Toyoshima S, Watanabe F, Saido H, Miyatake K, Nakano Y
Department of Applied Biological Chemistry, University of Osaka Prefecture, Japan.
J Nutr. 1995 Nov;125(11):2846-50. doi: 10.1093/jn/125.11.2846.
Methylmalonic acid (MMA), which accumulates and is excreted in urine in mammals during vitamin B-12 deficiency, has been reported to inhibit succinate dehydrogenase, an enzyme involved in the mitochondrial tricarboxylic acid (TCA) cycle in rat liver. The enzyme inhibition by MMA may lead to various metabolic disorders as well as inhibition of mitochondrial energy generation in vitamin B-12-deficient mammals. To clarify the inhibition of succinate dehydrogenase by MMA in intact rat liver mitochondria, the effect of MMA on mitochondrial respiration was studied. When 6 mmol/L MMA was added to the reaction mixture for measuring mitochondrial respiration with succinate as a substrate, MMA was taken up and accumulated by the mitochondria (34-53 mmol/L). The accumulation of mitochondrial MMA was stimulated by the addition of ADP. Methylmalonic acid competitively inhibited State 3 mitochondrial respiration, and the Ki for the acid was 4.2 +/- 0.4 mmol/L. Although the respiratory control ratio decreased with increasing MMA concentration, the acid did not affect the phosphorus/oxygen ratio. Mitochondrial MMA accumulation secondary to vitamin B-12 deficiency inhibits succinate dehydrogenase and may contribute to various metabolic disorders associated with vitamin B-12 deficiency.
甲基丙二酸（MMA）在维生素B12缺乏的哺乳动物体内会蓄积并随尿液排出，据报道，它能抑制琥珀酸脱氢酶，该酶参与大鼠肝脏线粒体三羧酸（TCA）循环。MMA对该酶的抑制作用可能会导致各种代谢紊乱，以及维生素B12缺乏的哺乳动物线粒体能量生成受到抑制。为了阐明完整大鼠肝脏线粒体中MMA对琥珀酸脱氢酶的抑制作用，研究了MMA对线粒体呼吸的影响。当向以琥珀酸为底物测量线粒体呼吸的反应混合物中添加6 mmol/L MMA时，MMA被线粒体摄取并蓄积（34 - 53 mmol/L）。添加ADP可刺激线粒体MMA的蓄积。甲基丙二酸竞争性抑制线粒体状态3呼吸，该酸的Ki为4.2±0.4 mmol/L。尽管呼吸控制率随MMA浓度增加而降低，但该酸不影响磷/氧比。维生素B12缺乏继发的线粒体MMA蓄积会抑制琥珀酸脱氢酶，并可能导致与维生素B12缺乏相关的各种代谢紊乱。
