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Chapter 7 Coenzymes and Vitamins

Chapter 7 Coenzymes and Vitamins. Coenzyme, p 192-193. Cofactors: nonprotein components Cofactors may be metal ions or organic molecules ( coenzyme ) Cofactor: metal ion + coenzyme Prosthetic groups : tightly bound coenzymes. Holoenzyme and Apoenzyme. Holoenzyme

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Chapter 7 Coenzymes and Vitamins

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  1. Chapter 7 Coenzymes and Vitamins Chapter 7

  2. Coenzyme, p192-193 • Cofactors: nonprotein components • Cofactors may be metal ions or organic molecules (coenzyme) • Cofactor: metal ion + coenzyme • Prosthetic groups: tightly bound coenzymes Chapter 7

  3. Holoenzyme and Apoenzyme • Holoenzyme • Complex of protein and prosthetic groups • Catalytically active • Apoenzyme • The enzyme without the prosthetic groups • Catalytically inactive Chapter 7

  4. Some enzymes requirecofactors for activity • (1) Essential ions (mostly metal ions) • (2) Coenzymes (organic compounds) Apoenzyme + CofactorHoloenzyme (protein only) (active) (inactive) Chapter 7

  5. Coenzymes, p192-193 • Group-transfer reagents • Transfer hydrogen, electrons, or other groups • Reactive center of the coenzyme Fig 7.1 Types of cofactors, p192 Chapter 7

  6. 7.1Many Enzymes Require Inorganic Cations, p193 • Enzymes requiring metal ions for full activity: • (1) Metal-activated enzymes • (2) Metalloenzymes Chapter 7

  7. Fig 7.2 Mechanism of carbonic anhydrase, p193 • A metalloenzyme • Zinc ion promotes the ionization of bound H2O. Resulting nucleophilic OH- attacks carbon of CO2 Chapter 7

  8. Iron in metalloenzymes, p193 • Fe3++ e- (reduced substrate)  • Fe2+ + (oxidized substrate) • Heme groups, heme protein • Cytochromes contain iron • Nonheme iron: iron-sulfur clusters • Iron-sulfur clusters can accept only one e- in a reaction Chapter 7

  9. 7.2Coenzyme Classification, p193-194 • (1) Cosubstrates • Prosthetic groups • - Vitamin-derived coenzymes Chapter 7

  10. 7.3 ATP and other nucleotidecosubstrate, p196 • Nucleoside triphosphates act as cosubstrate • Fig 7.4 ATP • Donate • (1) Phosphoryl group (g-phosphate) • (2) Pyrophosphoryl group (g, b-phosphates) • (3) Adenylyl group (AMP) • (4) Adenosyl group Chapter 7

  11. S-adenosylmethionine synthesis, p196 • ATP is also a source of other metabolite coenzymes such as S-adenosylmethionine • Equation 7.1 • S-adenosylmethioninedonates methyl groups in many biosynthesis reactions • Synthesis of the hormone epinephrine from norepinephrine • Equation 7.2 Chapter 7

  12. Nucleotide-sugar coenzymes are involved in carbohydrate metabolism • UDP-Glucose is a sugar coenzyme • Fig 7.6, p197 Chapter 7

  13. Vitamin-Derived Coenzymes and Nutrition, p194 • Animals rely on plants and microorganisms for vitamin sources (meat supplies vitamins also) • Most vitamins must be enzymatically transformed to the coenzyme • Table 7.1 Vitamins, nutritional deficiency diseases, p194 Chapter 7

  14. Box 7.1 Vitamin C: a vitamin but not a coenzyme, p195 • A reducing reagent for hydroxylation of collagen • Deficiency leads to the disease scurvy • Most animals (not primates) can synthesize Vit C • Anti-oxidant Chapter 7

  15. 7.4NAD+ and NADP+, p197 • Vitamin: Nicotinic acid (niacin) • Coenzyme:NAD+ and NADP+ • Lack of niacin causes the disease pellagra • Humans obtain niacin from cereals, meat, legumes • Fig 7.8 • Dehydrogenases transfer a hydride ion (H:-, one proton and two electrons) from a substrate to pyridine ring C-4 of NAD+ or NADP+ • The net reaction is: • NAD(P)+ + 2e- + 2H+  NAD(P)H + H+ Chapter 7

  16. Reaction of lactate dehydrogenase Equation 7.3 Fig 7.9 Mechanism of lactate dehydrogenase, p200 Chapter 7

  17. 7.5 FAD and FMN, p200-201 • Flavin adenine dinucleotide (FAD) • Flavin mono-nucleotide (FMN) • Derived from riboflavin (Vit B2) • In oxidation-reduction reactions • One or two electron transfers • Fig 7.10, Fig 7.11 Chapter 7

  18. Chapter 7

  19. 7.6Coenzyme A (CoA or HS-CoA)p201-202 • Derived from the vitamin pantothenate (Vit B3) • Acyl-group transfer reactions • Acyl groups are covalently attached to the -SH of CoA to form thioesters • Fig 7.12, Fig. 7.13 Chapter 7

  20. 7.7Thiamine Pyrophosphate (TPP)p202-203 • TPP is a derivative of thiamine (Vit B1) • Reactive center:thiazolium ring • Fig 7.14 • TPP participates in reactions of: (1)Decarboxylation(2) Oxidative decarboxylation of -keto acids(3) Transketolase enzyme reactions Chapter 7

  21. Yeast pyruvate decarboxylase, p203 • Pyruvate  acetaldehyde  acetyl CoA TPP Fig 7.15 Chapter 7

  22. 7.8Pyridoxal Phosphate (PLP), p203-206 • Derived from Vit B6 • Vitamin B6 (Pyridoxine) is phosphorylated to form PLP • Involving amino acid metabolism (isomerizations, decarboxylations, side chain eliminations or replacements) • The reactive center is the aldehyde group • Fig 7.16, Fig 7.17 • Fig 7.18 TPP in transaminase action Chapter 7

  23. 7.9 Biotin, p207 • Available from intestinal bacteria • Avidin (raw egg protein) binds biotin very tightly and may lead to a biotin deficiency (cooking eggs denatures avidin so it does not bind biotin) • Biotin (a prosthetic group) enzymes catalyze: • (1) Carboxyl-group transfer reactions • (2) ATP-dependent carboxylation reactions Chapter 7

  24. Fig 7.19 Enzyme-bound biotin, p207 • Biotin is linked by an amide bond to the e-amino group of a lysine residue of the enzyme • The reactive center of biotin is the N-1 • Fig 7.20 Reaction catalyzed by pyruvate carboxylase, p207 Chapter 7

  25. 7.10 Tetrahydrofolate (THF)p208, Fig 7.21, 7.22 • From vitamin folate: in green leaves, liver, yeast • The coenzyme THF is a folate derivative where positions 5,6,7,8 of the pterin ring are reduced (Equation 7.4). • THF contains 5-6 glutamate residues which facilitate binding of the coenzyme to enzymes • Transfers of one carbon units at the oxidation levels of methanol (CH3OH), formaldehyde (HCHO), formic acid (HCOOH) Chapter 7

  26. 1-7 1-7 Chapter 7

  27. Fig. 7.23 5,6,7,8, Tetrahydrobiopterin, a pterin coenzyme, p210 • Coenzyme has a 3-carbon side chain at C-6 • Not vitamin-derived, but synthesized by some organisms Chapter 7

  28. 7.11 Cobalamin (Vitamin B12), p210-211 • Coenzymes: methylcobalamin, adenosylcobalamin • Cobalamin contains a corrin ring system and a cobalt (it is synthesized by only a few microorganisms) • Humans obtain cobalamin from foods of animal origin (deficiency leads to pernicious anemia) • Coenzymes participate in enzyme-catalyzed molecular rearrangements • Fig. 7.24 • Fig 7.25 Intramolecular rearrangements catalyzed by adenosylcobalamin enzymes, p211 Chapter 7

  29. Methylcobalamin participates in the transfer of methyl groups, p211 • Equation 7.5 Chapter 7

  30. 7.12 Lipoamide, p212 • From lipoic acid • Coenzyme: lipoamide • Animals can synthesize lipoic acid, it is not a vitamin • Lipoic acid is an 8-carbon carboxylic acid with sulfhydryl groups on C-6 and C-8 • Lipoamide functions as a “swinging arm” that carries acyl groups between active sites in multienzyme complexes Chapter 7

  31. Fig 7.26 Lipoamide, p212 • Lipoic acid is bound via an amide linkage to the e-amino group of an enzyme lysine • Transfer of an acyl group between active sites • - Equation 7.6 Chapter 7

  32. Pyruvate dehydrogenase complexp385-386 • Equation 13.1 • Conversion of pyruvate to acetyl CoA • Pyruvate dehydrogenase complex (PDH complex) is a multienzyme complex containing: • 3 enzymes + 5 coenzymes + other proteins (+ ATP coenzyme as a regulator) • E1 = pyruvate dehydrogenase • E2 = dihydrolipoamide acetyltransferase • E3 = dihydrolipoamide dehydrogenase Chapter 7

  33. Fig 13.1 Reactions of the PDH complex, p388 Chapter 7

  34. 7.13 Lipid Vitamins- p212-213 • VitaminA, D, E, K • All contain rings and long, aliphatic side chains • Highly hydrophobic Chapter 7

  35. A. Vitamin A (Retinol), p213 • Vit A exists in 3 forms: alcohol (retinol), aldehyde and retinoic acid • Retinol and retinoic acid are signal compounds • Rentinal (aldehyde) is a light-sensitive compound with a role in vision • Fig 7.27 Chapter 7

  36. Chapter 7

  37. B. Vitamin D, p213, Fig 7.28 • Control of Ca2+ utilization in humans • Regulates intestinal absorption of calcium and its deposition in bones. • Active form: 1, 25-hydroxyvitamin D3 • Under the sunlight, vitamin D3 (cholecalciferol) is formed nonenzymatically in the skin from the steroid 7-dehydrocholesterol. • Vitamin D deficiency • Ricket in children, osteomalacia in adults • 軟骨病骨質軟化症 Chapter 7

  38. Vitamin D, p213 • Absorbed in the intestine or photosynthesized in the skin, cholecalciferol is transported to the liver by vitamin D-binding protein (DBP, or transcalciferin). • In the liver, cholecalciferol is 25-hydroxylated by mixed-function oxidase to form 25-hydroxyvitamin D3 Chapter 7

  39. Vitamin D, p213 • 25-hydroxyvitamin D is the mayor circulating form of vitamin D in the body, but the biological activity is far less than the final active form, 1, 25-hydroxyvitamin D3 • In the kidney, a mitochondrial mixed-function oxidase hydroxylates 25-hydroxyvitamin D to 1, 25-hydroxyvitamin D3 (Active form) Chapter 7

  40. C. Vitamin E (a-tocopherol), p213 • A reducingreagent that scavenges oxygen and free radicals • May prevent damage to fatty acids in membranes • Fig 7.29 Chapter 7

  41. Vitamin K (phylloquinone), p214Fig 7.29 • Required for synthesis of blood coagulation proteins • A coenzyme for mammalian carboxylases that convert glutamate to g-carboxyglutamate • Equation 7.7 Vit K-dependent carboxylation, p214 • Calcium binds to the g-carboxyGlu residues of these coagulation proteins which adhere to platelet surfaces • Vitamin K analogs (used as competitive inhibitors to prevent regeneration of dihydrovitamin K) are given to individuals who suffer excessive blood clotting Chapter 7

  42. Chapter 7

  43. 7.14 Ubiquinone (Coenzyme Q), p214 • Electrons transfer • Plastoquinone (ubiquinone analog) functions in photosynthetic electron transport • Hydrophobic tail:repeat of five-carbon isoprenoid units • Fig 7.30, p215 • Fig 7.31, p215 Chapter 7

  44. 7.15 Protein Coenzymes , p215 • Protein coenzymes (group-transfer proteins) • Participate in:(1) Group-transfer reactions (2) Oxidation-reduction reactions: transfer a hydrogen or an electron • Metal ions, iron-sulfur clusters and heme groups are commonly found in these proteins • Fig 7.32 Thioredoxin, p216 Chapter 7

  45. 7.16 Cytochromes, p216 • Heme-containing coenzymes • Fe(III) undergoes reversible one-electron reduction • Cytochromes a,b and c have different visible absorption spectra and heme prosthetic groups • Electron transfer potential varies among different cytochromes due to the different protein environment of each prosthetic group • Fig 7.33 Heme group of cyt a,b, and cp217 • Fig 7.34 Absorption spectra of oxidizedand reduced cytochrome c, p218 Chapter 7

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