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Chapter 8. Vitamins and Enzyme Cofactors

Chapter 8. Vitamins and Enzyme Cofactors. Introduction Fat-soluble vitamins ( 脂溶性维生素) Water-soluble vitamins and coenzymes ( 水溶性维生素和辅酶) Metal ions as cofactors ( 作为辅酶的金属离子). I. Introduction.

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Chapter 8. Vitamins and Enzyme Cofactors

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  1. Chapter 8. Vitamins and Enzyme Cofactors • Introduction • Fat-soluble vitamins (脂溶性维生素) • Water-soluble vitamins and coenzymes (水溶性维生素和辅酶) • Metal ions as cofactors (作为辅酶的金属离子)

  2. I. Introduction • Vitamins are compounds that are essential to the health of humans and other vertebrates but cannot be synthesized by these animals and must therefore be obtained in the diet (生物体发育所需但自身不能合成，需从食物中摄取). • Requirements (需要量): g-mg per day

  3. Vitamin deficiencies and sources

  4. History 1919 – Vitamin A 1922 – Vitamin D 1923 – Vitamin E 1926 – Thiamin (硫胺素，维生素B1) 1926 – Riboflavin (核黄素，维生素B2) 1928 – Bacterial synthesis of B vitamins 1928 – Vitamin C 1929 – Vitamin K 1930 – Pantothenic Acid (泛酸，维生素B5) 1932 – Choline 1934 – Vitamin B6 1935 – Niacin (烟酸，维生素B3) 1936 – Biotin (生物素，维生素H) 1943 – Folacin (叶酸) 1948 – Vitamin B12

  5. Nobel Laureates and Their Work with Vitamins Nobel Prize in Physiology or Medicine

  6. Nobel Prize in Chemistry

  7. Classification and functions of vitamins Vitamin B1 – Thiamin (硫氨素) Vitamin B2 – Riboflavin (核黄素) Vitamin B3 – Niacin (烟酸) Vitamin B5 – Pantothenic acid (泛酸) Vitamin B6 – Pyridoxine (吡哆醛) Vitamin B9 – Folic acid (叶酸) Vitamin B12 – Cobalamin (钴胺素)

  8. II. Fat-soluble vitamins Hormone precursors • Vitamin A • Vitamin D • Vitamin E • Vitamin K

  9. P.434 1. Vitamin A • Uptake of Vitamin A: can be absorbed in the diet from animal sources or synthesized from -carotene from plant sources. • Structure of vitamin A (维生素A的结构) • Precursor and derivatives of vitamin A (维生素A的前体和衍生物) • Basis of visual transduction (视觉转换) • Vitamin A deficiency (维生素A缺乏) • Dryness of skin, eyes, mucous membranes • Retarded development and growth • Night blindness (夜盲症), the early symptom used in diagnosing vitamin A deficiency. II. Fat-soluble vitamins

  10. Structure of vitamin A:isoprene derivatives 1 6 2 Vitamin A1 3 5 4 II. Fat-soluble vitamins Present in livers of mammals and sea fish Vitamin A2 Present in livers of freshwater fish Both types of vitamin have the similar physiological functions, but A2 shows only half of the activity as compared to A1.

  11. Vitamin A: Precursor and derivatives -Carotene (-胡萝卜素) Retinol (视黄醇) Vitamin A1 [O] Retinal (视黄醛) Opsin Rhodopsin (视紫质) (视蛋白) A pigment to initiate the response of retina cells to light [O] Retinoic acid (视黄酸) Signal to epithelial cells (上皮组织) A hormone that regulates gene expression in skin

  12. P.437 2. Vitamin D Two members of the vitamin D family: 7-脱氢胆甾醇 19 20 Prohormone Vitamin D3 D3: Prohormone (Hormone precursor) -- Biologically inactive Hormone A hormone regulating Ca & P homeostasis -- Active form of vitamin D 1,25-二羟维生素D3

  13. Vitamin D deficiency  rickets/osteomalacia (佝偻病/骨软化) Excess intake of vitamin D  hypervitaminosis (维生素过多症)

  14. P.438 3. Vitamin E • Vitamin E = a group of 8 tocopherols (生育酚) • Vitamin E is a most important natural antioxidant (天然抗氧化剂) -- Vitamin E provides the 1st line of defence against peroxidation (过氧化) of polyunsaturated fatty acids contained in cellular membranes. • Vitamin E and selenium act synergistically (与硒协同抗氧化). -- GSH peroxidase (谷胱苷肽过氧化物酶) provides the 2nd line of defence against peroxidation. • Deficiency of vitamin E may give rise to anemia (贫血) of the newborn. • Vitamin E may help prevent or delay coronary heart disease. -Tocopherol The most active form

  15. 4. Vitamin K • Vitamin K is a blood-clotting cofactor (凝血维生素) • Vitamin K is required for biosynthesis of blood clotting factors. • Hemorrhagic disease of the newborn (新生儿的出血病) is caused by vitamin K deficiency. II. Fat-soluble vitamins

  16. III. Water-soluble vitamins • Vitamin B1: Thiamine and thiamine pyrophosphate • Vitamins related to adenine nucleotides • Nicotinic acid and the nicotinamide coenzymes (NAD+/NADH, NADP+/NADPH) • Riboflavin (Vitamin B2) and the flavin coenzymes (FAD/FADH2, FMN/FMNH2) • Pantothenic acid and coenzyme A • Vitamin B6 and pyridoxal phosphate • Vitamin B12: Cyanocobalamin • Vitamin C: Ascorbic acid • Biotin • Lipoic acid • Folic acid

  17. Typical water-soluble vitamins and coenzymes

  18. Vitamins related to adenine nucleotides(与腺嘌呤核苷酸有关的维生素)

  19. III. Water-soluble vitamins 烟酰胺腺嘌呤二核苷酸 黄素腺嘌呤二核苷酸

  20. P.443 1). Vitamin PP and Nicotinamide coenzymes(维生素PP和烟酰胺辅酶) Vitamin PP NAD(P)+ Nicotinamide Adenine Dinucleotide Nicotinic acid (烟酸) Trp Nicotinamide (烟酰胺) (Vitamin B3)

  21. NAD+ – Nicotinamide adenine dinucleotide – coenzyme I – 辅酶I(烟酰胺腺嘌呤二核苷酸) NADP+ – Nicotinamide adenine dinucleotide phosphate – coenzyme II –辅酶II(烟酰胺腺嘌呤二核苷酸磷酸) • Coenzymes to many dehydrogenases catalyzing oxidoreduction reactions (作为脱氢酶的辅酶催化氧化还原反应) • NAD – oxidative pathways (e.g. citric acid cycle) • NADP – Reductive pathways (e.g. pentose phosphate pathway) • Key components of many metabolic pathways (是许多代谢途径的关键组分) e.g. carbohydrate, lipid amino acid metabolism • Lack of niacin causes the deficiency syndrome pellagra (糙皮病, 即烟酸缺乏症) III. Water-soluble vitamins

  22. III. Water-soluble vitamins Reduced (还原态) Oxidized (氧化态) AH2 + NAD(P)+ A + NAD(P)H + H+ Reduced Oxidized

  23. Nicotinamide coenzymes as electron carriers(烟酰胺辅酶充当电子载体) Oxidized form (氧化型) Reduced form (还原型) III. Water-soluble vitamins Oxidative (氧化途径) Catabolic (分解途径) NAD+ NADP+ NADH NADPH H+ + + 2e- + 2H+ Reductive ( 还原途径) Biosynthetic (合成途径) Electron acceptor (电子受体) Electron donor (电子供体) 2 H = 2 H+ + 2 e = H: + H+

  24. Pro-R Pro-S 2 H = 2 H+ + 2 e = H: + H+ The “+” sign in NAD(P)+ the charge on the N atom The “H” in NAD(P)H  the H: that is added

  25. Loose association between a dehydrogenase and its nicotinamide coenzymes(脱氢酶和烟酰胺辅酶之间的松散结合) Example: in the production of alcohol during fermentation of glucose by yeast cells, • Glyceraldehyde 3-phosphate + NAD+ 3-phosphoglycerate + NADH + H+ • Acetaldehyde + NADH + H+  ethanol + NAD+ Sum: Glyceraldehyde 3-phosphate + acetaldehyde  3-phosphoglycerate + ethanol • Glyceraldehyde 3-phosphate dehydrogenase (3-磷酸甘油醛脱氢酶), type B • Alcohol dehydrogenase (乙醇脱氢酶), type A There is no net change in the concentration of NAD+ + NADH.

  26. 2). Vitamin B2 and Flavin coenzymes(维生素B2和黄素辅酶) P.445 异咯嗪 Riboflavin, or vitamin B2 (核黄素，维生素B2) FMN Lack of riboflavin causes angular stomatitis, cheilosis, glossitis, seborrhea, photophobia, etc. FAD Flavin coenzymes FMN (Flavin mononucleotide, 黄素单核苷酸) FAD (Flavin adenine dinucleotide,黄素腺嘌呤二核苷酸) Adenine (腺嘌呤)

  27. How does a flavin coenzyme work? 异咯嗪 riboflavin H = H+ + e Flavoproteins/flavoenzymes (黄素蛋白) are enzymes that catalyze oxidation-reduction reactions using either FMN or FAD as coenzyme.

  28. P.446 Redox states of FAD and FMN(FAD和FMN的氧化还原态) +H+, e- +H+, e- FADH FMNH FADH2 FMNH2 FAD FMN Oxidized form (氧化态) max = 450 nm (yellow) Semiquinone form max = 570 nm – blue (at neutral pH) max = 490 nm – red (at higher pH) pKa = 8.4 Reduced form (还原态) (colorless) • Flavin coenzymes: • Are tightly bound to the enzyme • Exist in any of three different redox states • Change color according to the switch of the redox states • Participate in one-electron and two-electron transfer reactions • Work with different electron acceptors and donors (e.g. NAD)

  29. III. Water-soluble vitamins

  30. P.447 3). Pantothenic acid and coenzyme A(泛酸和辅酶A) III. Water-soluble vitamins Reactive –SH group 泛酸 Vitamin B5 -巯基乙胺 Pantothenic acid (vitamin B5) is essential for metabolism of fat, protein and carbohydrates in the citric acid cycle and other pathways.

  31. The two major functions of CoA Activation of acyl groups for transfer by nucleophilic attack (活化酰基) III. Water-soluble vitamins Activation of the -H of the acyl group for abstraction as a proton (活化酰基上的-H )

  32. P.461 Vitamin C: L-ascorbic acid (抗坏血酸) • The only water-soluble vitamin that is unrelated to coenzymes (与辅酶无关) • Simplest chemical structure of all the vitamins (结构最简单) • Physiological functions only presented by the L-form • Widely distributed in animals and plants, but humans are unable to synthesize it. • Acidity (酸性) • Strong reducing agent (强还原剂) – a powerful antioxidant acting like a cop in the body • Medical use: A panacea (万能药)? • Treatment and prevention of scurvy (坏血病) • Brain and nervous system • Mobilizing iron in the body • Preventing anemia (防止贫血) • Ameliorating allergic responses (改善变态反应) • Stimulating immune system (刺激免疫系统)

  33. III. Water-soluble vitamins 1 5 4 2 3

  34. P.450 Vitamin B12: Cobalamin (钴胺素) • Vitamin B12 = cobalamin (钴胺素) • Two active coenzyme forms • 5’-Deoxyadenosylcobalamin (5’-脱氧腺苷钴胺素) • Methylcobalamin (甲基钴胺素) • Major functions: • Preventing pernicious anemia (恶性贫血) • Forming red blood cells • Developing nerve cells • Uniqueness of vitamin B12: • The last to be discovered: 1948 • 4 Nobel prizes awarded: 1934, 1957, 1964, 1965 • Containing a metal (Co) • Lowest nutritional requirement: 3 g/day • Sources: produced by only a few microorganisms • Dependent on an intrinsic factor -- a stomach-made glycoprotein required for the absorption of B12 III. Water-soluble vitamins

  35. 5’-deoxyadenosylcobalamin (5’-脱氧腺苷钴胺素) -CH3: methylcobalamin (甲基钴胺素) -CN: cyanocobalamin (氰钴胺素) -OH: hydroxocobalamin (羟基钴胺素)

  36. Nobel Laureates and Their Work with Vitamin B12

  37. Reactions with B12 coenzymes involved • Intramolecular rearrangements (分子内重排) • Reductions of ribonucleotides to deoxyribonucleotides (in certain bacteria) (核苷酸还原成脱氧核苷酸) • Methyl group transfers (甲基转移) III. Water-soluble vitamins Methylcobalamin is a cofactor for methionine synthase involved in the conversion of the amino acid homocysteine into methionine.

  38. P.464 IV. Metal Ions as Cofactors • About 1/3 of enzymes require metal ions for catalytic activity(近1/3的酶需要金属离子) • Enzymes containing different metal ions: • Fe – e.g. cytochrome oxidase (细胞色素氧化酶) • Cu – e.g. ascorbic acid oxidase (抗坏血酸氧化酶) • Zn – e.g. carboxypeptidase (羧肽酶) • Ni – e.g. urease (尿酶) • Mo – e.g. nitrogenase (固氮酶) • Se – e.g. glutathion peroxidase (谷胱苷肽过氧化物酶) • Mn, V, etc. • These enzymes can be divided into two groups: • Metalloenzymes (金属酶) – Tightly bound e.g. tyrosinase (酪氨酸酶) • Metal-activated enzymes (金属激活酶) – Loosely bound e.g. carboxypeptidase A (羧肽酶A)

  39. The functions of metal ions • Orienting the substrate for reaction (帮助底物分子定位) • Stabilizing the charged reaction transition states (稳定带电荷的反应过渡态) • Mediating oxidation-reduction reactions by reversible changes in the metal ion’s oxidation state (通过氧化态的可逆变化来参与氧化还原反应) Carboxypeptidase A Thermolysin from Bacillus cereus Ca – for structural stability Zn Zn – for enzyme activity Loss of Zn  loss of activity Can be replaced by divalent metal ions (Zn2+, Co2+, Ni2+)

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