Novel activities of CYP11A1 and their potential physiological significance

Andrzej T. Slominski, Wei Li, Tae Kang Kim, Igor Semak, Jin Wang, Jordan K. Zjawiony, Robert C. Tuckey

Research output: Contribution to journalReview article

87 Citations (Scopus)

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 Δ7steroids in Smith-Lemli-Opitz syndrome patients. The activity of CYP11A1 is affected by the structure of the substrate with sterols having steroidal or Δ7-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 Δ7steroids 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’.

Original languageEnglish (US)
Pages (from-to)25-37
Number of pages13
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume151
DOIs
StatePublished - Jan 1 2015

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Cholesterol Side-Chain Cleavage Enzyme
Ergocalciferols
Ergosterol
Pregnenolone
Hydroxylation
Cholecalciferol
Cholesterol
Sterols
Substrates
Adrenal Glands
Metabolism
Epidermis
Desmosterol
Smith-Lemli-Opitz Syndrome
Phytosterols
Molecular modeling
Enzymes
Metabolites
Serum
Keratinocytes

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Novel activities of CYP11A1 and their potential physiological significance. / Slominski, Andrzej T.; Li, Wei; Kim, Tae Kang; Semak, Igor; Wang, Jin; Zjawiony, Jordan K.; Tuckey, Robert C.

In: Journal of Steroid Biochemistry and Molecular Biology, Vol. 151, 01.01.2015, p. 25-37.

Research output: Contribution to journalReview article

Slominski, Andrzej T. ; Li, Wei ; Kim, Tae Kang ; Semak, Igor ; Wang, Jin ; Zjawiony, Jordan K. ; Tuckey, Robert C. / Novel activities of CYP11A1 and their potential physiological significance. In: Journal of Steroid Biochemistry and Molecular Biology. 2015 ; Vol. 151. pp. 25-37.
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