Structure and regulation of mammalian squalene synthase.
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.
Tansey
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Department of Biochemistry and Molecular Biology, Uniformed Services University of the Health Sciences, 430l Jones Bridge Road, Bethesda, MD 20814-4799, USA.
Shechter
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D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000494:pharmacology; D002460:Cell Line; D002784:Cholesterol / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000235:genetics / Q000494:pharmacology; D004789:Enzyme Activation; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000737:chemistry / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008956:Models, Chemical; D008969:Molecular Sequence Data; D010088:Oxidoreductases / Q000737:chemistry / Q000235:genetics*; D011401:Promoter Regions, Genetic; D013185:Squalene / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors / Q000235:genetics / Q000494:pharmacology; D014158:Transcription, Genetic; D014162:Transfection
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; C497387:SREBF1 protein, human; C497390:SREBF2 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; D013185:Squalene; D002784:Cholesterol; D010088:Oxidoreductases; D013186:Farnesyl-Diphosphate Farnesyltransferase