title: Novel activities of CYP11A1 and their potential physiological significance.
abstract: CYP11A1, found only in vertebrates, catalyzes the first step of steroidogenesis where cholesterol is converted to pregnenolone. The purified enzyme, also converts desmosterol and plant sterols including campesterol and β-sitosterol, to pregnenolone. Studies, initially with purified enzyme, reveal that 7-dehydrocholesterol (7DHC), ergosterol, lumisterol 3, and vitamins D3 and D2 also serve as substrates for CYP11A1, with 7DHC being better and vitamins D3 and D2 being poorer substrates than cholesterol. Adrenal glands, placenta, and epidermal keratinocytes can also carry out these conversions and 7-dehydropregnenolone has been detected in the epidermis, adrenal glands, and serum, and 20-hydroxyvitamin D3 was detected in human serum and the epidermis. Thus, this metabolism does appear to occur in vivo, although its quantitative importance and physiological role remain to be established. CYP11A1 action on 7DHC in vivo is further supported by detection of Δ(7)steroids in Smith-Lemli-Opitz syndrome patients. The activity of CYP11A1 is affected by the structure of the substrate with sterols having steroidal or Δ(7)-steroidal structures undergoing side chain cleavage following hydroxylations at C22 and C20. In contrast, metabolism of vitamin D involves sequential hydroxylations that start at C20 but do not lead to cleavage. Molecular modeling using the crystal structure of CYP11A1 predicts that other intermediates of cholesterol synthesis could also serve as substrates for CYP11A1. Finally, CYP11A1-derived secosteroidal hydroxy-derivatives and Δ(7)steroids are biologically active when administered in vitro in a manner dependent on the structure of the compound and the lineage of the target cells, suggesting physiological roles for these metabolites. This article is part of a special issue entitled 'SI: Steroid/Sterol signaling'.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Tennessee HSC, Memphis, TN, USA; Division of Rheumatology of the Department of Medicine, University of Tennessee HSC, Memphis, TN, USA. Electronic address: aslominski@uthsc.edu.
authors.forename: Andrzej T
authors.initials: AT
authors.lastname: Slominski
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee HSC, Memphis, TN, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Tennessee HSC, Memphis, TN, USA.
authors.forename: Tae-Kang
authors.initials: TK
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, Belarusian State University, Minsk, Belarus.
authors.forename: Igor
authors.initials: I
authors.lastname: Semak
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee HSC, Memphis, TN, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677-1848, USA.
authors.forename: Jordan K
authors.initials: JK
authors.lastname: Zjawiony
authors.affiliation: School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA, Australia. Electronic address: robert.tuckey@uwa.edu.au.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Tuckey
mesh_terms: D000818:Animals; D002762:Cholecalciferol / Q000378:metabolism; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000378:metabolism*; D003684:Dehydrocholesterols / Q000378:metabolism; D004872:Ergocalciferols / Q000378:metabolism; D006801:Humans; D013261:Sterols / Q000378:metabolism
chemical_list: D003684:Dehydrocholesterols; D004872:Ergocalciferols; D013261:Sterols; D002762:Cholecalciferol; C016705:7-dehydrocholesterol; D002786:Cholesterol Side-Chain Cleavage Enzyme
keywords: 7-Dehydrocholesterol; CYP11A1; Cholesterol; Ergosterol; Plant sterols; Vitamin D