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首页> 外文期刊>Acta crystallographica.Section D Biological crystallography. >Structural insights into the catalytic mechanism of human squalene synthase
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Structural insights into the catalytic mechanism of human squalene synthase

机译：结构对催化机理人类的角鲨烯合酶

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摘要

Squalene synthase (SQS) is a divalent metal-ion-dependent enzyme that catalyzes the two-step reductive 'head-to-head' condensation of two molecules of farnesyl pyrophosphate to form squalene using presqualene diphosphate (PSPP) as an intermediate. In this paper, the structures of human SQS and its mutants in complex with several substrate analogues and intermediates coordinated with Mg2+ or Mn2+ are presented, which stepwise delineate the biosynthetic pathway. Extensive study of the SQS active site has identified several critical residues that are involved in binding reduced nicotinamide dinucleotide phosphate (NADPH). Based on mutagenesis data and a locally closed (JK loop-in) structure observed in the hSQS-(F288L)-PSPP complex, an NADPH-binding model is proposed for SQS. The results identified four major steps (substrate binding, condensation, intermediate formation and translocation) of the ordered sequential mechanisms involved in the '1′-1' isoprenoid biosynthetic pathway. These new findings clarify previous hypotheses based on site-directed mutagenesis and biochemical analysis.
机译：角鲨烯合酶(SQS)是一种二价metal-ion-dependent酶催化的两步还原“肉搏战”凝结两个分子的通过焦磷酸形成有squalene presqualene diphosphate (as PSPP)一个中间。人类SQS及其突变体在复杂的有几个底物类似物和中间体协调Mg2 +或Mn2 +,逐步描述生物合成途径。SQS活性位点的研究已经确定了几个关键残基参与绑定还原型烟酰胺二核苷酸磷酸(NADPH)。观察局部闭(JK循环)结构hSQS - (F288L) -PSPP复杂,一个NADPH-binding模型提出了SQS。结果确定了四个主要步骤(衬底绑定,冷凝,中间形成和易位)的命令序列机制参与' 1 ' 1 '的类异戊二烯生物合成途径。之前的假设基于定点诱变和生物化学分析。

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