Lactate dehydrogenase activity is inhibited by methylmalonate in vitro.
Lactate dehydrogenase activity is inhibited by methylmalonate in vitro.
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体外，丙二酸甲酯可抑制乳酸脱氢酶活性。
DOI：
10.1007/s11064-006-9054-6
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发表时间：
2006
影响因子：
4.4
通讯作者：
Castilho,RogerF
中科院分区：
文献类型：
--
作者：
Saad,LauraO;Mirandola,SandraR;Maciel,EveliseN;Castilho,RogerF
甲基丙二酸血症（MMA血症）是一种遗传性支链氨基酸和奇链脂肪酸代谢障碍，涉及甲基丙二酰辅酶A转化为琥珀酰辅酶A的缺陷。这种疾病的全身和神经系统表现被认为与甲基丙二酸（MMA）在组织和生物体液中的蓄积相关，从而损害能量代谢和氧化应激。在目前的工作中，我们研究了MMA和其他两个线粒体呼吸链复合物II（丙二酸和3-硝基丙酸）的抑制剂对乳酸脱氢酶（LDH）的活性在成年大鼠组织匀浆的影响。MMA有效地抑制LDH催化的转化乳酸丙酮酸在肝脏和脑匀浆，以及在纯化的牛心脏LDH制剂。LDH催化丙酮酸转化为乳酸时，对MMA抑制的敏感性降低约一个数量级。对脑LDH抑制的动力学研究表明，MMA与作为底物的乳酸竞争性地抑制该酶（Ki=3.02±0.59 mM）。丙二酸盐和3-硝基丙酸盐也强烈抑制LDH催化的脑匀浆中乳酸盐向丙酮酸盐的转化，而琥珀酸盐或丙酸盐在浓度高达25 mM时未观察到抑制作用。我们认为MMA对乳酸/丙酮酸转化的抑制有助于在MMA血症患者中观察到的血液中乳酸蓄积、代谢性酸血症和新生儿生长抑制。此外，中枢神经系统中LDH的抑制也可能损害星形胶质细胞和神经元之间的乳酸穿梭，损害神经元能量代谢。
Methylmalonic acidemia (MMAemia) is an inherited metabolic disorder of branched amino acid and odd-chain fatty acid metabolism, involving a defect in the conversion of methylmalonyl-coenzyme A to succinyl-coenzyme A. Systemic and neurological manifestations in this disease are thought to be associated with the accumulation of methylmalonate (MMA) in tissues and biological fluids with consequent impairment of energy metabolism and oxidative stress. In the present work we studied the effect of MMA and two other inhibitors of mitochondrial respiratory chain complex II (malonate and 3-nitropropionate) on the activity of lactate dehydrogenase (LDH) in tissue homogenates from adult rats. MMA potently inhibited LDH-catalyzed conversion of lactate to pyruvate in liver and brain homogenates as well as in a purified bovine heart LDH preparation. LDH was about one order of magnitude less sensitive to inhibition by MMA when catalyzing the conversion of pyruvate to lactate. Kinetic studies on the inhibition of brain LDH indicated that MMA inhibits this enzyme competitively with lactate as a substrate (Ki=3.02±0.59 mM). Malonate and 3-nitropropionate also strongly inhibited LDH-catalyzed conversion of lactate to pyruvate in brain homogenates, while no inhibition was observed by succinate or propionate, when present in concentrations of up to 25 mM. We propose that inhibition of the lactate/pyruvate conversion by MMA contributes to lactate accumulation in blood, metabolic acidemia and inhibition of gluconeogenesis observed in patients with MMAemia. Moreover, the inhibition of LDH in the central nervous system may also impair the lactate shuttle between astrocytes and neurons, compromising neuronal energy metabolism.