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首页> 外文期刊>Biochemistry >Selective inactivation of alpha-ketoglutarate dehydrogenase and pyruvate dehydrogenase: Reaction of lipoic acid with 4-hydroxy-2-nonenal
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Selective inactivation of alpha-ketoglutarate dehydrogenase and pyruvate dehydrogenase: Reaction of lipoic acid with 4-hydroxy-2-nonenal

机译：α-酮戊二酸脱氢酶和丙酮酸脱氢酶的选择性失活：硫辛酸与4-羟基-2-壬烯醛的反应

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Previous research has established that 4-hydroxy-2-nonenal (HNE), a highly toxic product of lipid peroxidation, is a potent inhibitor of mitochondrial respiration. HNE exerts its effects on respiration by inhibiting alpha-ketoglutarate dehydrogenase (KGDH). Because of the central role of KGDH in metabolism and emerging evidence that free radicals contribute to mitochondrial dysfunction associated with numerous diseases, it is of great interest to further characterize the mechanism of inhibition. In the present study, treatment of rat heart mitochondria with HNE resulted in the selective inhibition of KGDH and pyruvate dehydrogenase (PDH), while other NADH-linked dehydrogenases and electron chain complexes were unaffected. KGDH and PDH are structurally and catalytically similar multienzyme complexes, suggesting a common mode of inhibition. To determine the mechanism of inhibition, the effects of HNE on purified KGDH and PDH were examined. These studies revealed that inactivation by HNE was greatly enhanced in the presence of substrates that reduce the sulfur atoms of lipoic acid covalently bound to the E2 subunits of KGDH and PDH. In addition, loss of enzyme activity induced by HNE correlated closely with a decrease in the availability of lipoic acid sulfhydryl groups. Use of anti-lipoic acid antibodies indicated that HNE modified lipoic acid in both purified enzyme preparations and mitochondria and that this modification was dependent upon the presence of substrates. These results therefore identify a potential mechanism whereby free radical production and subsequent lipid peroxidation lead to specific modification of KGDH and PDH and inhibition of NADH-linked mitochondrial respiration. [References: 57]
机译：先前的研究已经确定，脂质过氧化的高毒性产物4-羟基-2-壬烯醛（HNE）是线粒体呼吸的有效抑制剂。 HNE通过抑制α-酮戊二酸脱氢酶（KGDH）发挥其呼吸作用。由于KGDH在新陈代谢中的重要作用以及越来越多的证据表明自由基会导致与许多疾病相关的线粒体功能障碍，因此进一步表征抑制机制具有极大的兴趣。在本研究中，用HNE处理大鼠心脏线粒体可选择性抑制KGDH和丙酮酸脱氢酶（PDH），而其他NADH连接的脱氢酶和电子链复合物则不受影响。 KGDH和PDH是结构上和催化上相似的多酶复合物，提示了常见的抑制方式。为了确定抑制机理，研究了HNE对纯化的KGDH和PDH的作用。这些研究表明，在底物的存在下，HNE的失活作用大大增强，该底物减少了与KGDH和PDH的E2亚基共价结合的硫辛酸的硫原子。另外，由HNE诱导的酶活性的丧失与硫辛酸巯基的可用性的降低密切相关。抗硫辛酸抗体的使用表明在纯化的酶制剂和线粒体中HNE修饰了硫辛酸，并且这种修饰取决于底物的存在。因此，这些结果确定了潜在的机制，其中自由基的产生和随后的脂质过氧化作用导致KGDH和PDH的特异性修饰以及对NADH连接的线粒体呼吸的抑制。 [参考：57]

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