Clofibric acid, phenylpyruvate, and dichloroacetate inhibition of branched-chain alpha-ketoacid dehydrogenase kinase in vitro and in perfused rat heart.
Clofibric acid, phenylpyruvate, and dichloroacetate inhibition of branched-chain alpha-ketoacid dehydrogenase kinase in vitro and in perfused rat heart.
复制标题
氯贝酸、苯丙酮酸和二氯乙酸在体外和灌注大鼠心脏中抑制支链 α-酮酸脱氢酶激酶。
DOI：
10.1016/0003-9861(84)90362-x
复制
发表时间：
1984
影响因子：
3.9
通讯作者：
Harris,RA
中科院分区：
文献类型：
--
作者：
Paxton,R;Harris,RA
从兔肝中提纯的支链α-酮酸脱氢酶可被环丙酮酸、苯丙酮酸和二氯乙酸酯以一种相对于三磷酸腺苷的混合方式抑制。I40值与75μ的mATP值分别为0.33、1.70和3.0mM。醋酸盐、丙酮酸和乳酸盐对该酶的抑制作用很小；而这些化合物的AP-羟基苯基取代提高了它们作为酶抑制剂的效力，苯基取代给出了最有效的抑制剂。氯丙酮酸、苯丙酮酸和二氯乙酸酯激活灌流大鼠心脏支链α-酮酸脱氢酶。给予50%激活的灌流液浓度(A50)分别为0.1、0.32和0.63 mM。A50浓度的氯纤酸和苯丙酮酸也增加了灌流大鼠心脏通过支链α-酮酸脱氢酶的流量(α-酮[1-14C]异戊酸的脱羧基)。这些发现表明，尽管环丙酮酸和苯丙酮酸可以抑制支链α-酮酸脱氢酶复合体对底物的利用，但这些化合物对支链氨基酸代谢的主要影响是通过抑制支链α-酮酸脱氢酶激酶而激活和增加通过该复合体的通量。
Branched-chain α-ketoacid dehydrogenase kinase, purified from rabbit liver, was inhibited by clofibric acid, phenylpyruvate, and dichloroacetate in a mixed manner relative to ATP. I40values relative to 75 μmATP were 0.33, 1.7, and 3.0 mm, respectively. Inhibition of the kinase by acetate, pyruvate, and lactate was minimal; whereas ap-hydroxyphenyl substitution of these compounds increased their potency as kinase inhibitors, a phenyl substitution gave the most potent inhibitors. Clofibric acid, phenylpyruvate, and dichloroacetate activated branched-chain α-ketoacid dehydrogenase in perfused rat hearts. Perfusate concentrations that gave 50% activation (A50) were 0.1, 0.32, and 0.63 mm, respectively. A50concentrations of clofibric acid and phenylpyruvate also increased flux (decarboxylation of α-keto[1-14C]isovalerate) through branched-chain α-ketoacid dehydrogenase in perfused rat heart. These findings suggest that, although clofibric acid and phenylpyruvate can inhibit substrate utilization by the branched-chain α-ketoacid dehydrogenase complex, the major effect of these compounds on branched-chain amino acid metabolism is due to inhibition of branched-chain α-ketoacid dehydrogenase kinase with subsequent activation of and increased flux through the complex.