羧酸循环柠檬酸循环.ppt
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1、第23章 柠檬酸循环,主要内容,TCA准备阶段TCA循环阶段TCA产能计算TCA的调节TCA双重作用,TCA背景知识,1、为什么称为柠檬酸循环、三羧酸循环(Tricarboxylic acid cycle,TCA)、Krebs循环?在有氧的情况下,葡萄糖酵解产生的丙酮酸氧化脱羧形成乙酰CoA。乙酰CoA经一系列氧化、脱羧,最终生成C2O和H2O并产生能量的过程,称为柠檬酸循环,亦称为三羧酸循环(tricarboxylic acid cycle),简称TCA循环。由于它是由(德国)正式提出的,所以又称Krebs循环。,“It is convenient to use a brief term f
2、or the kind of scheme.Its essential feature is the periodic formation of a number of di-and tricarboxylic acids.As there is no term which would serve as a common denominator for all the various acids,it seemed reasonable to name the cycle,after one,or some,of its characteristic and specific acids.It
3、 was from such considerations that the term citric acid cycle was proposed in 1937.”(Hans A.Krebs,The citric acid cycle,Nobel Lecture,December 11,1953),Krebs,1901-1981,Brief history of TCA,The first major investigation into the intermediary metabolism of oxidation was that of Thunberg,who examined s
4、ystematically the oxidizability of organic substances in isolated animal tissues.Between 1906 and 1920 he tested the oxidation of over 60 organic substances,chiefly in muscle tissue.He discovered the rapid oxidation of the salts of a number of acids,such as lactate(乳酸盐),succinate(琥珀酸盐),fumarate(延胡索酸
5、盐),malate(苹果酸盐),citrate(柠檬酸盐),and glutamate(谷氨酸盐).,In 1932,Krebs was studying the rates of oxidation of small organic acids by kidney and liver tissue.Only a few of substances were active in these experiments-notably succinate,fumarate,acetate,malate,and citrate.,An important development came from t
6、he laboratory of Szent-Gyorgyi of Szegedin 1935,who confirmed on pigeon breast muscle the rapid oxidation of the C4-dicarboxylic acids-succinic,fumaric,malic,and oxaloacetic acids-and arrived at the new conclusion that those dicarboxylic acids were linked by an enzymatic pathway that was important f
7、or aerobic metabolism.,A decisive contribution to the field was made in March 1937 by Martius and Knoop,who discovered-ketoglutarate(-酮戊二酸)as a product of citrate oxidation.Because it was already known that-ketoglutarate could be enzymatically oxidized to succinate,the pathway from citrate to oxaloa
8、cetate was seemed as:,In 1937,Krebs found that citrate could be formed in muscle suspensions if oxaloacetate and either pyruvate or acetate were added.Now,he get a cycle:,TCA背景知识,2、细胞呼吸(cell respiration)要经历三个阶段:糖酵解阶段、柠檬酸循环阶段、氧化磷酸化阶段。3、糖酵解的产物丙酮酸进入TCA之前有一准备过程,即形成乙酰CoA。,TCA准备阶段,丙酮酸在丙酮酸脱氢酶系催化下氧化脱羧形成乙酰辅酶
9、A。,丙酮酸脱氢酶系复合物含三种酶和五个辅助因子,E1:pyruvate dehydrogenase,thiamine pyrophosphate(TPP)E2:dihydrolipoyl transacetylase,lipoic acid,coenzyme A-SH E3:dihydrolipoyl dehydrogenase,NAD+,FAD,IRREVERSIBLE,TCA准备阶段,H+,丙酮酸脱氢酶系作用机理(1),1.丙酮酸与TPP结合并 脱羧形成羟乙基TPP。2.羟乙基TPP氧化转变成 乙酰基同时转移到E2的 辅基硫辛酰胺上。3.在E2上的乙酰基在E2 催化下转移到CoASH 上
10、形成游离的乙酰CoA.从而形成了一个高能硫 酯键。,The mechanistic details of the first three steps of the pyruvate dehydrogenase complex reaction,TCA准备阶段,TCA准备阶段,丙酮酸脱氢酶系作用机理(2),4.还原型的E2将二个SH基H 转移到E3的辅酶FAD上形 成还原型FADH,5.E3上的还原型的FADH将 H交给NAD+形成NADH,E3辅基又形成氧化型的 FAD,TCA准备阶段,丙酮酸脱氢酶系反应图解,E1,E3,TCA准备阶段,砷化物对硫辛酰胺的毒害作用 有机砷化物和亚砷酸能与丙酮酸
11、脱氢酶系中的E2辅基硫辛酰胺共价结合,使还原型的硫辛酰胺形成失去催化能力的砷化物。这类砷化物同样表现在对酮戌二酸脱氢酶系的抑制上。,TCA概貌,2C,6C柠檬酸,6C异柠檬酸,5C 酮戌二酸,4C琥珀酰CoA,4C琥珀酸,4C延胡索酸,4C苹果酸,4C草酰乙酸,1、草酰乙酸与乙酰辅酶A形成柠檬酸催化此反应的酶为柠檬酸合酶;反应的中间产物为柠檬酰辅酶A;柠檬酸合酶属于调控酶,其活性受ATP、NADH、琥珀酰CoA、酯酰CoA等的抑制;另一种抑制剂是丙酮酰CoA。它是TCA循环的限速酶,由氟乙酸形成的氟乙酰CoA可被该酶催化形成氟柠檬酸,从而抑制下一步的顺乌头酸酶催化的反应。此称为致死性合成反应。
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