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Fig 7.2 Mechanism of carbonic anhydrase • Action of carbonic anhydrase, a metalloenzyme • Zinc ion promotes the ionization of bound H2O. Resulting nucleophilic OHattacks carbon of CO2 (continued next slide) Prentice Hall c2002 Chapter 7 1 Fig. 7.2 (continued) Prentice Hall c2002 Chapter 7 2 Iron in metalloenzymes • Iron undergoes reversible oxidation and reduction: Fe3+ + e- (reduced substrate) Fe2+ + (oxidized substrate) • Enzyme heme groups and cytochromes contain iron • Nonheme iron exists in iron-sulfur clusters (iron is bound by sulfide ions and S- groups from cysteines) • Iron-sulfur clusters can accept only one e- in a reaction Prentice Hall c2002 Chapter 7 3 Fig 7.3 Iron-sulfur clusters • Iron atoms are complexed with an equal number of sulfide ions (S2-) and with thiolate groups of Cys side chains Prentice Hall c2002 Chapter 7 4 Reactions of ATP, a metabolite coenzyme • ATP is a versatile reactant that can donate its: (1) Phosphoryl group (g-phosphate) (2) Pyrophosphoryl group (g,b phosphates) (3) Adenylyl group (AMP) (4) Adenosyl group Prentice Hall c2002 Fig 7.4 Chapter 7 5 SAM synthesis • ATP is also a source of other metabolite coenzymes such as Sadenosylmethionine (SAM) • SAM donates methyl groups in many biosynthesis reactions Methionine + ATP S-Adenosylmethionine + Pi + PPi Fig 7.5 S-Adenosylmethionine • Activated methyl group in red Prentice Hall c2002 Chapter 7 6 S-Adenosylmethionine (SAM) is a methyl donor in many biosynthetic reactions • SAM donates the methyl group for the synthesis of the hormone epinephrine from norepinephrine Prentice Hall c2002 Chapter 7 7 Vitamin-Derived Coenzymes and Nutrition • Vitamins are required for coenzyme synthesis. Animals must obtain vitamins from diet. (Plants, microorganisms, meat) • Most vitamins are enzymatically transformed to the coenzyme Table 7.1 Vitamins, nutritional deficiency diseases Vitamin Ascorbate (C) Nicotinic acid Riboflavin (B2) Pantothenate (B3) Thiamine (B1) Pyridoxal (B6) Biotin Folate Prentice Hall c2002 Cobalamin (B12) Disease Scurvy Pellagra Growth retardation Dermatitis in chickens Beriberi Dermatitis in rats Dermatitis in humans Anemia Chapter 7 Pernicious anemia 8 Box 7.2 Vitamin C: a vitamin but not a coenzyme • A reducing reagent for hydroxylation of collagen • Deficiency leads to the disease scurvy • Most animals (not primates) can synthesize Vit C Prentice Hall c2002 Chapter 7 9 NAD+ and NADP+ • Nicotinic acid (niacin) is precursor of NAD+ and NADP+ • Lack of niacin causes the disease pellagra • Humans obtain niacin from cereals, meat, legumes Prentice Hall c2002 Chapter 7 10 Fig 7.8 Oxidized, reduced forms of NAD+ (NADP+) Prentice Hall c2002 Chapter 7 11 NAD+ and NADP+ are cosubstrates for dehydrogenases • Oxidation by NAD+ and NADP+ occurs two electrons at a time • Dehydrogenases transfer a hydride ion (H:-) from a substrate to pyridine ring C-4 of NAD+ or NADP+ • The net reaction is: NAD(P)+ + 2e- + 2H+ NAD(P)H + H+ Fig 7.9 Catalysis by lactate dehydrogenase Prentice Hall c2002 Chapter 7 12 FAD and FMN • Flavin adenine dinucleotide (FAD) and Flavin mono-nucleotide (FMN) are derived from riboflavin (Vitamin B2) • Flavin coenzymes are involved in oxidationreduction reactions for many enzymes (flavoenzymes or flavoproteins) • FAD and FMN catalyze one or two electron transfers Prentice Hall c2002 Chapter 7 13 Fig 7.11 Riboflavin and its coenzymes (a) Riboflavin, (b) FMN (black), FAD (black/blue) Prentice Hall c2002 Chapter 7 14 Fig 7.12 Reduction, reoxidation of FMN or FAD Prentice Hall c2002 Chapter 7 15 Coenzyme A (CoA or HS-CoA) • Derived from the vitamin pantothenate (Vit B3) • Participates in acyl-group transfer reactions with carboxylic acids and fatty acids • CoA-dependent reactions include oxidation of fuel molecules and biosynthesis of carboxylic acids and fatty acids • Acyl groups are covalently attached to the -SH of CoA to form thioesters Prentice Hall c2002 Chapter 7 16 Fig 7.13 (a) Coenzyme A Prentice Hall c2002 Chapter 7 17 Thiamine Pyrophosphate (TPP) • TPP is a derivative of thiamine (Vitamin B1) • TPP participates in reactions of: (1) Decarboxylation (2) Oxidative decarboxylation Fig 7.14 Thiamine (Vitamin B1) and TPP Prentice Hall c2002 Chapter 7 18 Pyridoxal Phosphate (PLP) • PLP is derived from Vit B6 family of vitamins • Vitamin B6 is phosphorylated to form PLP • PLP is a prosthetic group for enzymes catalyzing reactions involving amino acid metabolism (isomerizations, decarboxylations, side chain eliminations or replacements) Fig 7.16 B6 Vitamins and pyridoxal phosphate (PLP) Prentice Hall c2002 Chapter 7 19 Fig 7.18 Mechanism of transaminases Prentice Hall c2002 Chapter 7 20 Biotin (Why you shouldn’t eat raw eggs!) • Biotin is required in very small amounts because it is available from intestinal bacteria. Avidin (egg protein) binds biotin very tightly and may lead to a biotin deficiency (cooking eggs denatures avidin so it does not bind biotin) • Enzymes using biotin as a prosthetic group catalyze : (1) Carboxyl-group transfer reactions (2) ATP-dependent carboxylation reactions Prentice Hall c2002 Chapter 7 21 Fig 7.21 Pterin, folate and tetrahydrofolate (THF) Prentice Hall c2002 Chapter 7 22 Fig 7.24 Abbreviated structure of cobalamin coenzymes Prentice Hall c2002 Chapter 7 23 Fig 7.25 Intramolecular rearrangements catalyzed by adenosylcobalamin enzymes (a) Rearrangement of an H and substituent X on an adjacent carbon Prentice Hall c2002 Chapter 7 24 Fig 7.27 Formation of vitamin A from b-carotene Prentice Hall c2002 Chapter 7 25 Retinoic acid is a hormone that regulates gene expression in skin Prentice Hall c2002 Chapter 7 26 Vitamin D • A group of related lipids involved in control of Ca2+ utilization in humans • Fig 7.28 Vitamin D3 and 1,25-dihydroxycholecalciferol Prentice Hall c2002 Chapter 7 27 Vitamin D deficiency causes rickets Prentice Hall c2002 Chapter 7 28 Vitamin E (a-tocopherol) • A reducing reagent that scavenges oxygen and free radicals • May prevent damage to fatty acids in membranes Fig 7.29 Vitamin E (a-tocopherol) Prentice Hall c2002 Chapter 7 29 Fig 7.30 (a) Structure of vitamin K (b) Vit K-dependent carboxylation Prentice Hall c2002 Chapter 7 30 Warfarin is an anticoagulant Prentice Hall c2002 Chapter 7 31