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Chapter 7 - Coenzymes and Vitamins

Chapter 7 - Coenzymes and Vitamins. Some enzymes require cofactors for activity (1) Essential ions (mostly metal ions) (2) Coenzymes (organic compounds). Apoenzyme + Cofactor Holoenzyme (protein only) (active) (inactive) . Coenzymes.

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Chapter 7 - Coenzymes and Vitamins

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

  2. Coenzymes • Coenzymes act as group-transferreagents • Hydrogen, electrons, or other groups can be transferred • Larger mobile metabolic groups can be attached at the reactive center of the coenzyme • Coenzyme reactions can be organized by their types of substrates and mechanisms

  3. Types of cofactors

  4. Many Enzymes Require Inorganic Cations • Enzymes requiring metal ions for full activity: • (1) Metal-activated enzymes have an absolute requirement or are stimulated by metal ions (examples: K+, Ca2+, Mg2+) • (2) Metalloenzymescontain firmly bound metal ions at the enzyme active sites (examples: iron, zinc, copper, cobalt )

  5. Mechanism of carbonic anhydrase • Action of carbonic anhydrase, a metalloenzyme • Zinc ion promotes the ionization of bound H2O. Resulting nucleophilic OH- attacks carbon of CO2

  6. Iron in metalloenzymes • Iron undergoes reversible oxidation and reduction: • Fe3++ e- (reduced substrate) • Fe2+ + (oxidized substrate) • Enzyme hemegroups and cytochromes contain iron • Nonhemeiron 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

  7. Iron-sulfur clusters • Iron atoms are complexed with an equal number of sulfide ions (S2-) and with thiolate groups of Cys side chains

  8. Coenzyme Classification • There are two classes of coenzymes • (1) Cosubstrates are altered during the reaction and regenerated by another enzyme • (2) Prosthetic groups remain bound to the enzyme during the reaction, and may be covalently or tightly bound to enzyme

  9. Classification of coenzymes in mammals (1) Metabolite coenzymes - synthesized from common metabolites (2) Vitamin-derived coenzymes - derivatives of vitamins (vitamins cannot be synthesized by mammals, but must be obtained as nutrients)

  10. Metabolite Coenzymes • Nucleoside triphosphates are examples

  11. Reactions of ATP • 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

  12. Methionine + ATP S-Adenosylmethionine + Pi + PPi SAM synthesis ATP is also a source of other metabolite coenzymes such as S-adenosylmethionine (SAM) SAM donates methyl groups in many biosynthesis reactions

  13. S-Adenosylmethionine

  14. Vitamin-Derived Coenzymes and Nutrition • Vitamins are required for coenzyme synthesis and must be obtained from nutrients • Animals rely on plants and microorganisms for vitamin sources (meat supplies vitamins also) • Most vitamins must be enzymatically transformed to the coenzyme

  15. Vitamins, nutritional deficiency diseases Vitamin Disease Ascorbate (C) Scurvy Nicotinic acid Pellagra Riboflavin (B2) Growth retardation Pantothenate (B3) Dermatitis in chickens Thiamine (B1) Beriberi Pyridoxal (B6) Dermatitis in rats Biotin Dermatitis in humans Folate Anemia Cobalamin (B12) Pernicious anemia

  16. 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

  17. 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

  18. Oxidized, reduced forms of NAD+ (NADP+)

  19. NAD and NADP are cosubstrates for dehydrogenases • Oxidation by pyridine nucleotides always 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 netreaction is: • NAD(P)+ + 2e- + 2H+ NAD(P)H + H+

  20. Ordered mechanism for lactate dehydrogenase • Reaction of lactate dehydrogenase • NAD+ is bound first and NADH released last

  21. Mechanism of lactate dehydrogenase • Hydride ion (H:-) is transferred from C-2 of L-lactate to the C-4 of NAD+

  22. FAD and FMN(Riboflavin and its coenzymes)

  23. Reduction, reoxidation of FMN or FAD

  24. Coenzyme A (CoA or HS-CoA) • Derived from the vitamin pantothenate (Vit B3) • Participates in acyl-grouptransferreactions 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 covalentlyattached to the -SH of CoA to form thioesters

  25. Coenzyme A

  26. Acyl carrier protein

  27. Thiamine Pyrophosphate (TPP) • TPP is a derivative of thiamine (Vit B1) • Reactive center is the thiazolium ring (with a very acidic hydrogen atom at C-2 position) • TPP participates in reactions of: (1) Decarboxylation(2) Oxidative decarboxylation(3) Transketolase enzyme reactions

  28. Thiamine (Vitamin B1) and TPP

  29. Mechanism of pyruvate dehydrogenase

  30. Pyridoxal Phosphate (PLP) • PLP is derived from Vit B6 family of vitamins (deficiencies lead to dermatitis and disorders of protein metabolism) • Vitamin B6 is phosphorylated to form PLP • PLP is a prosthetic group for enzymes catalyzing reactions involving aminoacidmetabolism (isomerizations, decarboxylations, side chain eliminations or replacements)

  31. B6 Vitamins andPyridoxal Phosphate (PLP)

  32. Mechanism of transaminases

  33. Binding of substrate to a PLP-dependent enzyme

  34. Isomerization

  35. Isomerization

  36. Isomerization

  37. Biotin • Biotin is required in very small amounts because it is 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

  38. Enzyme-bound biotin • 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 (red)

  39. Reaction catalyzed by pyruvate carboxylase Two step mechanism Step 1: Formation of carboxybiotin-enzyme complex (requires ATP) Step 2: Enolate form of pyruvate attacks the carboxyl group of carboxybiotin forming oxaloacetate and regenerating biotin

  40. Tetrahydrofolate (THF) • Vitamin folate is found in green leaves, liver, yeast • The coenzyme THF is a folate derivative where positions 5,6,7,8 of the pterin ring are reduced • THF contains 5-6 glutamate residues which facilitate binding of the coenzyme to enzymes • THF participates in transfers of onecarbonunits at the oxidation levels of methanol (CH3OH), formaldehyde (HCHO), formic acid (HCOOH)

  41. Pterin, folate and tetrahydrofolate (THF)

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