title: Structural insights into the function of steroidogenic cytochrome P450 17A1.
abstract: Cytochrome P450 17A1 (CYP17A1) operates at the core of human steroidogenesis, directing precursors into mineralocorticoids, glucocorticoids, or sex steroids. Although the 17α-hydroxylase and 17,20-lyase activities of this dual function enzyme have been investigated extensively, until recently no CYP17A1 structures were available to inform our understanding. Structures of CYP17A1 with a range of steroidal inhibitors and substrates are now available. This review relates functional knowledge of this enzyme to structural features defining the selective differentiation between its various substrates. While both hydroxylase and lyase substrates have similar orientations with respect to the heme, subtle differences in hydrogen bonding between CYP17A1 and the C3 substituent at the opposite end of ligands appear to correlate with differential substrate utilization and product formation. Complementary structural information from solution NMR supports cytochrome b5allosteric modulation of the lyase reaction, implicating regions involved in ligand access to the otherwise buried active site.
authors: Department of Medicinal Chemistry, 1251 Wescoe Hall Dr., The University of Kansas, Lawrence, KS 66045, USA.
authors: Rahul
authors: R
authors: Yadav
authors: Department of Medicinal Chemistry, 1251 Wescoe Hall Dr., The University of Kansas, Lawrence, KS 66045, USA.
authors: Elyse M
authors: EM
authors: Petrunak
authors: Department of Medicinal Chemistry, 1251 Wescoe Hall Dr., The University of Kansas, Lawrence, KS 66045, USA.
authors: D Fernando
authors: DF
authors: Estrada
authors: Department of Medicinal Chemistry, 1251 Wescoe Hall Dr., The University of Kansas, Lawrence, KS 66045, USA. Electronic address: eescott@ku.edu.
authors: Emily E
authors: EE
authors: Scott
mesh_terms: D000818:Animals; D006801:Humans; D006900:Hydroxylation; D011284:Pregnenolone / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism; D013237:Stereoisomerism; D013254:Steroid 17-alpha-Hydroxylase / Q000737:chemistry* / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D011374:Progesterone; D011284:Pregnenolone; D013254:Steroid 17-alpha-Hydroxylase
keywords: 17,20-Lyase; 17α−hydroxylase; Cytochrome P450 17A1; Steroidogenesis; X-ray crystallography