Structure and regulation of mammalian squalene synthase.
Structure and regulation of mammalian squalene synthase.
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DOI：
10.1016/s1388-1981(00)00137-2
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发表时间：
2000-12
期刊：
影响因子：
--
通讯作者：
Terese R. Tansey;I. Shechter
中科院分区：
文献类型：
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作者：
Terese R. Tansey;I. Shechter
哺乳动物角鲨烯合成酶（SQS）催化类异戊二烯代谢途径分支的第一反应，专门用于甾醇生物合成。SQS产生角鲨烯是一个不寻常的两步反应，其中两个法尼酯二磷酸分子头对头浓缩。最近的研究对该酶的反应机制、功能域和转录调控有了更深入的了解。定点诱变已经鉴定出对SQS活性至关重要的保守的Asp、Tyr和Phe残基。假设Asp残基是底物结合所必需的；Tyr和Phe残基可以稳定碳正离子反应中间体。对SQS晶体结构的研究将为进一步研究酶的结构与功能之间的关系提供指导。SQS活性、蛋白和mRNA水平受胆固醇状态和细胞因子TNF-α和IL-1β的调节。胆固醇不足时SQS启动子的激活是由固醇调节元件结合蛋白SREBP-1a和SREBP-2介导的。单个SREBPs及其附属转录因子对SQS转录控制的精确贡献以及细胞因子调控SQS的机制是当前研究的重点。
Mammalian squalene synthase (SQS) catalyzes the first reaction of the branch of the isoprenoid metabolic pathway committed specifically to sterol biosynthesis. SQS produces squalene in an unusual two-step reaction in which two molecules of farnesyl diphosphate are condensed head-to-head. Recent studies have advanced understanding of the reaction mechanism, the functional domains of the enzyme, and transcriptional regulation of the gene. Site-directed mutagenesis has identified conserved Asp, Tyr, and Phe residues that are essential for SQS activity. The Asp residues are hypothesized to be required for substrate binding; the Tyr and Phe residues may stabilize carbocation reaction intermediates. The elucidation of SQS crystal structure will most likely direct future research on the relationship between enzyme structure and function. SQS activity, protein, and mRNA levels are regulated by cholesterol status and by the cytokines TNF-α and IL-1β. Activation of the SQS promoter in response to cholesterol deficit is mediated by sterol regulatory element binding proteins SREBP-1a and SREBP-2. The precise contributions made by individual SREBPs and accessory transcription factors to SQS transcriptional control, and the mechanisms underlying cytokine regulation of SQS are major foci of current research.