Chuang David T, Chuang Jacinta L, Wynn R Max
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9038, USA.
J Nutr. 2006 Jan;136(1 Suppl):243S-9S. doi: 10.1093/jn/136.1.243S.
Genetic disorders of BCAA metabolism produce amino acidopathies and various forms of organic aciduria with severe clinical consequences. A metabolic block in the oxidative decarboxylation of BCAA caused by mutations in the mitochondrial branched-chain alpha-keto acid dehydrogenase complex (BCKDC) results in Maple Syrup Urine Disease (MSUD) or branched-chain ketoaciduria. There are presently five known clinical phenotypes for MSUD, i.e., classic, intermediate, intermittent, thiamin-responsive, and dihydrolipoamide dehydrogenase (E3)-deficient, based on severity of the disease, response to thiamin therapy, and the gene locus affected. Reduced glutamate, glutamine, and gamma-aminobutyrate concentrations induced by the accumulation of branched-chain alpha-ketoacids in the brain cortex of affected children and neonatal polled Hereford calves are considered the cause of MSUD encephalopathies. The long-term restriction of BCAA intake in diets and orthotopic liver transplantation have proven effective in controlling plasma BCAA levels and mitigating some of the above neurological manifestations. To date, approximately 100 mutations have been identified in four (branched-chain alpha-ketoacid decarboxylase/dehydrogenasealpha [E1alpha], E1beta, dihydrolipoyl transacylase [E2], and E3) of the six genes that encode the human BCKDC catalytic machine. We have documented a strong correlation between the presence of mutant E2 proteins and the thiamin-responsive MSUD phenotype. We show that the normal E1 component possesses residual decarboxylase activity, which is augmented by the binding to a mutant E2 protein in the presence of the E1 cofactor thiamin diphosphate. Our results provide a biochemical model for the effectiveness of thiamin therapy to thiamin-responsive MSUD patients.
支链氨基酸（BCAA）代谢的遗传紊乱会导致氨基酸病和各种形式的有机酸尿症，产生严重的临床后果。线粒体支链α-酮酸脱氢酶复合体（BCKDC）突变导致的BCAA氧化脱羧代谢阻滞会引发枫糖尿症（MSUD）或支链酮酸尿症。目前，根据疾病严重程度、对硫胺素治疗的反应以及受影响的基因位点，MSUD有五种已知的临床表型，即经典型、中间型、间歇型、硫胺素反应型和二氢硫辛酰胺脱氢酶（E3）缺乏型。受影响儿童和新生无角海福特犊牛大脑皮质中支链α-酮酸的积累导致谷氨酸、谷氨酰胺和γ-氨基丁酸浓度降低，这被认为是MSUD脑病的病因。饮食中长期限制BCAA摄入和原位肝移植已被证明可有效控制血浆BCAA水平并减轻上述一些神经学表现。迄今为止，在编码人类BCKDC催化机制的六个基因中的四个（支链α-酮酸脱羧酶/脱氢酶α [E1α]、E1β、二氢硫辛酰基转乙酰酶 [E2] 和E3）中已鉴定出约100种突变。我们已证明突变E2蛋白的存在与硫胺素反应型MSUD表型之间存在强相关性。我们发现正常的E1组分具有残余脱羧酶活性，在E1辅因子硫胺素二磷酸存在的情况下，与突变E2蛋白结合可增强该活性。我们的结果为硫胺素治疗对硫胺素反应型MSUD患者的有效性提供了一个生化模型。
