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Human cytochrome P450 17A1 bound to inhibitors (R)- and (S)- orteronel
Structural highlights
DiseaseCP17A_HUMAN Congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency;46,XY disorder of sex development due to isolated 17, 20 lyase deficiency. The disease is caused by mutations affecting the gene represented in this entry. FunctionCP17A_HUMAN Conversion of pregnenolone and progesterone to their 17-alpha-hydroxylated products and subsequently to dehydroepiandrosterone (DHEA) and androstenedione. Catalyzes both the 17-alpha-hydroxylation and the 17,20-lyase reaction. Involved in sexual development during fetal life and at puberty.[1] Publication Abstract from PubMedHuman steroidogenic cytochrome P450 17A1 (CYP17A1) is a bifunctional enzyme that performs both hydroxylation and lyase reactions, with the latter required to generate androgens that fuel prostate cancer proliferation. The steroid abiraterone, the active form of the only FDA- approved CYP17A1 inhibitor, binds the catalytic heme iron, nonselectively impeding both reactions and ultimately causing undesirable corticosteroid imbalance. Some non-steroidal inhibitors reportedly inhibit the lyase reaction more than the preceding hydroxylase reaction, which would be clinically advantageous, but the mechanism is not understood. Thus, the non- steroidal inhibitors seviteronel and orteronel and the steroidal inhibitors abiraterone and galeterone were compared with respect to their binding modes and hydroxylase vs. lyase inhibition. Binding studies and X-ray structures of CYP17A1 with non-steroidal inhibitors reveal coordination to the heme iron like the steroidal inhibitors. (S)-Seviteronel binds similarly to both observed CYP17A1 conformations. However, (S)-orteronel and (R)-orteronel bind to distinct CYP17A1 conformations that differ in a region implicated in ligand entry/exit and the presence of a peripheral ligand. To reconcile these binding modes with enzyme function, side- by-side enzymatic analysis was undertaken and revealed that neither the non-steroidal seviteronel or (S)-orteronel inhibitors demonstrated significant lyase selectivity, but the less potent (R)-orteronel was 8- to 11-fold selective for lyase inhibition. While active site iron coordination is consistent with competitive inhibition, conformational selection for binding of some inhibitors and the differential presence of a peripheral ligand molecule suggest the possibility of CYP17A1 functional modulation by features outside the active site. Structural and Functional Evaluation of Clinically-Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 (CYP17A1).,Petrunak EM, Rogers SA, Aube J, Scott EE Drug Metab Dispos. 2017 Apr 3. pii: dmd.117.075317. doi: 10.1124/dmd.117.075317. PMID:28373265[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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