降血糖化合物戊-4-烯酸及相关非降血糖脂肪酸的生化效应。游离酸及其肉碱酯对大鼠肝线粒体中辅酶A依赖性氧化的影响。

Biochemical effects of the hypoglycaemic compound pent-4-enoic acid and related non-hypoglycaemic fatty acids. Effects of the free acids and their carnitine esters on coenzyme A-dependent oxidations in rat liver mitochondria.

作者信息

Holland P C, Sherratt H S

出版信息

Biochem J. 1973 Sep;136(1):157-71. doi: 10.1042/bj1360157.

DOI:10.1042/bj1360157

PMID:4772622

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1165935/

Abstract

The synthesis of pent-4-enoyl-l-carnitine, cyclopropanecarbonyl-l-carnitine and cyclobutanecarbonyl-l-carnitine is described. 2. Pent-4-enoate strongly inhibits palmitoyl-l-carnitine oxidation in coupled but not in uncoupled mitochondria. Pent-4-enoyl-l-carnitine strongly inhibits palmitoyl-l-carnitine oxidation in uncoupled mitochondria. Prior intramitochondrial formation of pent-4-enoyl-CoA is therefore necessary for inhibition. 3. There was a small self-limiting pulse of oxidation of pent-4-enoyl-l-carnitine during which the ability to inhibit the oxidation of subsequently added palmitoyl-l-carnitine developed. 4. Pent-4-enoate and pent-4-enoyl-l-carnitine are equally effective inhibitors of the oxidation of all even-chain acylcarnitines of chain length C(4)-C(16). Pent-4-enoyl-l-carnitine also inhibits the oxidation of pyruvate and of 2-oxoglutarate. 5. Pent-4-enoate strongly inhibits the oxidation of palmitate but not that of octanoate. This is presumably due to competition between octanoate and pent-4-enoate for medium-chain acyl-CoA ligase. 6. There was less inhibition of the oxidation of pyruvate by pent-4-enoyl-l-carnitine, and of palmitoyl-l-carnitine by cyclopropanecarbonyl-l-carnitine, after pre-incubation with 10mm-arsenate. This suggests that these inhibitions were caused either by depletion of free CoA or by increase of acyl-CoA concentrations, since arsenate deacylates intramitochondrial acyl-CoA. There was little effect on the inhibition of palmitoyl-l-carnitine oxidation by pent-4-enoyl-l-carnitine. 7. Penta-2,4-dienoate strongly inhibited palmitoyl-l-carnitine oxidation in coupled mitochondria; acrylate only inhibited slightly. 8. Pent-4-enoate (0.1mm) caused a rapid and almost complete decrease in free CoA and a large increase in acid-soluble acyl-CoA when incubated with coupled mitochondria. Cyclopropanecarboxylate caused a similar decrease in CoA, with an equivalent rise in acid-soluble acyl-CoA concentrations. n-Pentanoate caused extensive lowering of CoA and a large increase in acid-soluble acyl-CoA and acetyl-CoA concentrations. Octanoate caused a 50% lowering of CoA and an increase in acid-soluble acyl-CoA and acetyl-CoA concentrations. 9. Cyclopropanecarboxylate and n-pentanoate were less potent inhibitors of palmitate oxidation than was pent-4-enoate. 10. It is concluded that pent-4-enoate causes a specific inhibition of beta-oxidation after the formation intramitochondrially of its metabolites.

摘要

本文描述了戊-4-烯酰-L-肉碱、环丙烷甲酰-L-肉碱和环丁烷甲酰-L-肉碱的合成。2. 戊-4-烯酸在偶联的线粒体中强烈抑制棕榈酰-L-肉碱的氧化，但在解偶联的线粒体中则不然。戊-4-烯酰-L-肉碱在解偶联的线粒体中强烈抑制棕榈酰-L-肉碱的氧化。因此，线粒体内戊-4-烯酰辅酶A的预先形成是抑制所必需的。3. 戊-4-烯酰-L-肉碱存在一个小的自限性氧化脉冲，在此期间抑制随后添加的棕榈酰-L-肉碱氧化的能力得以发展。4. 戊-4-烯酸和戊-4-烯酰-L-肉碱对链长为C(4)-C(16)的所有偶数链酰基肉碱的氧化具有同等有效的抑制作用。戊-4-烯酰-L-肉碱还抑制丙酮酸和2-氧代戊二酸的氧化。5. 戊-4-烯酸强烈抑制棕榈酸的氧化，但不抑制辛酸的氧化。这可能是由于辛酸和戊-4-烯酸竞争中链酰基辅酶A连接酶所致。6. 与10mM砷酸盐预孵育后，戊-4-烯酰-L-肉碱对丙酮酸氧化的抑制作用以及环丙烷甲酰-L-肉碱对棕榈酰-L-肉碱氧化的抑制作用减弱。这表明这些抑制作用要么是由于游离辅酶A的消耗，要么是由于酰基辅酶A浓度的增加，因为砷酸盐使线粒体内的酰基辅酶A脱酰基。戊-4-烯酰-L-肉碱对棕榈酰-L-肉碱氧化的抑制作用几乎没有影响。7. 戊-2,4-二烯酸在偶联的线粒体中强烈抑制棕榈酰-L-肉碱的氧化；丙烯酸仅略有抑制。8. 戊-4-烯酸（0.1mM）与偶联的线粒体一起孵育时，导致游离辅酶A迅速且几乎完全减少，酸溶性酰基辅酶A大幅增加。环丙烷羧酸导致辅酶A有类似的减少，酸溶性酰基辅酶A浓度相应升高。正戊酸导致辅酶A大幅降低，酸溶性酰基辅酶A和乙酰辅酶A浓度大幅增加。辛酸导致辅酶A降低50%，酸溶性酰基辅酶A和乙酰辅酶A浓度增加。9. 环丙烷羧酸和正戊酸对棕榈酸氧化的抑制作用比戊-4-烯酸弱。10. 得出的结论是，戊-4-烯酸在其代谢产物在线粒体内形成后对β-氧化产生特异性抑制作用。