Differential effects of fatty acyl coenzyme A derivatives on citrate synthase and glutamate dehydrogenase.

J C Lai, B B Liang, E J Jarvi, A J Cooper, D R Lu
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Abstract

We investigated the hypothesis that one mechanism underlying fatty acid toxicity is the selective inhibition of rate-limiting and/or regulated tricarboxylic acid cycle and related enzymes by fatty acyl coenzyme A (CoA) derivatives by examining the effects of several fatty acyl CoAs on purified citrate synthase (CS) and glutamate dehydrogenase (GDH). The results indicate that, at pathophysiological levels, palmitoyl CoA, a long-chain acyl CoA, is a potent inhibitor of CS and GDH with IC50 values of 3-15 microM. At much higher levels (in the pathological and toxicological range), octanoyl and decanoyl CoA (medium-chain acyl CoAs) inhibited both enzymes with IC50 values of 0.4-1.6 mM. Butyryl CoA, a short-chain acyl CoA, inhibited CS (IC50 = 0.9 mM) at toxicological levels but inhibited GDH poorly. These results suggest that the long-chain fatty acyl CoA inhibition of CS and GDH may assume some pathophysiological importance in fatty acid toxicity and in metabolic encephalopathies in which organic acidemia is persistent. The findings also provide additional support for the original hypothesis.

脂肪酸酰基辅酶A衍生物对柠檬酸合成酶和谷氨酸脱氢酶的差异影响。
我们通过研究几种脂肪酸辅酶A对纯化柠檬酸合成酶(CS)和谷氨酸脱氢酶(GDH)的影响,研究了脂肪酸毒性的一种机制是脂肪酸辅酶A (CoA)衍生物选择性抑制限速和/或调节的三羧酸循环及相关酶的假设。结果表明,在病理生理水平上,棕榈酰辅酶a(一种长链酰基辅酶a)是一种有效的CS和GDH抑制剂,IC50值为3-15微米。在更高水平(病理和毒理学范围内),辛烷酰辅酶a和癸烷酰辅酶a(中链酰基辅酶a)抑制这两种酶的IC50值为0.4-1.6 mM。丁基辅酶a(短链酰基辅酶a)在毒理学水平上抑制CS (IC50 = 0.9 mM),但对GDH的抑制作用较差。这些结果表明,长链脂肪酸酰基辅酶a对CS和GDH的抑制可能在脂肪酸毒性和持续有机酸血症的代谢性脑病中具有一定的病理生理学意义。这些发现也为最初的假设提供了额外的支持。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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