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Chapter 10 Glycolysis

Chapter 10 Glycolysis. 2010.11.02. An overview on D-glucose metabolism. 是大多数生命有机体的能量来源 , 如果完全氧化成 CO 2 和 H 2 O,  G ‘ o 为 2840 kJ/mole. 在氧化过程中能产生 NADPH, 以及 ribose-5-P. 能以多聚体的形成存在或转变成脂肪 , 作为能量的长期贮存 . 是所有生物大分子碳骨架的前体 . 葡萄糖的代谢产物参与了各种各样的化学反应. 生物化学的创建来源于糖酵解的发现.

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Chapter 10 Glycolysis

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  1. Chapter 10 Glycolysis 2010.11.02

  2. An overview on D-glucose metabolism • 是大多数生命有机体的能量来源,如果完全氧化成CO2和H2O, G‘o为2840 kJ/mole. • 在氧化过程中能产生NADPH,以及ribose-5-P. • 能以多聚体的形成存在或转变成脂肪,作为能量的长期贮存. • 是所有生物大分子碳骨架的前体. • 葡萄糖的代谢产物参与了各种各样的化学反应.

  3. 生物化学的创建来源于糖酵解的发现 • 1897, Buchner 偶然发现酵母的细胞提取液能将蔗糖迅速的发酵成为酒精 • 1900s, Harden &Young 发现: 磷酸是酵母提取液发酵葡萄糖所必需的; 在发酵过程中生成了一种六碳糖的二磷酸物质;酵母提取液能分成两个组分,一个组分是热不稳定的、不可透析的酵素（zymase），另一个组分是热稳定的、可以透析的辅酵素（cozymase）

  4. 1910s-1930s, Embden 和 Meyerhof 研究了在肌肉中和肌肉提取液里糖代谢： • 在体外重建了糖原转变成乳酸的所有反应步骤，并发现肌肉和酵母的发酵过程极其的相似 • 在氧气存在的条件下，乳酸能转变成糖类（糖异生），且在此过程中产生的一些磷酸化合物“高能”物质。

  5. 什么是糖酵解？ 在无氧条件下，葡萄糖降解产生丙酮酸的过程 什么是发酵？ 在无氧条件下，葡萄糖通过糖酵解途径最终产生酒精的过程

  6. An overview on Glycolysis • 10步反应 • 两个阶段，每个阶段5步反应 六碳糖 三碳糖，消耗2分子ATP 三碳糖 丙酮酸，产生4分子ATP • 每个反应步骤都是由一个酶催化的

  7. Reaction 1 第一个磷酸化 (己糖激酶)

  8. 葡萄糖磷酸化的意义： • 使葡萄糖带负电荷，避免葡萄糖通过扩散作用从细胞质中穿过细胞膜而渗出 • 使细胞内的葡萄糖浓度降低，保证了细胞内外葡萄糖的浓度差，有利于胞外的葡萄糖扩散进细胞内

  9. 己糖激酶和葡萄糖、Mg2+-ATP形成复合体，使ATP上的磷酸基团和C6靠近己糖激酶和葡萄糖、Mg2+-ATP形成复合体，使ATP上的磷酸基团和C6靠近 激酶(kinase)：催化ATP上的g-磷酸基团转移到其他亲核受体上的酶 同工酶(isozyme)：催化同一化学反应的酶；它们在动力学或调节机制上、辅酶的选择上以及细胞分布上都可能不同。同工酶往往具有相似的的氨基酸序列，并且具有共同的进化起源。

  10. Reaction 2 醛酮异构 (磷酸葡萄糖异构酶) ketose aldose (醛糖) (酮糖)

  11. Reaction 3 第二个磷酸化 (磷酸果糖激酶-1) PFK-1 限速步骤

  12. Reaction 4 六碳糖的裂解 （醛缩反应的逆反应） 4 1 5 2 6 3 (醛缩酶) (二羟丙酮磷酸) DHAP (甘油醛-3-磷酸) GAP

  13. Reaction 5 三碳糖的异构 3,4 2,5 1,6 (丙糖磷酸异构酶) TIM

  14. Reaction 6 第一个高能中间产物的产生 酰基磷酸 (甘油醛-3-磷酸脱氢酶) GAPDH (1,3-二磷酸甘油酸) 1,3-BPG

  15. GAPDH的催化机制 thioester

  16. 抑制GAPDH的作用导致磷酸六碳糖的堆积 羧甲基 (碘丙酮)

  17. Reaction 7 第一个底物水平的磷酸化 (磷酸甘油酸激酶) PGK 3-GP

  18. 底物水平的磷酸化（substrate-level phosphorylation）：高能磷酸化合物将磷酸基团转移给ADP形成ATP的反应过程

  19. Reaction 8 磷酸基团在分子内的位移 (磷酸甘油酸变位酶)

  20. Reaction 9 脱水 第二个高能中间产物的产生 (烯醇化酶) (磷酸烯醇式丙酮酸) PEP 1.8 The transfer potential of the phosphoryl group is dramatically increased via the dehydration reaction ( G`0 changed from –17.6 to –61.9 kJ/mol)

  21. Reaction 10 第二个底物水平的磷酸化 （丙酮酸激酶）

  22. The overall glycolytic pathway can be divided into two phases • The preparatory phase (five steps) : glucose phosphorylation and cleavage, consuming 2ATP. • The payoff phase (five steps): producing 4ATP and 2NADH, and two pyruvates. • All the enzymes are found in the cytosol. • All intermediates are phosphorylated. • Other hexoses (e.g., Man, Gal, Fru) will also be converted glycolytic intermediates for further oxidation.

  23. Fates of Pyruvate Limitation of NAD+ for redox balance drives the fates of pyruvate

  24. NAD+ regenerated; O2 is not needed; glycolysis continues; occurring in very active skeleton muscle (乳酸脱氢酶)

  25. Present only in alcohol fermentative organisms TPP: 硫胺素焦磷酸 (丙酮酸脱羧酶) Present in many organisms including human (乙醇脱氢酶)

  26. TPP is derived from vitamin B1 (needed for treating Beriberi)

  27. Biochemistry in Life：Brewing Beer malt (contains enzymes to break down the polysaccharide) cereal grains (e.g. barley) add yeast cells and oxygens (aerobic metabolism) wort (liquid obtained from the smashed malt) anaerobic metabolism remove yeast cells adjust the foams (by adding some proteolytic enzymes)

  28. THE GLYCOLYTIC PATHWAY IS TIGHTLY CONTROLLED In metabolic pathways, enzymes catalyzing essentially irreversible reactions are potential sites of control. △G

  29. phosphofructokinase

  30. Fructose 2,6-bisphosphate is an allosteric activator （别构激活剂）for phosphofructo kinase 1 phosphofructokinase 2 (PFK2) Fructose-6-phosphate Fructose 2,6-bisphosphate. fructose bisphosphatase 2 (FBPase2)

  31. feedforward stimulation an abundance of fructose 6-phosphate leads to a higher concentration of F-2,6-BP, which in turn stimulates phosphofructokinase 1. When glucose is scarce, a rise in the blood level of the hormone glucagon triggers a cyclic AMP cascade, leading to the phosphorylation of this bifunctional enzyme by protein kinase A. This covalent modification activates FBPase2 and inhibits PFK2, lowering the level of F-2,6-BP. Thus, glucose metabolism by the liver is curtailed. Conversely, when glucose is abundant, the enzyme loses its attached phosphate group. This covalent modification activates PFK2 and inhibits FBPase2, raising the level of F-2,6-BP and accelerating glycolysis. This coordinated control is facilitated by the location of the kinase and phosphatase domains on the same polypeptide chain as the regulatory domain.

  32. 己糖激酶受产物Glc-6-P，Fru-6-P的抑制 丙酮酸激酶受Fru-1,6-P的激活，受ATP、丙酮酸的变构抑制；磷酸化和去磷酸化是其去活化或活化的机制

  33. Entry of hexoses into glycolysis 被动转运(passive transport) ：物质顺浓度梯度跨膜转移，不需要能量，需要转运蛋白 主动转运(active transport)：物质逆浓度梯度跨膜转移，需要能量，需要转运蛋白 协同转运(cotransport)：转运蛋白能同时跨膜转运两种物质

  34. Fructose metabolism (果糖激酶) (果糖-1-磷酸醛缩酶) Glyceraldyhyde Glycerol Glycerol-3-phosphate Alternative Way

  35. Galactose metabolism (半乳糖激酶) G6P G1P phosphoglucomutase

  36. Galactosemia（半乳糖血症） galactose 1-phosphate uridyl transferase deficiency 半乳糖醇

  37. Lactose intolerance (hypolactasia,乳酸不耐受,低乳糖酶症) Many adults are intolerant of Milk because they are deficient in lactase Lactobacillus Lactose ——— CH4 + H2 + Lactic acid flatulence diarrhea

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