Role of short-chain hydroxyacyl CoA dehydrogenases in SCHAD deficiency
Role of short-chain hydroxyacyl CoA dehydrogenases in SCHAD deficiency
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DOI：
10.1016/j.bbrc.2007.10.188
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发表时间：
2008-03-28
影响因子：
3.1
通讯作者：
Oppermann, Udo
中科院分区：
文献类型：
--
作者：
Filling, Charlotta;Keller, Brigitte;Oppermann, Udo
短链羟基酰辅酶A脱氢酶缺乏症是一种定义不清、严重的儿科线粒体脂肪酸P氧化短链羟基酰辅酶A缺乏症。为了了解这两个已知的短链羟酰辅酶A脱氢酶(HADH)的相对贡献，我们分析了6个不同家系个体的组织活检组织，并比较了动力学参数。HADH I和HADH 2的稳态动力学常数表明，I型酶是参与短链羟酰基COAS线粒体P氧化的主要酶。2例患者为HADH I基因杂合子携带者，而所有患者的HADH 2基因均未检测到突变。这些数据表明，蛋白质相互作用而不是HADH突变是导致疾病表型的原因。重组HADH-I和HADH-2与人线粒体提取物的下拉实验表明，有两种蛋白质与HADH-1相互作用，其中一种被鉴定为谷氨酸脱氢酶。这种联系提供了脂肪酸代谢和高胰岛素/高氨综合征之间的可能联系。(C)2007 Elsevier Inc.保留所有权利。
Short-chain hydroxyacyl CoA dehydrogenase deficiency is an ill-defined, severe pediatric disorder of mitochondrial fatty acid P-oxidation of short-chain hydroxyacyl CoAs. To understand the relative contributions of the two known short-chain hydroxyacyl CoA dehydrogenases (HADH) tissue biopsies of six distinct family individuals were analyzed and kinetic parameters were compared. Steady-state kinetic constants for HADH I and HADH 2 suggest that type I is the major enzyme involved in mitochondrial P-oxidation of short-chain hydroxyacyl-CoAs. Two patients are heterozygous carriers of a HADH I polymorphism, whereas no mutation is detected in the HADH 2 gene of all patients. The data suggest that protein interactions rather than HADH mutations are responsible for the disease phenotype. Pull-down experiments of recombinant HADH I and 2 with human mitochondrial extracts reveal two proteins interacting with HADH 1, one of which was identified as glutamate dehydrogenase. This association provides a possible link between fatty acid metabolism and the hyperinsulinism/hyperammonia syndrome. (C) 2007 Elsevier Inc. All rights reserved.