catabolismoffattyacids2

1、Fatty acyl-CoA isformed from fattyacids and coenzymeA via a fatty acyl-AMP intermediate活化的脂酰辅酶活化的脂酰辅酶A由肉碱带进线粒体由肉碱带进线粒体 The fatty acyl group is attached to carnitine (肉肉碱碱） via transesterification by the action of carnitine acyltransferase I located on the outer face of the inner membrane, forming fa

2、tty acyl-carnitine, leaving the CoA in the cytosol. The acyl carnitine/carnitine transporter moves acyl-carnitine across the inner membrane of mitochondria via facilitated diffusion(易化扩散易化扩散). Medium-chain acyl-CoAs seem to enter the matrix by themselves, without being carried by carnitine. The acyl

3、 group is then transferred back to CoA to form fatty acyl-CoA by the action of carnitine acyltransferase II located on the inner face of the inner membrane. This entering step seems to be rate-limiting for fatty acid oxidation in mitochondria and disease have been found to be caused by a defect of t

4、his step (with aching muscle cramp(抽筋抽筋), especially during fasting, exercise or when on a high-fat diet).脂酰辅酶脂酰辅酶A通过通过 -氧化生成乙酰辅酶氧化生成乙酰辅酶A The oxidation consists of four reactions: oxidation by FAD, hydration, oxidation by NAD+, and thiolysis by CoA (mainly revealed by David Green, Severo Ochoa, and

5、 Feodor Lynen). The 1st oxidation is catalyzed by the membrane-bound acyl-CoA dehydrogenase, converting acyl-CoA to trans- 2-enoyl-CoA with electrons collected by FAD and further transferred into the respiratory chain via the electron-transferring flavoprotein (ETFP), also bound to the inner membran

6、e of the mitochondria. Acyl-CoA dehydrogenase exists in three isozymes acting on the acyl-CoAs of long (12-18C), medium (4-14C) and short (4-8C) chains. The hydration step, stereospecifically catalyzed by enoyl-CoA hydratase, converts the trans- 2-enoyl-CoA to L- -hydroxylacyl-CoA (the cis isomer ca

7、n also be converted, but to the D isomer). The second oxidation is catalyzed by L- -hydroxylacyl-CoA dehydrogenase, converting L- -hydroxylacyl-CoA to -ketoacyl-CoA (not act on the D isomer), with electrons collected by NAD+. The acyl-CoA acetyltransferase (or commoly called thiolase,硫解酶硫解酶) catalyz

8、es the nucleophilic attack of CoA to the carbonyl carbon, cleaving -ketoacyl-CoA between the a a and carbon (thiolysis), generating two acyl-CoA molecules with one entering the citric acid cycle and the other reenter the oxidation pathway. The first three reactions of the oxidation used the same rea

9、ction strategy as the last three reactions in the citric acid cycle, all involving the oxidation of a highly reduced carbon (from -CH2- to -CHO-). The complete oxidization of each 16-carbon palmitate (to H2O and CO2) yields 106 ATP (32 ATP per glucose, both having about 60% of actual energy recovery

10、).Three similarreactions between the -oxidationand citric acidcycle不饱和脂肪酸的降解不饱和脂肪酸的降解 The isomerase异构酶异构酶 converts a cis- 3 double bond to a trans- 2 double bond. The reductase还原酶还原酶 (2,4-dienoyl-CoA reductase) converts a trans- 2, cis- 4 structure to a trans- 3 structure, which will be further conv

11、erted to a trans- 2 structure by the isomerase. NADPH is needed for the reduction (from two double bonds to one).单不饱和脂肪酸单不饱和脂肪酸的降解的降解（Oxidation of amonounsaturatedfatty acid）: the enoyl-CoA isomerase helps toreposition the double bondBoth an isomerase and a reductase are needed for oxidizing polyuns

12、aturated fatty acids.多不饱和脂肪酸的氧化多不饱和脂肪酸的氧化奇数脂肪酸的降解奇数脂肪酸的降解 Odd-chain fatty acids, commonly found in the lipids of some plants and marine(海生海生) organisms, will also be oxidized via the oxidation pathway, but generating a propionyl-CoA(丙酰丙酰- CoA) at the last step of thiolysis. Propionyl-CoA is converte

13、d to succinyl-CoA（琥珀酰（琥珀酰-CoA） via an unusual enzymatic pathway of three reactions. Propionyl-CoA is first carboxylated at the a a carbon to form D-methylmalonyl-CoA(甲基丙二酰甲基丙二酰-CoA), catalyzed by a carboxylase using a mechanism similar to that of acetyl-CoA and pyruvate carboxylases. The D-mathylmal

14、onyl-CoA is then epimerized to the L-isomer by the action of an epimerase(表异构酶表异构酶). The L-mathylmalonyl-CoA (甲基丙二酰甲基丙二酰-CoA) is then converted to succinyl-CoA by an intramolecular rearrangement via free radical intermediates, with the catalysis of mathylmalonyl-CoA mutase, using deoxyadenosyl-cobal

15、amin (腺苷甲硫腺苷甲硫氨酸氨酸-谷胺素谷胺素) or coenzyme B12.Coenzyme B12has a complex structure (determined by X-ray crystallography in 1956), having a heme-like corrin(咕啉咕啉) ring system (four connected pyrrole(吡咯吡咯) units), a coordinated trace element cobalt(钴钴), a 5-deoxyadenosyl group covalently bound to cobalt v

16、ia its 5 carbon (the only known carbon-metal bond in biomolecules).Propionyl- CoA can beconverted to succinyl-CoAvia a carboxylation, an epimerization andan intramolecular groupshifting.丙酰丙酰-CoA转变成转变成琥珀酰琥珀酰-CoA的反应的反应在肝脏中乙酰辅酶在肝脏中乙酰辅酶A可以转化为酮体可以转化为酮体 Under fasting(禁食禁食) or diabetic(糖尿病糖尿病) conditions,

17、oxaloacetate concentration in hepatocyte(肝细胞肝细胞) will be low: the rate of glycolysis is low (thus the supply of precursors for replenishing oxaloacetate is cut off) and oxaloacetate is siphoned off（吸收）（吸收） into gluconeogenesis (to maintain blood glucose level). The acetyl-CoA generated from active f

18、atty acid oxidation can not be oxidized via the citric acid cycle and will be converted to acetoacetate(乙酰乙酸乙酰乙酸), -hydroxylbutyrate(羟基丁酸羟基丁酸), and acetone(丙酮丙酮) (i.e., the ketone bodies) in mitochondria for export to other tissues. For ketone body formation, first two condense(缩合缩合) to form acetoac

19、etyl-CoA catalyzed by thiolase (the reverse reaction of the one it catalyzes in oxidation); then addition of another acetyl-CoA forms -hydroxyl- -methylglutaryl-CoA (catalyzed by the synthase, which is then cleaved to form acetoacetate and acetyl-CoA (catalyzed by the lyase). Acetoacetate can be dec

20、arboxylated to form acetone (decarboxylase) or reduced to (dehydrogenase). The overproduction of acetoacetate and will lower the pH of the blood (a condition called ketoacidosis), causing serious problems.酮体的形成：酮体的形成：Acety-CoA can be convertedto ketone bodies（酮体） in liverunder fasting（禁食） and diabet

21、ic （糖尿病）conditionsketone bodies (酮体)：acetoacetate(乙酰乙酸乙酰乙酸), -hydroxylbutyrate(羟基羟基丁酸丁酸), and acetone(丙酮丙酮)Ketone bodies are converted back to acetyl-CoA in extrahepatic tissues is reoxidized to acetoacetate (catalyzed by the dehydrogenase). Acetoacetate is then converted to acetoacetyl-CoA using su

22、ccinyl-CoA (-ketoacyl-CoA transferase); Acetoacetyl-CoA is cleaved to two (again catalyzed by thiolase). Heart muscle and the renal cortex（肾外皮质） use acetoacetate in preference to glucose. The brain adapts to the utilization of acetoacetate during starvation and diabetes.酮体的利用：酮体的利用：Ketone bodies are

23、converted to acetyl-CoA(乙酰辅酶A) in extrahepaticTissues(肝外组织).Summary Diet triacylglycerols are emulsified（乳化）by bile salts（胆盐）in the intestines（小肠）before absorbed and transported in blood as chylomicron particles（乳糜微粒）. Stored triacylglycerols are mobilized（动员）in response to hormones and fatty acids

24、in blood are carried by serum albumin（血清蛋白）. Fatty acids are activated to the acyl-CoA form and is then carried into mitochondria by carnitine（肉碱） with the help of two carnitine acyltranseferase isozymes (I and II) located on the outside and inside of the inner membrane. Acyl-CoA is converted to ace

25、tyl-CoA after going through multiple rounds of the four-step (dehydrogenation, hydration, dehydrogenation and thiolysis) -oxidation pathway. Oxidative degradation of unsaturated fatty acids need two extra enzymes: an isomerase and a reductase. The propionyl-CoA（丙酰（丙酰-CoA） generated from odd-numbered fatty acids is converted to succinyl-CoA afte