三羧酸循环Citric acid cycle

乙酰辅酶 A（二碳）与草酰乙酸（四碳）缩合为柠檬酸（六碳），异构化为异柠檬酸后经两次氧化脱羧生成琥珀酰辅酶 A，释放 2 个 CO₂。琥珀酰辅酶 A 经底物水平磷酸化生成琥珀酸和 GTP，琥珀酸再经脱氢（生成 FADH₂）、水合、脱氢（生成 NADH）重新生成草酰乙酸。每轮共生成 3 NADH、1 FADH₂ 和 1 GTP，经氧化磷酸化约相当于 10 个 ATP。

Acetyl-CoA (two carbons) condenses with oxaloacetate (four) to give citrate (six), which isomerises to isocitrate and undergoes two oxidative decarboxylations to succinyl-CoA, releasing two CO₂. Succinyl-CoA gives succinate and GTP by substrate-level phosphorylation, and succinate is regenerated to oxaloacetate by dehydrogenation (making FADH₂), hydration and another dehydrogenation (making NADH). Each turn yields 3 NADH, 1 FADH₂ and 1 GTP, worth about 10 ATP after oxidative phosphorylation.

1935 年圣捷尔吉发现琥珀酸、富马酸、苹果酸等四碳二羧酸能显著促进肌肉组织的呼吸作用。1937 年德国出生的英国生化学家汉斯·克雷布斯和约翰逊在鸽子胸肌中发现柠檬酸可由草酰乙酸生成，提出这些反应构成一个循环。他向《自然》投稿被退回，最终发表于《酶学》杂志。克雷布斯因此获 1953 年诺贝尔生理学或医学奖。1951 年李普曼和奥乔亚等确定了乙酰辅酶 A 是进入循环的物质。

In 1935 Szent-Györgyi found that the four-carbon dicarboxylic acids succinate, fumarate and malate greatly stimulate respiration in minced muscle. In 1937 Hans Krebs, a German-born British biochemist, and William Johnson found in pigeon breast muscle that citrate is formed from oxaloacetate and proposed that the reactions form a cycle. Nature rejected the paper, which appeared in Enzymologia. Krebs received the 1953 Nobel Prize in Physiology or Medicine. In 1951 Lipmann, Ochoa and others established acetyl-CoA as the entry compound.

柠檬酸合酶、异柠檬酸脱氢酶和 α-酮戊二酸脱氢酶是主要调控点，受 NADH、ATP 抑制，受 ADP、Ca²⁺ 激活。循环中间物被抽出用于合成氨基酸、血红素和脂肪酸，需由丙酮酸羧化等“回补反应”补充。异柠檬酸脱氢酶突变产生的 2-羟基戊二酸与某些脑胶质瘤相关。

Citrate synthase, isocitrate dehydrogenase and α-ketoglutarate dehydrogenase are the main control points, inhibited by NADH and ATP and activated by ADP and Ca²⁺. Intermediates withdrawn to make amino acids, haem and fatty acids are replaced by anaplerotic reactions such as pyruvate carboxylation. Mutant isocitrate dehydrogenase makes 2-hydroxyglutarate, which is linked to certain gliomas.