. Cobra venom and banded kait venom bind to acetylcholine receptor. Tetanus toxin and black-widow-spider toxin affect acetylcholine vesicle release. Tetanus toxin prevents glycine release. Benzodiazepines, phencyclidine, and strychnine are toxins. Poisons can stay inside cells {endotoxin} or secrete to outside {exotoxin}. LAL chemical, from horseshoe crab blood, tests for endotoxins in drugs and implants.
Botulinus toxin {botulism}| affects acetylcholine vesicle release.
Proteins {enzyme}| can be catalysts. Enzyme and ribozyme catalysts regulate biochemical reactions. Coenzymes can bind to or assist enzymes.
history
Schwann discovered pepsin [1825], which cuts proteins. Robiquet and Boutron discovered emulsin [1830]. Leuchs discovered ptyalin [1831]. Payen and Persoz discovered amylase [1833], which cuts starches. Corvisart discovered trypsin [1856], which cuts proteins. Kuhne invented the word enzyme [1878]. Bertrand discovered need for coenzymes [1897]. Arthur Harden and William John Young discovered coenzyme for zymase [1906]. Henri studied enzyme kinetics and proposed enzyme-substrate complex [1903]. Barger and Stedman discovered that physostigmine inhibited cholinesterase [1923], which metabolizes choline. Jones and Perkins discovered ribonuclease [1923], which cuts RNA. Enzymes are proteins [1925]. Briggs and Haldane used steady state for enzyme kinetics [1925]. Sumner discovered urease [1926], which metabolizes urea. Stedman discovered acetylcholinesterase [1932], which metabolizes acetylcholine. Aeschlimann discovered that neostigmine inhibited cholinesterase [1931]. Hellerman hypothesized need for thiol groups in enzymes, as did Bersin and Logemann [1933]. Hellerman hypothesized need for metal bridges in enzymes [1937]. Mann and Keilin discovered that sulfanilamide inhibited carbonic anhydrase [1940]. Sanger and Tuppy found insulin amino-acid sequence [1951]. Sutherland discovered cyclic AMP in animal cells [1956]. Koshland hypothesized enzyme conformation changes upon binding [1958]. Kendrew used x-ray crystallography on myoglobin [1958]. Merrifield developed solid-phase peptide synthesis and built insulin and ribonuclease [1963].
types
Chymotrypsin, cytochrome, diastase, flavin, lipase, lysozyme, nuclease, RNA polymerase, thermolysin, and DNA polymerase are enzymes.
transition states
About 100,000,000 transition-state shapes exist for enzymes.
In competitive inhibition, inhibitor shape can be similar to substrate shape, so inhibitor can bind to enzyme at substrate site {active site}.
In non-competitive inhibition, inhibitors can bind to enzymes at other sites {allosteric site} to alter active sites.
Molecules {coenzyme}| can bind to enzymes to activate them. Michaelis and Wollman discovered that free radicals formed from alpha-tocopherol [1950]. Lipmann isolated coenzyme A [1945]. Mitchell, Snell, and Williams isolated folic acid [1941]. O'Kane and Gunsalus isolated lipoic acid [1948]. Metals can be coenzymes [1930]. Jansen and Donath isolated thiamine [1926]. Fildes hypothesized that molecules similar to natural substrates or coenzymes compete and are therapeutic. Methotrexate treats leukemia (Farber) [1946].
Post-transcription, enzymes {proteolytic enzyme} can cleave terminal amino acids and break peptide chains into pieces: proteinase, peptidase, pepsin, trypsin, chymotrypsin, carboxypeptidase, amino peptidase, dipeptidase, endopeptidase, and exopeptidase.
Reagents {substrate} can bind to enzymes at active sites.
Enzyme precursors {zymogen} can split or react to create enzymes.
Molecules {inhibitor} can bind to enzyme to reduce reaction rate {enzyme inhibition}.
Inhibitor shape can be similar to substrate shape, so inhibitor can bind to enzyme at active site {competitive inhibition}.
Inhibitor can bind to enzyme at allosteric site to alter active site {non-competitive inhibition}.
Inhibitor can bind directly to enzyme-substrate complex to change activation energy {uncompetitive inhibition}.
Heat-shock proteins {foldase}, such as HSP60, envelope proteins as they fold to prevent partly folded proteins from hitting others.
Heat-shock proteins {chaperone} bind to misfolded intermediates to restart folding.
Molecules {ubiquitin, protein}| can bind misfolded proteins and go to proteosomes to break peptide bonds.
Proteins can be for protection {immunity}|. Antigen binding to beta-lymphocyte surface triggers process that creates plasma cells. Plasma cells specialize to make antibody to antigen.
Antigens can enter body. Immunoglobulin proteins {antibody}| bind antigens, so body can remove foreign molecules. Antibodies bind to antigens by hydrogen bonds, van der Waals forces, and ionic bonds. Antibody-connecting subunits can cross plasma membrane and bind to cells.
structure
Antibodies have three subunits. Two subunits can bind to one antigen each. One subunit connects two binding subunits to make Y-shaped structure. Antibodies have two light protein chains and two heavy protein chains, linked by disulfide bonds. Light chains are at Y tips. All antibodies have kappa or lambda light chain but different heavy-chain constant regions. Heavy chains are in arms and base of Y. Light and heavy chains have variable end and constant end. Several hundred genes code variable regions, making millions of different antibodies. About 100,000,000 different antibody shapes can exist.
precipitation
When one antibody binds to two antigens, complex becomes insoluble. Bound molecules precipitate from solution, and then cell phagocytes eat them.
Five proteins {immunoglobin}| affect immunity. IgA is in secretions. Immune system makes IgM first. IgG increases as IgM decreases. IgE is for allergies. IgD is another immunoglobin.
Large molecules {antigen}| can enter body from outside.
Antigens have regions {epitope}| where other molecules can bind.
Small molecules {hapten} can bind to epitope.
Protein groups {complement, protein} can lyse cells if antibodies bind to cells.
Genes {joint gene} {J gene} can code for connections between light and heavy chains.
Parasites {virus, organism} can have DNA or RNA surrounded by protein.
nucleic acid
Virus has nucleic acid 4 to 250 genes long. Nucleic acid can be RNA or DNA, single or double-stranded.
injection
Protein coat has sites that attach to cell membrane. After attachment, protein coat contracts to inject nucleic acid into cell.
replication
After injection, viral genes can transcribe. Proteins from those viral genes prevent host-cell DNA transcription. Then cells transcribe viral genes whose proteins replicate virus and protect viral DNA from attack. Enzyme protects from attack by methylating sites that are vulnerable to attack by cell nucleases.
protein coat
After rod-like-virus nucleic acid replicates, nucleic acid binds protein-subunit disks at a site and then adds more subunit disks as nucleic acid folds into helix inside.
After sphere-like-virus nucleic acid replicates in cell, cell makes protein spheres, and enzyme inserts nucleic acid into protein sphere. One cell can make up to 200 viruses.
types
After assembly, virus can lyse cell and let viruses out to attack more cells. Virus can allow cell to remain packed with viruses, without bursting.
Viruses have protein coats {capsid}, with identical subunits hydrogen-bonded into symmetric structures. Special capsid proteins recognize cells by binding to cell-membrane proteins. After attachment, virus nucleic acid enters cell by injection through cell membrane, using energy from ATP.
Nucleic acids {bacteriophage}| can act like viruses in bacterial cells. It is DNA or RNA that has protein coat. It tries to enter cell from outside and then integrate into chromosome. Bacteriophages replicate in cell along with chromosome.
Viruses {RNA virus} can have RNA instead of DNA. RNA viruses can use RNA-directed RNA polymerase for direct RNA replication. RNA viruses can use RNA-directed DNA polymerase to make DNA from RNA and then make viral RNA from DNA. RNA viruses include polio, colds, foot-in-mouth disease, rabies, cancer retrovirus, and human immune deficiency virus.
Viruses {Sendai virus} can alter membranes and allow two cells to fuse, even if they are from different species.
Carbon transfers among many forms {carbon cycle, Earth}.
ocean
Rivers remove land sediments, and calcium carbonate enters sea. Carbonate buffers sea and is in equilibrium with carbon dioxide in air. Carbonates can becomes shells or skeletons. Eaten shells and skeletons later sink and dissolve. Carbonates can remain in sponges, algae, and coral reefs. Algae reefs began 2,000,000,000 years ago. Animal reefs began 600,000,000 years ago. Reefs collapsed 530,000,000; 350,000,000; 225,000,000; and 65,000,000 years ago.
organisms
Autotroph organisms get carbon from carbon dioxide. Heterotroph organisms get carbon from glucose.
cells
Photosynthetic cells convert carbon dioxide and water to glucose. Cells break down glucose to carbon dioxide and water for energy.
carbon
Carbon atoms can bond to carbon atoms and other non-metals, with single and multiple bonds, to make rings, chains, and branching chains. Many polarities and charge structures are possible. Carbon covalent bonding provides stability, alterability, and variety in organic molecules.
Cells make nitrogen into nitrate or ammonia, then make nitrate or ammonia into amino acids, then break down amino acids to ammonia and urea, and then break down ammonia and urea to nitrate and nitrite {nitrogen cycle, biochemistry}. Nitrogen-fixing bacteria {chemolithotroph} change nitrogen gas to ammonia. Nitrate-making bacteria make nitrate from ammonia.
Cells reduce oxygen and hydrogen donors to water, and then oxidize water to oxygen {oxygen cycle}. Aerobe organisms use oxygen as electron acceptors to cause reduction. Obligate-anaerobe organisms use sugar as electron acceptor to cause reduction. Facultative-aerobe organisms use either oxygen or sugar but prefer oxygen as electron acceptor to cause reduction. Anaerobe organisms do not use oxygen.
Water is both inside and outside cells {water cycle, biochemistry}. Water is 70% of human body weight. Cell water has phosphate buffer and is at pH 6.8. Cell proteins make high osmotic pressure. Intercellular fluid has bicarbonate buffer and is at pH 7.2. Osmotic pressure is low outside cells.
Cells change light energy into chemical-bond energy {energy cycle, cells}. Cells make glucose and can make ATP high-energy bonds. Cells diffuse ATP to all cell parts. Cells use ATP to phosphorylate other compounds. Cells use ATP to make acetyl-CoA for making carbon-carbon bonds. Cells use high-energy compounds to synthesize molecules, cause movement, send electrical signals, or generate heat. Cells break down synthesized molecules, dissipate electric energy, and make energy into heat through friction.
reduced molecule
Cells use ATP to make NADH, NADPH, and FADH2 [2 is subscript] electron acceptors and hydrogen donors. Reduced molecules, which can oxidize to release energy, store energy for biochemical reactions. Oxidation-reduction reactions are reversible. NAD can add one hydrogen atom to make reduced NADH. Phosphated NADP can reduce to NADPH. FAD can add two hydrogens to make reduced FADH2 [2 is subscript].
Adenosine triphosphate (ATP) transfers energy {ATP cycle}. Cells cannot store ATP. ATP cannot cross membranes.
functions
ATP actively transports, contracts muscle, phosphorylates molecules, makes thioester with acetyl-CoA, makes enols, and makes guanidiene.
metabolism
ATP can break down to adenosine monophosphate (AMP) and pyrophosphate. ATP can break down to adenosine diphosphate (ADP) and orthophosphate. Orthophosphate transfers to arginine or creatinine. Cells regenerate ATP by ADP and orthophosphate oxidation, in respiration pathway or glycolysis pathway.
acidity
At high pH, energy in ATP is less, because electron repulsion is less.
concentration
If ATP concentration increases, energy in ATP is less, because dissociation is less.
magnesium
Magnesium binds to ATP phosphates. If magnesium increases, energy in ATP decreases, because magnesium blocks charges more.
Basic organism energy flow {basal metabolism rate}| sustains life. People have energy-use rate while completely resting, typically 1600 calories per day. Human rate averages 1000 calories per kilogram per hour. Rate is proportional to body surface and body weight. Whole-body average energy flow is 20% to 50% higher than basal metabolism rate.
gender
Rate is higher in males. Rate increases in pregnancy and lactation, up to three times more.
hormones
Thyroid and growth hormones affect basal metabolism rate.
factors
Rate increases in fever. Rate lowers during fasting.
isothermal
Metabolism typically is in isothermal environments, like sea or warm-blooded animals.
warm-bloodedness
Warm-blooded animals use up to ten times more energy than cold-blooded animals. Warm-blooded animals can live in wider temperature ranges and move faster. Temperature constancy requires muscle movement to heat tissues. Temperature constancy requires mechanisms to cool tissues. Brain controls temperature. Parents must keep eggs and babies warm. Temperature control turns off during sleep. Warm-bloodedness can be at different temperatures in different conditions. Food quantity must be more. Senses must find food. Memory must remember food locations. Planning must improved for better food strategies. Chewing must be more efficient. Breathing passage alters to allow breathing while eating.
Bonds {phosphate bond}| can store energy for biochemical reactions. Phosphate bonding is reversible. Molecules {adenosine monophosphate} (AMP) can have one nucleotide and one phosphate. Molecules {adenosine diphosphate} (ADP) can have one nucleotide and two phosphates. Adenosine triphosphate (ATP) has one nucleotide and three phosphates.
Cells use energy in different ways {troph}. Organisms {phototroph} can use sunlight for energy. Non-sulfur purple bacteria {photoorganotroph} are photosynthetic. Organisms {chemotroph} can use energy-containing molecules and oxidation-reduction reactions for energy. Organisms {lithotroph} can use water, hydrogen sulfide, sulfur, ammonia, hydrogen, or ferrous compounds as electron donors to cause oxidation. Organisms {organotroph} can use glucose and other organic electron donors to cause oxidation.
Files {MOL File} with file extension .mol can describe molecule atoms and connections.
Files {PDB File} from Brookhaven Protein Databank with file extension .pdb can contain XYZ coordinates for all protein atoms, as well as hydrogen bonding information.
Files {SD File} with file extension .sd or .sdf can describe molecule atoms and connections, in two dimensions.
Files {TGF File} with file extension .tgf can describe molecule atoms and connections, in three dimensions.
Files {XYZ File} with file extension .xyz can describe molecule atoms and connections, in three dimensions.
Compounds {drug, chemistry} {drug-like compound} can metabolize with biological molecule.
size
Drugs have molecular weight 200 to 700.
side effects
Drugs must have few side effects.
absorption
Body can absorb drugs.
distribution
Drugs can go to body organs and/or tissues.
metabolism
Drugs have chemical reactions at sites. Drugs have orientation at receptor site. Drugs can sterically interact with receptor site.
excretion
Drugs do not excrete too quickly.
solubility
Drugs have solubility, partition coefficients, diffusivity, and ionization degree.
variation
Drugs can vary using different salts, esters, and side groups for different sizes and surface areas.
form
Drugs can be solutions, suspensions, capsules, or tablets. They can be oral, subcutaneous, intravenous, inhaled, or patch.
history
In England, William Morton [? to 1868] used inhaled ether [1846] during surgery on October 16 (Ether Day). inhaled chloroform [1850]. inhaled nitrous oxide and oxygen [1868]. hypodermic syringe [1868]. intravenous morphine [1868]. chloral hydrate [1869]. inhaled nitrous oxide and oxygen followed by chloroform or ether [1876]. paraldehyde [1882]. cocaine [1884]. sulfones [1888]. ethyl p-aminobenzoate [1890]. Novocaine is procaine hydrochloride. Phenacetin comes from aniline by hydroxylation and conjugation [1890 to 1899]. aspirin [1899]. Anti-pyrine came from quinine [1900]. urethane [1900].
Organizations regulated by the Food and Drug Administration (FDA) are required to comply with Good Laboratory Practices {good laboratory practices} (GLP). GLP compliance requires organizations to have administrative policies, written procedures, competent personnel, and trained personnel. As part of GLP compliance, software products used in regulated organizations should comply with FDA regulations and document how compliance was achieved.
Code of Federal Regulations (CFR), Title 21, Chapter I, Part 11
Specific functions, electronic records, and auditing of software systems are required to be compliant with Code of Federal Regulations (CFR), Title 21, Chapter I, Part 11, Electronic Records; Electronic Signatures Final Rule (FDA CFR21 Part 11).
FDA CFR21 Part 11 requires accurate, reliable, and consistent software.
FDA CFR21 Part 11 does not necessarily require encryption.
FDA CFR21 Part 11 requires versioning of data and audit records.
FDA CFR21 Part 11 requires data to be entered in specific fields before processing.
FDA CFR21 Part 11 requires auditing.
FDA CFR21 Part 11 requires electronic signatures.
FDA CFR21 Part 11 has installation requirements. All necessary software components must be successfully installed and a report generated.
FDA CFR21 Part 11 has logon and logoff requirements. Systems limit access to only authorized persons, by checking user name and password. After a specific time period, automatic logoff occurs.
FDA CFR21 Part 11 has security requirements for data and audit record management, with file and operating system permissions. Attempts at unauthorized use are sent by electronic mail to the Administrator. User and user groups have privileges to files, directories, and functions. Systems can detect invalid or altered records. Auditing of user events detects creation, modification, and deletion of files, using checksums.
FDA CFR21 Part 11 requires instrument maintenance logs.
FDA CFR21 Part 11 has requirements for reporting data, parameters, and auditing information.
Drugs have absorption, distribution, metabolism, and excretion {ADME}.
Pharmacokinetics (PK) is about absorption, distribution, metabolism, and excretion {ADME/PK profile}.
Drug Metabolism and PharmacoKinetics {DMPK}.
Inactive chemicals {excipient}, such as solvent or powder, can carry active drugs.
Plasma proteins {human serum albumin} (HSA) can carry other molecules.
Drugs {pharmacodynamic drug, complex} can make complexes but not cause chemical reactions or conformational changes.
Drugs have absorption, distribution, metabolism, and elimination {pharmacodynamics} (PD).
Population genotypes can identify SNPs affecting drug metabolism {pharmacogenomics}.
Absorption, distribution, metabolism, and elimination affect drugs {pharmacokinetics} (PK).
High-enough concentration {potency}| causes biologic response.
Drugs {prodrug} can require metabolization to transport or be active.
Drugs can cause birth defects {teratogenicity}|, by acting on development processes.
Drug can damage tissues {toxicity}|.
Foreign compounds {xenobiotics} are vapors, alcohol, drugs, pollutants, solvents, food toxins, pesticides, and pyrolysis products. Pyrolysis products come from charring fat or protein.
Drugs have activity {drug, activity}, depending on structures and other factors.
Activity is half maximum at a concentration {IC50}.
Mopac quantum-mechanical calculation can find activation energy {initial activation energy} (Ea0).
Structure can associate with physicochemical property {property-activity relationship}.
Measured activity equals physicochemical-variable function {quantitative structure-activity relationship} (QSAR). QSAR relates activity magnitude, such as tissue concentration, to compound physico-chemical or structural property magnitudes, such as carbon-atom numbers. QSAR (3D-QSAR) can be in three dimensions.
Activity equals physicochemical-variable function {structure-activity relationship} (SAR).
Structures and properties have relation {structure-property correlation} (SPC).
Systems {Corey Pauling Koltun} (CPK) can display space-filling compound models.
Molecule alignments can adjust {field-fit procedure}.
Indexes {kappa index, drug} can depend on molecular shape and flexibility.
Network mappings {Kohonen topology-preserving mapping} can retain topology.
Calculations {Morgan algorithm} can make unique numberings for connection tables.
Strings {SMILES} can uniquely describe three-dimensional structure.
Searches {substructure searching} can use connectivity-table parts as search criteria.
Topological indexes {Tanimoto index} can represent graphs as numbers.
Indexes {topological index} can represent graphs as numbers.
Indexes {valence molecular-connectivity index} can use valence to indicate connectivity.
Sums {branching index} over all bonds, of inverse of square root of end-atom-valence product, can measure branching amount.
Indexes {molecular connectivity index} can depend on branching.
Normal-distribution outlier tests {Dixon's Q-test, drug} {Dixon Q-test, drug} can measure smallest and largest difference ratio.
Normal-distribution outlier tests {Grubbs' s-test, drug} {Grubbs s-test, drug} can compare absolute value, of difference between mean and value, divided by standard deviation, to T-distribution value.
Rules {Active Analog Approach} can align molecule activities by analogous structures.
Rules can align molecule activities by structural group {active pharmaceutical ingredient} (API).
Non-parametric methods {alternating conditional expectations} (ACE) can analyze activity.
Input "neuron" layer can hold physico-chemical properties and feed to middle layer using sigmoidal function {transfer function} with weights for outputs. Middle-layer "neurons" feed to one output {artificial neural network} (ANN).
Mathematical tools {chemometrics} applied to structure-activity relationships can find correlations and regression, recognize patterns, classify compounds and properties, design experiments for random screening and measuring, and validate results.
Quantum mechanics can pair with empirical approaches {computer-assisted metabolism prediction} (CAMP).
Cell arrays can pool more than one sample in cells, which allows fewer cells. Methods {deconvolution} can track sample pooling.
convolution
Convolution puts each sample into several cells, in regular pattern. Testing looks for one effect. Some cells show effect, but most do not. If sample causes effect, all cells with that sample show effect. Cells that contain that sample form pattern, so pattern indicates sample name.
deconvolution
Deconvolution uses convolution method and resulting cell pattern to find sample name. For example, for 100-cell array, 10 samples can feed into 90 cells, each cell receiving two samples. Ten cells have control samples. See Figure 1. Samples are in 18 cells. If testing shows that all 18 have activity over threshold, then that sample is effective.
If sample interactions cause effect, deconvolution can find interactions. If testing shows that only one cell has activity over threshold, those two samples must interact to be effective.
Combining quantum mechanics and physico-chemical properties {empirical-quantum chemical} {combined empirical/quantum chemical approach} can predict chemical behavior.
Models {Korzekwa-Jones model} can be for P-450 hydrogen abstraction and depend on difference between radical free energy and hydrogenated-atom free energy, as well as radical ionization potential and constant additive term.
Steric effects and van der Waals forces can cause fields {Lennard-Jones potential}.
Plots {loading plot} can use variable weights.
Semiempiric methods {modified neglect of differential overlap} (MNDO) can ignore overlap.
Molecule-modeling programs {molecular modeling}, such as Alchemy III and SYBYL from Tripos, can use electrostatics or quantum mechanics.
Non-parametric methods {non-linear partial least-squares, drug} (NPLS) can find least squares.
Response-surface methods {non-parametric method}, such as ACE, NPLS, and MARS, can be non-parametric.
IF/THEN statement sets {rule induction system, drug} can make output from input.
Graphs {score plot} can plot compound activities.
In multidimensional property space, compound clusters make classes separated by distance {cluster analysis} (CA). CA reduces unimportant variables. Substructure, topological index, physico-chemical property, calculated physico-chemical property, or hydrophobicity can determine classes.
Using discrete or continuous data and embedded data can put compounds into groups by activity level {cluster significance analysis} (CSA). CSA locates small clusters in large spaces.
Methods {Cone and Hodgkin similarity index} can measure molecular similarity.
Models {discriminant-regression model} (DIREM) can locate small clusters in large spaces.
Methods {distance-b program} (EVE) can locate small clusters in large spaces.
Unsupervised methods {hierarchical cluster analysis} (HCA) can measure distances between all points and make point vs. distance dendograms.
Structures can cluster in large databases by rating different compounds by similarity {Jarvis-Patrick method}.
Supervised methods {k-nearest neighbor} (k-NN) can calculate new-object distances from all other objects, to locate small clusters in large spaces.
Processes {partitioning} can merge individuals into groups or split whole into clusters.
Values {similarity measure} can compare distances.
Methods {single class discrimination} (SCD) can locate small clusters in large spaces.
Classifications {supervised method} can use already known patterns and clusters.
Activity and descriptor correlation vectors {trend vector analysis} can rank compound similarity.
Hierarchical methods {Ward's clustering method} {Ward clustering method} can agglomerate compounds to find clustering.
Supervised methods {Soft Independent Modeling of Class Analogies} (SIMCA) can use region-boundary or envelope models, to locate small clusters in large spaces.
Clustering methods {class analogy} can be SIMCA methods.
Distance measures {city-block distance} between structure-space points can be the same as Manhattan distance.
Distance measures {Manhattan distance} between structure-space points can be the same as city-block distance.
Distance measures {Minkowski distance} between structure-space points can be the same as Lp-metric.
Distance measures {Lp-metric} between structure-space points can be the same as Minkowski distance.
Structure-space points have distances {Mahalanobis distance}.
Hierarchical methods {centroid linkage} that agglomerate compounds can find clustering.
Hierarchical methods {complete linkage} that agglomerate compounds can find clustering.
Hierarchical methods {single linkage} that agglomerate compounds can find clustering.
Processes have factors {factor analysis}. Physico-chemical or structural properties describe compounds and have components {descriptor, factor} {X-variable, factor} {X descriptor, factor}. Chemical activities relate to variables {response variable}.
Methods {canonical factor analysis} can be for factor analysis.
Methods {centroid method} can be for factor analysis.
QSAR {combinatoric QSAR} can find similarities using different descriptor combinations.
Moments of inertia, and dipole and quadrupole moments, can be descriptors to calculate molecular moments {Comparative Molecular Moment Analysis} (CoMMA). CoMMA depends on shapes and charges.
Properties and structures have relations {Correlation Analysis}.
Factor-analysis methods {correspondence analysis} {correspondence factor analysis} (CFA) can use variable frequencies relative to activities, finds chi-square values, and finds principal components.
Principal components {disjoint principal component} (DPP) can be independent.
Thresholds {eigenvalue-one criterion} can be how many components have eigenvalues greater than one.
Unsupervised linear methods {eigenvector projection} can find factors.
Models {Evolutionary Programming} (EP) can add and subtract randomly selected variables, with crossing-over, and evaluate for "fitness" or best fit.
Methods {evolving factor analysis} (EVA) can analyze ordered data.
Methods {percentage of explained variance} {explained variance percentage} can indicate number of components required to reach 90% of total variance.
Parameters and descriptors can linearly relate to free energy {extrathermodynamic approach}.
Factor-analysis methods {free energy perturbation} (FEP) can use free-energy changes.
Binary descriptors can note molecule-substructure presence or absence {Free-Wilson approach}.
Linear property sets can have different values, change values by crossing-over between related such genes, and have random change {Genetic Function Algorithm} (GFA), to select best fit.
Values {Hammett sigma value} can relate to electronic and electrostatic properties.
Activity, partition coefficients for hydrophobicity, ionization degree, and molecular size relate {Hansch equation}.
Variables {latent variable} can be linear-descriptor combination.
Supervised methods {linear discriminant analysis} (LDA), in which boundary surface minimizes region variance and maximizes variance between regions, can put compounds into groups by activity level.
log K = k1 * sigma + k2 {linear free energy equation, drug} (LFE).
Supervised methods {linear learning machine} (LLM) can divide n-dimensional space into regions, using discriminant function.
Factor-analysis methods {maximum-likelihood method} can find factors.
Metric or non-metric methods {multidimensional scaling} (MDS) can analyze similarity or dissimilarity matrices to find dimension number and place objects in proper relative positions.
Non-parametric methods {multivariate adaptive regression spline} (MARS) can find factors.
Models {Mutation and Selection Uncover Models} (MUSEUM) can add and subtract randomly selected variables, with no crossing-over, and evaluate for "fitness" or best fit.
Unsupervised linear methods {non-linear iterative partial least-squares} (NIPALS) can represent data as product of score matrix, for original observations, and loading-matrix transform, for original factors.
Topological mappings {non-linear mapping} (NLM) can be factor-analysis methods in which linear-variable combinations make two or three new variables.
Information about compound physico-chemical properties can predict compound chemical or physiological behavior in vitro and in vivo {predictive computational model}.
Variables {principal component} (PC) can be linear-descriptor combinations. Unsupervised linear method {principal component analysis, factor} (PCA) represents data as product of score matrix, for original observations, and loading-matrix transform, for original factors. PCA is factor-analysis method in which linear variable combinations make two or three new variables. PCA reduces unimportant variables.
Singular-value decomposition (SVD) can find best singular values for predicting {principal component regression} (PCR). SVD projects regression to latent structures.
Modified PCA {principal factor analysis} can find principal factors.
Methods {Procrustes analysis} can identify descriptor sets for describing similarity.
Methods {QR algorithm} can diagonalize matrices.
Unsupervised linear methods {rank annihilation} can find factors.
Residual variance approaches constancy {Scree-test, drug}, and plotted slope levels off {Scree-plot}, depending on component number.
In unsupervised linear methods {singular value decomposition, drug} (SVD), correlation matrix is product of score, eigenvalue, and loading matrices, with diagonalization using QR algorithm.
Factor-analysis methods {spectral mapping analysis} (SMA) can first take data logarithm to eliminate outliers and then subtract means from rows and columns, to leave only variation, showing which variables are important and how much.
Spaces {structure space} can have two or three principal components.
Methods {target-transformation factor analysis} can rotate features to match known pattern, such as hypothesis or signature.
Factors and response variable have relations {Unsupervised Method}, without using factor information or predetermined models.
Designs {factorial design} can try to ensure design-space sampling, if position varies.
Designs {fractional factorial design} can try to ensure design-space sampling, if position varies.
Three-level designs {response surface method} (RSM) can have three factors that quantify relationships among responses and factors. RSM includes MLR, OLS, PCR, and PLS linear designs; non-linear regression analysis (NLR); and non-parametric methods, such as ACE, NPLS, and MARS.
isomer-enumeration method {Cayley tree structure}.
Isomer-enumeration methods {CONGEN program} can be successors to DENDRAL.
Isomer-enumeration methods {DENDRAL program} can be forerunners of CONGEN.
isomer-enumeration method {Henze and Blair recursion formulas}.
Isomer-enumeration methods {Polya's enumeration theorem} {Polya enumeration theorem} can use group theory.
Electron orbitals {molecular orbital} can be for whole molecule.
Analyses {ab initio analysis} can use all electrons.
Adding atomic orbitals can approximate molecular orbitals {linear combinations of atomic orbitals} (LCAO).
Semiempiric methods {perturbative configuration interaction using localized orbitals} (PCILO) can use perturbations.
Analyses {semiempiric} can use valence electrons and parameterize core electrons.
Sigma electrons can contribute {simple delta index, drug}.
Factors, properties, or structures {regressor} can contribute to response values {regression, regressor} {Regression Analysis}.
Regression can project to latent structures {canonical correlation} (CC), to put compounds in classes.
Regression {continuum regression} (CR) can project to latent structures, to put compounds in classes.
Variance-covariance matrix {correlation matrix, drug} can scale to normalize data.
Regression can project to latent structures {kernel algorithm}, to put compounds in classes.
Methods {matrix diagonalization, drug} can simplify data variance-covariance matrix.
Parametric methods {non-linear regression} (NLR) can find descriptor coefficients by non-linear regression.
Regression can project to latent structures {ridge regression} (RR), to put compounds in classes.
Methods {Spearman rank correlation coefficient} can measure molecular similarity.
Complete, symmetric, square matrix {variance-covariance matrix} uses property values and structure values.
Regression can project to latent structures {adaptive least-squares} {ALS algorithm}, to put compounds in classes.
Methods {classical least-squares, drug} (CLS) can be the same as ordinary least-squares analysis.
Partial least-squares {Comparative Molecular Field Analysis} (CoMFA) can analyze grid around site atom and find grid-point electrostatic and steric interactions, to make sampled-point descriptors.
Compounds have different classes with different weights {fuzzy adaptive least-squares} (FALS).
Methods {Generating Optimal Linear PLS Estimations} (GOLPE) can use PLS and D-optimal design to select variables, and cross-validates.
Fitting methods {inverse least-squares} (ILS) can find regression line.
Methods {least-squares regression, drug} can be the same as ordinary least-squares analysis.
Methods {linear least-squares regression, drug} can be the same as ordinary least-squares analysis.
Partial least-squares methods {matrix bidiagonalization method, drug} can simplify data variance-covariance matrix.
Regression can project to latent structures {multi-block PLS}, to put compounds in classes.
Methods {multiple least-squares regression, drug} can be the same as ordinary least-squares analysis.
Methods {multiple linear regression} (MLR) can measure linear component dependence on physico-chemical or structural properties and finds descriptor coefficients.
Methods {multivariate least-squares regression, drug} can be the same as ordinary least-squares analysis.
Methods {non-least-squares} (NLS) can detect non-linear relationships.
Fitting methods {ordinary least-squares} (OLS) can find descriptor coefficients.
Methods {partial least-squares} (PLS) can use least-squares to find independent variables and dependencies among variables. It projects regression to latent structures. It maximizes latent-variable and observable covariation. It diagonalizes the matrix.
Methods {SAMPLS algorithm} can apply PLS to trend vector analysis.
Estimates {best linear unbiased estimator} (BLUE) can give smallest variance among estimators.
Error measures {standard error} can be square root of MSE.
SSE, SSR, or SST {sum of squares of differences} {squares of differences sum}.
SSE / (observation number + factor number - 1) {mean square error} (MSE).
Errors or residuals can cause sum {SSE} of squares of differences between observed and predicted responses.
Regression can cause sum {SSR} of squares of differences between observed and mean.
Sum {SST} of squares of differences between predicted and mean makes total: SST = SSE + SSR.
Drugs have tests {drug experiment}.
experimental design
Samples can test properties and activities. Experiment uses numbers and sample types from population, as well as methods and instruments. Three-level design assigns three levels (-1,0,1) to each factor to determine how responses vary with factors or variables, for making mechanistic physico-chemical models, using physical chemical properties as factors, or empirical polynomial models, using arbitrary variables as factors. Three-level mixture design determines whether factor is useful or significant or not. Two-level design assigns two levels (0,1) to each factor to determine whether factor is useful or significant, for screening, searching, or filtering.
kinetics
Experiments can read samples multiple times over time to find reaction rate or inhibition constant.
Biological reaction series can makes protocols {assay, experiment}. Protocol or method series use reagents to identify compounds, genes, proteins, or quantities.
Methods {protocol, experiment}| can run experiments. Experiments can perform steps or tasks on samples: prepare samples, mix with reagents, hybridize, wash, detect, and analyze.
Samples can be read more than once {replication, sample}.
In screening, calculated results translate into given ranges {scoring}, like high, medium, or low.
three-level design {Box-Behnken design}.
Experimental designs {CARSO approach} can be for random compound screening in experiment series.
three-level design {central composite design}.
Experimental designs {Craig plot} can be for random compound screening in experiment series.
Test-set selection methods {D-optimal design} can try to ensure design-space sampling, if positions vary, and can account for excluded volumes.
Experiment designs {sequential optimization} can use steps toward optimum.
Experimental designs {Topliss tree} can be for random compound screening in experiment series.
Experiments {dose response curve} can read samples at different concentrations and fit IC50 curves.
Experiments {ELISA} can back-calculate sample concentration, using reference curve.
Automated assays {High-Throughput Screening} (HTS) can test many diverse compounds against enzymes or cell targets, to identify possible new drugs.
More than one sample can be in wells {pooling} in screening experiment. Samples mix in plate wells according to patterns, so system measures all samples the same number of times. Total well number is fewer than with one sample per well.
Experiments {ratio experiment} can read samples twice, for agonist vs. antagonist, to determine activity ratios.
Automated assays {screening} {high-throughput screening} can identify promising compounds from compound libraries.
users and groups
Roles (types of users) have a set of privileges. Users have roles.
inventory
Inventory database has sample IDs.
experiment type: ELISA
Plate has high and low controls (averages), dose-response titration (IC50), and replicated samples (averages of % inhibition); Fit the result into the standard curve for a first estimate IC50, and back calculate the concentration of an expressed protein by using a standard reference curve on each plate. Look for the well that has a result which falls on the linear portion of the standard curve.
experiment type: ratio
Each plate is read twice, first reading the growth of a specific protein, and second measuring the survival of various cells (or agonist vs. antagonist receptors). % inhibitions are calculated for each of these readings, and then the ratio. Sort on any of the three results. Since plates are carried from one reader station to the next, they may get out of order, may be put into the reader backwards, or may get dropped, so data system should be able to deal with all of these problems. This is a case of 'multiple data points per well'.
experiment type: dose response, multiple calculations
Several different models calculate, fit, and display the IC50 curves simultaneously, like straight line regression and 4-parameter curve fitting, with constant high and low inflection points. Then register one or more, with model name, parameters, and comments.
experiment type: titration
From each daughter plate, 3 to 4 assay plates at different concentrations are made. An activity value is calculated for each well, as well as the activity changes as a function of concentration.
experiment type: titration and dose response across plates
A single 96 well plate is filled with 48 samples in duplicate. The plate is then copied across 8 other plates at different concentrations. The result from the 9 plates is used to calculate a dose response curve and IC50.
experiment type: no controls on data plates
All controls (high, low, reference, dose-response curve) are on one or more reference plates, interspersed throughout the runset. Calculate a 'curve' for the standards on the reference plates, by plate sequence or time. Could use controls only on nearest reference plate.
experiment type: whole plant experiment
Growth of different plant species at time intervals, with qualitative and quantitative (Scores) results. At the end of the experiment, a report of the changes over time. A ''score' is based on observing the well and is a coded value that means something like 'severe yellowing of stem' or "intense chlorosis of stem" with more than one score per well.
experiment type: colormetric assay
Inhibition makes well white, but experiment failure makes "milky white". A scientist can see the difference, but the automated reader can be fooled. so scientist marks specific wells as bogus BEFORE the results are read into the data system.
experiment type: kinetics
Each well is read multiple times over time and the calculated value is based on the multiple raw values. All raw data is saved or only the final derived value. Plot of the timed values.
experiment type: Ki values
Dose response experiment, with a ligand of known activity value and concentration recorded. The IC50, and further calculations based on IC50, ligand activity, and ligand concentration are saved for each sample.
experiment type: pooling and replicates
Pooled plates have replicated mixtures. Same as HTS and REP, but with a reference to mixture in Inventory.
experiment type: non-plate based experiments
Row of tubes, lawn format, and so on.
variable group
A candidate variable group is selected or built. The group should take account of the dimension variables to be used for the RFM upload and for the layout. The group should take account of the layout actual and placeholder values. The group should have clauclations from raw data and places to mark data invalid or promotable. The group might have a Review check.
layout
A candidate layout for the Well table is developed. The layout should have an actual concentration, actual well types for High/Low/Data/Reference wells, and placeholders for the sample IDs. The dimension, calculation, and set variables should work with the layout.
calculations
Candidate calculations are selected or made for the calculation variables of the variable group. The calculations need to follow the default or nondefault rules for calcs, especially for parent-child relations, performance, and using ASSOC, MATCHALL, and CONDITION= correctly.
reader file and format
An actual or realistic reader file is available from such an experiment, and the reader file sections are made and tested, and the sections assigned to variables of the variable group. Ordinals are assigned to Row and Column variables, along with dimensions that match the variable group and layout.
protocols and templates
Protocol assays or attributes might be added to the protocol. (Sections or templates might be built for the protocol display.) A protocol is selected or made, which contains the variable group, layout(s), and RFM formats, plus any required fields.
dictionaries and terms
Dictionary terms and dictionaries might be added for use in the protocol.
result tables
Result tables are selected or made, together with the result maps from the variable group to the result table(s).
experiments
The completed protocol is used to start an experiment, the layout and the RFM format are added, then the reader file(s) are selected. Any placeholders in the layout must be filled in. (Assembler). The experiment is calculated and stored.
analysis
The experiment is analyzed to determine if any data is invalid or questionable, and a recalculation and store occurs. A rule might be used for automatic checking for bad controls, dropped plates, and so on. The analysis might include a mod to a calc formula, data, or a change of model for a curve.
decision
The experiment is analyzed to determine if any samples are worthy of further experimentation. Such samples are marked for further testing. A score might be assigned based on rules.
review and/or release
A review is made (typically by a higher authority) of the results. That such a review has been made is noted somewhere. Perhaps the data is allowed to be used or seen by other workgroups, or is sent to corporate database.
browsing
Other persons at a company want to see a summary of the validated results, in a set format for all researchers, to avoid duplication and error.
Blood drug amount {bioavailability} relates to dose.
Brain-compartment drug concentration to blood-compartment drug concentration makes ratios {Blood-Brain Barrier penetration}.
Drug diffusion calculations {diffusivity} can measure drug-diffusion ease.
Distribution and elimination can combine {disposition, drug}.
Drugs have different concentrations in various body tissues {distribution, drug}.
Excretion {elimination, drug} uses urine and feces.
Ingested drugs affect intestinal-wall cells {enterocyte}.
Bile goes back to GI tract for recycling {enterohepatic cycling} (EHC).
Liver removes drugs from blood {intrinsic clearance} (CL).
Compounds above 500 to 700 cannot diffuse across lipid membrane {molecular weight theory}.
Percentage of orally administered drug in general blood circulation, or in urinary excretion, compares to intravenous administration {absolute oral bioavailability} {oral bioavailability}.
A vein {portal vein} carries blood to liver from GI tract.
Active or passive transport carries drug from intestine to portal vein {absorption, drug}.
Compounds absorbed from intestine {human intestinal absorption} (HIA) go to portal vein.
Intestines have contents travel rate {motility}.
Acidic or neutral drugs can diffuse across GI-tract lipid membrane, but basic drugs cannot diffuse {pH partition theory}.
Drug goes from intestine to portal vein {predicted fraction of human absorption} (Fa). Fraction is in percent.
Compounds can have good solubility in lipids {lipophilicity}.
Values {Fujita-Hansch pi value} can relate to lipophilicity.
Octanol/water partition coefficient logarithms {log P} can measure lipophilicity.
Hydrophobicity measures {molecular lipophilicity potential} (MLP) can calculate lipophilicity surface.
Lipophilic compounds can diffuse across lipid membrane {octanol-buffer partition coefficient theory}.
On brain-capillary endothelial-cell insides, proteins {P-glycoprotein} can prevent high-lipophilicity drugs from crossing BBB.
Drugs must get to sites {transport, drug} {drug transport}.
Diffusion carries molecules across membranes {passive transport}.
Drug breakdown by oxidation {drug metabolism} is mainly in liver.
Compounds can have an added group {adduct}.
Drug can inhibit or induce another drug {drug-drug interaction}.
Proteins {flavoprotein} can bind FAD or FMN.
Molecules {glutathione} (GSH) can participate in phase II conjugations.
Phase I oxidations, Phase II conjugations, and transport into bile reduce drug in hepatic blood {hepatic first-pass elimination} (HFPE).
Iron compounds {iron-oxene} {iron-oxenoid} can contain free oxygen atoms.
Drug metabolism makes products {metabolite}.
Nitrosoalkanes irreversibly bind to reduced heme intermediates of CYP450 enzymes {metabolite intermediate complexation}.
Compounds or forces can mutate genes {mutagenicity}.
Metabolism percentage {regioselectivity} categorizes sites as major, minor, or unobservable. Rate constant differences among sites cause metabolic-site regioselectivity.
Drugs can affect targets {selectivity, drug} and other sites.
Substrates {agonist} can bind to receptors and cause biologic response.
Substrates {antagonist, chemistry} can bind to receptor but cause no biologic response.
Hydrogen atoms can bind to carbon atoms {acetylation}.
Amino acids can bind to carboxylic-acid groups {amino acid conjugation}, on anti-inflammatory, hypolipidaemic, diuretic, and analgesic drugs.
Enzymes can change drugs to make them toxic {bioactivation}.
Drug metabolism has oxidations and reductions {biotransformation}.
Two charges can exchange {charge-transfer coupling} in reactions.
Molecules can attach small molecule {conjugation, molecule}.
Processes can make rings {cyclization}.
Glucuronic acid allows glucuronide formation {glucuronic acid conjugation}.
Molecules can conjugate with glutathione {glutathione conjugation} to form mercapturic acid.
Atoms {hydrogen bond acceptor} (HBA) can add hydrogen atom.
Atoms {hydrogen bond donor} (HBD) can release hydrogen atom.
Hydrogen atoms can abstract {hydrogen transfer}.
Hydrogen atoms can bind to oxygen atom {hydroxylation}.
Enzymes can change conformation to allow substrate binding {induced fit}.
Drugs can form complexes with receptors and then cause chemical or conformational changes {intrinsic activity, drug}.
Drug metabolism has oxidation or reduction {Phase I enzyme reaction}.
Drug metabolism has conjugation with small molecules {Phase II enzyme reaction}.
Hydrogen atoms removed from molecules {proton abstraction} can make water.
After ATP activates sulfate, sulfotransferase makes sulfate esters {sulfate conjugation}.
nucleophosphate energy compound {guanidine diphosphate} (GDP).
Energy molecules {uridine diphosphate} (UDP) can participate in phase II reactions.
Enzymes {adenylate cyclase} {adenylcyclase} can alter cAMP.
Enzymes {carboxylesterase} can catalyze phase I reactions.
Enzymes {cytochrome P-450} catalyze phase I reactions 3A4, 2D6, 2C9, 1A2, and 2E1.
Enzymes {epoxide hydratase} {epoxide hydrolase} can oxidize olefins and aromatics to make epoxide or oxirane metabolites. It can produce carcinogens.
Enzymes {glucuronyl-transferase} can catalyze phase II reactions, adding glucuronide to drugs.
Enzymes {glutathione-S-transferase}, in liver-cell cytoplasm, can catalyze phase II reactions to conjugate compounds to glutathione.
Enzymes {microsomal flavoprotein mono-oxygenase} can oxidize nitrogen or sulfur organics.
Enzymes {microsomal hydroxylase} can catabolize many compounds, mostly by oxidation, in endoplasmic reticulum.
Enzymes {mixed-function oxidase} (MFO) can catabolize many compounds, mostly by oxidation, in endoplasmic reticulum.
Enzymes {phospholipase A2} can catabolize lipids.
Enzymes {phospholipase C} can catabolize lipids.
Enzymes {protein kinase} can catabolize proteins.
Enzymes {uridine diphosphoglucose transferase} {uridine-diphosphate-glucuronosyl-transferase} (UDP-GT) (UGT) can catalyze phase II reactions, adding glucuronide to drugs.
Chemicals can inhibit drugs {drug inhibition}. Inhibitor has binding constant.
Inhibitor can bind to non-active site {allosteric non-competitive inhibition}.
Drugs {entry inhibitor} can prevent viruses from entering cells.
Drugs {integrase inhibitor} can prevent virus DNA from inserting into host DNA.
Drugs {maturation inhibitor} can block gag-protein protease receptor, so gag protein is not split, and HIV virus coat is not made. PA-457 comes from betulinic acid from Taiwan herb, plane trees, and birch trees.
Metabolized compounds can bind to enzymes {mechanism-based inhibition}.
Drugs {protease inhibitor} can inhibit protease enzymes.
Most-reactive electron {highest occupied molecular orbital} (HOMO) can be in electron-rich nucleophilic molecules.
Most-reactive electron {lowest unoccupied molecular orbital} (LUMO) can be in electron-poor electrophilic molecules.
Total metabolism has rate {absolute metabolism rate}.
Reaction rate typically depends on concentration and temperature {enzyme kinetics}.
Metabolism rate at site has estimated ease {lability}.
Enzymes have binding constants {Michaelis-Menten constant} (Km).
Sites {labile site} can have high metabolism rate and low activation energy.
Sites {moderate site} can have intermediate metabolism rate and activation energy.
Sites {stable site} can have low metabolism rate and high activation energy.
Active compounds have small clusters {asymmetric set} in compound space.
Automated assays {biological screening} can identify promising compounds from compound libraries.
Active compounds have small clusters {embedded set} in compound space.
Sample collections {inventory, sample} {sample inventory} can be ready for testing, stored in plate wells.
From many compounds, processes {lead finding} {lead generation} {lead selection} can identify compounds that have significant chemical activity.
Processes {lead optimization} can efficiently identify structure-activity relationships for generated leads.
Sample points {outlier} can be far from expected values.
Samples can go to further testing {promotion}.
Drug-receptor geometry {drug structure} is a physico-chemical property and can be quantitative.
structure-activity relationships
Drugs have structure-activity relationships (SAR), which can be quantitative (QSAR). Drugs have property-activity relationships.
activity
Drug activity equals physicochemical-variable function. Drug activity relates to concentration, partition coefficient, or product formation. Stages have probabilities. Drug activity is proportional to concentration product, complexing probability, changing probability, and partitioning probability.
activity: complex formation
Drugs form complexes with receptors {intrinsic activity, complex}. Drugs {chemotherapeutic drug} can cause chemical reactions or conformational changes. Drugs {pharmacodynamic drug, complexes} can make complexes but do not change conformation or cause reactions.
Complex-formation probability is formation-reaction equilibrium constant. Equilibrium constant depends on both equilibrium type and substituent electronic influence on reaction center. log(K) = k1 * sigma + k2 {linear free energy equation, structure} (LFE). log(1 / concentration) = k1 * sigma + k2. Electronic influences are universal and have tables of values. Equilibrium type results from multiple regression analysis of simultaneous equations.
activity: partitioning
If hydrophobicity affects drug structure, partition coefficient affects activity. log(K) = k3 * pi + k1 * sigma + k2 and log(1 / concentration) = k3 * pi + k1 * sigma + k2. Partition coefficients are universal and have tables of values.
activity: transport
Drugs have to get to target site. Drug transport involves diffusion, active transport, adsorption, binding to serum proteins, or membrane interactions. Mechanisms that oppose drug transport are excretion, metabolism, and localization in fat. Excretion is faster for hydrophilic. Metabolism is faster for hydrophobic. Localization in fat is faster for hydrophobic. Drug transport affects drug activity. log(K) = k3 * pi + k1 * sigma + k2 - k4 * pi^2. log(1 / concentration) = k3 * pi + k1 * sigma + k2 - k4 * pi^2. Drug transport factors are universal and have tables of values.
structure
Molecule structure depends on atom types, atom numbers, chemical bonds, spatial relations, and atom locations. Features are either present or absent, with no interactions.
structure: molecular connectivity indices
Kier and Hall used features such as electrotopologic state index, valence, molecular shape and flexibility {kappa index, structure}, branching, unsaturation, cyclization, and heteroatom position. They found molecular connectivity indices, based on Randic's branching index, calculated from hydrogen-suppressed chemical graph or skeleton structure. For example, atoms can have number of sigma electrons contributed {simple delta index, structure} or number of valence electrons {valence delta}.
structure: molecular orbital
Quantum-mechanical structure description uses molecular orbital (MO) theory. Molecular orbitals depend on electron location and energy. Total conformation energy gives probability. MO typically ignores solvents.
Highest occupied molecular orbital gives the most-reactive electron for electron-rich nucleophilic molecules. Lowest unoccupied molecular orbital gives the most-reactive electron for electron-poor electrophilic molecules.
MO can test reaction paths and find thermodynamic information, by checking energies in different configurations.
Molecular orbitals can be linear combinations of atomic orbitals (LCAO). Atomic-orbital contribution probability is linear-coefficient squared, and point charge is probability sum.
structure: interactions
Comparative Molecular Field Analysis (CoMFA) uses partial least-squares to analyze grid around site atom and find grid-point hydrophobic, electrostatic, and steric interactions.
structure: ab initio
Ab initio analysis uses electron locations to find charges, electrostatic potentials, dipole moments, ionization energies, electron affinity, and activation energies. Semiempiric analysis uses only valence electrons and parameterizes core electrons. Modified neglect of differential overlap (MNDO) ignores overlaps. Perturbative configuration interaction using localized orbitals (PCILO) uses perturbations. Varying bond angles, bond lengths, and torsion angles can find minimum energy and preferred conformation.
structure: axial-equatorial configuration
Non-conjugated-ring substituent positions can be in ring plane {equatorial configuration} or perpendicular {axial configuration}.
structure: branching
Carbon chain can have fork {branching}.
structure: ionization degree
Molecule can have charge {degree of ionization} {ionization degree}.
structure: dipole moment
Opposite charges can separate by distance.
structure: electrostatic potential
Electric potential energy comes from electric field.
structure: molecular similarity
Molecules can be similar in 3D atomic configuration, atom pairs, chemical graphs, electron densities, field potentials, molecular fragments, molecular properties, molecular surfaces, steric volumes, or topological/information theory indexes.
structure: orientation
Molecule spatial alignment is at receptor site.
structure: radical
Atoms can have one electron in outer orbital.
structure: singlet or triplet state
Orbital state can have paired electrons {singlet state}. Orbital state can have unpaired electrons {triplet state}.
Connection tables number non-hydrogen atoms, name atomic elements, name atom number to which they connect, and name atom types {Chemical Abstracts Service} (CAS).
Molecules can be vectors, including chemical activity, in abstract space {Chemical Descriptor Space} (CDS).
Base compounds {building block} can attach one to four small molecules {combinatorial chemistry} to add functional groups and make compound libraries with molecular weights 300 to 750.
Tables {connection table} can describe three-dimensional structures.
Matrices {connectivity matrix} can graph molecular connections.
Electrostatic fields make potentials {Coulombic potential}.
Polar solute can cross lipid membrane if hydrogen bonds to water break {desolvation}. Polar solute with fewer hydrogen bonds to water and lower hydrogen-bonding potentials can diffuse more easily.
Indexes {electrotopologic state index} can depend on topology structures.
Molecular markers {encoding tag} can track combinatorial-chemistry molecules.
Molecule atoms {hetero} can be not carbon C or hydrogen H. Hetero can refer to solvent, non-solvent, water, ion, or ligand atoms.
Compounds {heterocyclic compound} can have rings with atoms other than carbon.
Molecular regions can repel water {hydrophobicity}.
Cytochrome P450 has types {isoform}.
Combinatorial chemistry makes compound permutations {library of compounds}.
Tables {nearest neighbor table} can rank different compounds by similarity.
Superimposed molecules show constants across diverse molecules and so identify sites and reactions {pharmacophore}.
Molecules have atomic properties, functional groups, and molecular properties {similarity matrix}.
Oxygen can have positive charge {superoxide anion}.
Possible compound permutations can be in database {virtual compound library}.
Strings {Wiswesser line notation} (WLN) can uniquely describe three-dimensional structure.
X-ray crystallography patterns {X-ray structure} can indicate atom positions.
Methods {validation methods} can check structure-activity relationship correlations, predictions, and designs.
Validation methods {bootstrapping validation method} can use only internal data.
Methods {cross-validated correlation coefficient} can validate and predict data.
For all data subsets, algorithms {cross-validation} (CV) can remove one data subset and calculate remainder.
Other data can pair with model to predict activity {external validation}.
Validation methods {Fisher F-test} can use F test.
Validation methods {fitness function} (FIT) can measure fit.
cross-validation method {jackknife validation method, drug}.
Methods {lack-of-fit} (LOF) can measure fit.
cross-validation method {leave-groups-out, drug} (LGO).
cross-validation method {leave-one-out, drug} (LOO).
Methods {predictive residual sum of squares, drug} (PRESS) can measure fit.
cross-validation method {scrambling dependent Y-values, drug}.
Methods {standard deviation method, drug} (sPRESS) can measure fit.
Methods {standard error of predictions, drug} (SDEP) can measure fit.
Methods {standard error of regression, drug} can measure fit.
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Description of Outline of Knowledge Database
Date Modified: 2022.0225