title: Towards a unifying mechanism for CYP17 mutations that cause isolated 17,20-lyase deficiency.
abstract: Cytochrome P450c17 (CYP17) is a single hemoprotein that catalyzes both the 17alpha-hydroxylase and 17,20-lyase reactions in all species thus far examined. Severe defects in CYP17 cause classical 17-hydroxylase deficiency, but other defects result in partial or selective deficiency states. One such variant is the syndrome of isolated 17,20-lyase deficiency. Recent detailed studies of the biochemical properties of the mutant CYP17 enzymes from patients with isolated 17,20-lyase deficiency demonstrate that alterations in the interaction of CYP17 with its redox partner proteins P450-oxidoreductase and cytochrome b5 form the biochemical basis for these selective enzyme defects. Site-directed mutagenesis studies have confirmed that neutralization of any of several positive charges on the redox partner binding surface results in selective disruption of 17,20-lyase activity. In one case diagnosed as isolated 17,20-lyase deficiency, the identified mutation did not map to the redox partner binding surface; however, we have shown that this mutation cannot be the cause of isolated 17,20-lyase deficiency in this patient. These consistent results have prompted us to propose a paradigm in which neutralization of positive charges in the redox partner binding surface of CYP17 may be the predominant if not sole mechanism leading to isolated 17,20-lyase deficiency.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390-8857, USA. richard.auchus@utsouthwestern.edu
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Auchus
authors.forename: Manisha K
authors.initials: MK
authors.lastname: Gupta
mesh_terms: D000312:Adrenal Hyperplasia, Congenital / Q000201:enzymology* / Q000235:genetics*; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D019556:COS Cells; D004563:Electrochemistry; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000502:physiology*; D010084:Oxidation-Reduction; D013254:Steroid 17-alpha-Hydroxylase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D013254:Steroid 17-alpha-Hydroxylase