The mitochondrial-encoded subunits of respiratory complex I (NADH:ubiquinone oxidoreductase): identifying residues important in mechanism and disease
The mitochondrial-encoded subunits of respiratory complex I (NADH:ubiquinone oxidoreductase): identifying residues important in mechanism and disease
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DOI：
10.1042/bst0390799
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发表时间：
2011-06-01
影响因子：
3.9
通讯作者：
Hirst, Judy
中科院分区：
文献类型：
--
作者：
Bridges, Hannah R.;Birrell, James A.;Hirst, Judy
复合物 I（NADH：泛醌氧化还原酶）对于许多需氧生物的呼吸至关重要。复合物 I 的亲水结构域含有九个或更多氧化还原辅因子，并包含七个保守的核心亚基，突出到线粒体基质或细菌细胞质中。 α-螺旋膜结合疏水结构域还包含七个核心亚基，它们在真核生物中由线粒体编码，并命名为 ND 亚基（ND1-ND6 和 ND4L）。复合物 I 将亲水域中 NADH 的氧化与疏水域中的泛醌还原和质子易位耦合起来。尽管人们对 NADH 氧化和分子内电子转移的机制越来越了解，但泛醌还原和质子易位的机制仍然知之甚少。最近，细菌复合物I疏水结构域的α螺旋模型[Efremov, Baradaran and Sazanov (2010) Nature 465, 441-447]揭示了7个核心亚基的63个跨膜螺旋的排列方式，从而为功能数据的解释和机制建议的制定奠定了基础。在本文中，我们的目标是将来自序列分析、定点诱变研究和与人类疾病相关的突变的信息与来自最新结构模型的信息关联起来。因此，我们的目的是鉴定和讨论哺乳动物复合物 I ND 亚基中的残基，这些残基对于催化和维持酶的结构和功能完整性很重要。
Complex I (NADH:ubiquinone oxidoreductase) is crucial to respiration in many aerobic organisms. The hydrophilic domain of complex I, containing nine or more redox cofactors, and comprising seven conserved core subunits, protrudes into the mitochondrial matrix or bacterial cytoplasm. The a-helical membrane-bound hydrophobic domain contains a further seven core subunits that are mitochondrial-encoded in eukaryotes and named the ND subunits (ND1-ND6 and ND4L). Complex I couples the oxidation of NADH in the hydrophilic domain to ubiquinone reduction and proton translocation in the hydrophobic domain. Although the mechanisms of NADH oxidation and intramolecular electron transfer are increasingly well understood, the mechanisms of ubiquinone reduction and proton translocation remain only poorly defined. Recently, an alpha-helical model of the hydrophobic domain of bacterial complex I [Efremov, Baradaran and Sazanov (2010) Nature 465, 441-447] revealed how the 63 transmembrane helices of the seven core subunits are arranged, and thus laid a foundation for the interpretation of functional data and the formulation of mechanistic proposals. In the present paper, we aim to correlate information from sequence analyses, site-directed mutagenesis studies and mutations that have been linked to human diseases, with information from the recent structural model. Thus we aim to identify and discuss residues in the ND subunits of mammalian complex I which are important in catalysis and for maintaining the enzyme's structural and functional integrity.