title: The terminal enzymes of cholesterol synthesis, DHCR24 and DHCR7, interact physically and functionally.
abstract: Cholesterol is essential to human health, and its levels are tightly regulated by a balance of synthesis, uptake, and efflux. Cholesterol synthesis requires the actions of more than twenty enzymes to reach the final product, through two alternate pathways. Here we describe a physical and functional interaction between the two terminal enzymes. 24-Dehydrocholesterol reductase (DHCR24) and 7-dehydrocholesterol reductase (DHCR7) coimmunoprecipitate, and when the DHCR24 gene is knocked down by siRNA, DHCR7 activity is also ablated. Conversely, overexpression of DHCR24 enhances DHCR7 activity, but only when a functional form of DHCR24 is used. DHCR7 is important for both cholesterol and vitamin D synthesis, and we have identified a novel layer of regulation, whereby its activity is controlled by DHCR24. This suggests the existence of a cholesterol "metabolon", where enzymes from the same metabolic pathway interact with each other to provide a substrate channeling benefit. We predict that other enzymes in cholesterol synthesis may similarly interact, and this should be explored in future studies.
authors: School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW 2052, Australia.
authors: Winnie
authors: W
authors: Luu
authors: School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW 2052, Australia.
authors: Gene
authors: G
authors: Hart-Smith
authors: School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW 2052, Australia.
authors: Laura J
authors: LJ
authors: Sharpe
authors: School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW 2052, Australia.
authors: Andrew J
authors: AJ
authors: Brown
mesh_terms: D000818:Animals; D016466:CHO Cells; D002784:Cholesterol / Q000096:biosynthesis*; D006224:Cricetinae; D003412:Cricetulus; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D047468:Immunoprecipitation; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D040901:Proteomics; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D002784:Cholesterol; D044925:Oxidoreductases Acting on CH-CH Group Donors; C499055:DHCR24 protein, human; C019995:7-dehydrocholesterol reductase
keywords: 24-dehydrocholesterol reductase; 7-dehydrocholesterol; 7-dehydrocholesterol reductase; desmosterol
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