Tansey T R, Shechter I
Department of Biochemistry and Molecular Biology, Uniformed Services University of the Health Sciences, 430l Jones Bridge Road, Bethesda, MD 20814-4799, USA.
Biochim Biophys Acta. 2000 Dec 15;1529(1-3):49-62. doi: 10.1016/s1388-1981(00)00137-2.
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-alpha and IL-1beta. 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.
哺乳动物鲨烯合酶（SQS）催化类异戊二烯代谢途径中专门用于甾醇生物合成分支的第一步反应。SQS通过一种不同寻常的两步反应生成鲨烯，即两分子法呢基二磷酸进行头对头缩合。最近的研究增进了对该反应机制、酶的功能结构域以及基因转录调控的理解。定点诱变已确定了对SQS活性至关重要的保守天冬氨酸、酪氨酸和苯丙氨酸残基。推测天冬氨酸残基是底物结合所必需的；酪氨酸和苯丙氨酸残基可能稳定碳正离子反应中间体。SQS晶体结构的阐明很可能会指导未来关于酶结构与功能关系的研究。SQS活性、蛋白质和mRNA水平受胆固醇状态以及细胞因子肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）的调节。胆固醇缺乏时SQS启动子的激活由甾醇调节元件结合蛋白SREBP-1a和SREBP-2介导。单个SREBP和辅助转录因子对SQS转录控制的确切贡献，以及细胞因子对SQS调节的机制是当前研究的主要重点。
