吡啶核苷酸转氢酶的结构及功能

吡啶核苷酸转氢酶(pyridine nucleotide transhydrogenases)是能直接催化NADP(H)与NAD(H)之间氢负离子可逆转移的氧化还原酶, 主要调控分解代谢和合成代谢过程中NADH与NADPH之间的动态平衡. 膜结合吡啶核苷酸转氢酶(TH)是ATP依赖性跨膜蛋白, 由2个亚基构成, 每个亚基包含dⅠ、dⅡ和dⅢ三个结构域. 在TH结合可变催化机制中, 氢负离子的转移总是与质子转移相偶联. 可溶性吡啶核苷酸转氢酶(STH)是非能量依赖性的黄素蛋白, 以可溶性多聚体形式存在. 目前认为,很多因活性氧自由基异常增多而引起的线粒体疾病都与TH的活性有关, 包括糖尿病、癌症、神经退行性疾病及心血管疾病等. TH分子机制的研究将有助于揭示这些线粒体疾病的致病机理以及为其诊断和基因治疗提供分子依据. STH作用机理的研究及其在辅酶再生系统中的应用, 将会推动代谢工程和工业生物催化过程的进一步发展.

Structure and Function of Pyridine Nucleotide Transhydrogenases

Pyridine nucleotide transhydrogenases are the redox enzymes for directly catalyzing the reversible hydride transfer between NAD(H) and NADP(H), where they regulate and restore the homeostasis of those two redox cofactors in catabolism and anabolism. The membrane bound pyridine nucleotide transhydrogenase (TH), ATP linked transmembrane protein, is composed of two subunits, each of which contains three domains (dⅠ, dⅡ and dⅢ). TH drives the transfer of hydride from NADH to NADP+ coupled with transmembrane proton import via binding change catalytic mechanism. The soluble pyridine nucleotide transhydrogenase (STH) is energy independent flavoprotein and form remarkably large polymers. Recently, it is considered that many mitochondrial diseases and cell damage caused by mitochondrial reactive oxygen species are related to TH activities, including diabetes, cancer, neurodegenerative diseases, cardiovascular diseases, and also apoptosis and aging. To investigate the molecular mechanism of TH may reveal the pathogenic mechanism of mitochondrial diseases and provide the molecular basis for diagnosis and gene therapy. Research of mechanism and utilization of STH in cofactor regenerating system may promote the further development of metabolic engineering and industrial biocatalysis process.