Steroid 17-alpha-hydroxylase/17,20 lyase

Definition:

A cytochrome P450 monooxygenase involved in corticoid and androgen biosynthesis. Catalyzes 17-alpha hydroxylation of C21 steroids, which is common for both pathways. A second oxidative step, required only for androgen synthesis, involves an acyl-carbon cleavage. The 17-alpha hydroxy intermediates, as part of adrenal glucocorticoids biosynthesis pathway, are precursors of cortisol (Probable). Hydroxylates steroid hormones, pregnenolone and progesterone to form 17-alpha hydroxy metabolites, followed by the cleavage of the C17-C20 bond to form C19 steroids, dehydroepiandrosterone (DHEA) and androstenedione. Has 16-alpha hydroxylase activity. Catalyzes 16-alpha hydroxylation of 17-alpha hydroxy pregnenolone, followed by the cleavage of the C17-C20 bond to form 16-alpha-hydroxy DHEA. Also 16-alpha hydroxylates androgens, relevant for estriol synthesis. Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase).

References:

[1]. Elyse M Petrunak, et al. Structures of human steroidogenic cytochrome P450 17A1 with substrates. J Biol Chem. 2014 Nov 21;289(47):32952-64. [Content Brief]

[2]. Natasha M DeVore, et al. Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001. Nature. 2012 Jan 22;482(7383):116-9. [Content Brief]

[3]. R J Auchus, et al. Cytochrome b5 augments the 17,20-lyase activity of human P450c17 without direct electron transfer. J Biol Chem. 1998 Feb 6;273(6):3158-65. [Content Brief]

[4]. C E Fardella, et al. Point mutation of Arg440 to His in cytochrome P450c17 causes severe 17 alpha-hydroxylase deficiency. J Clin Endocrinol Metab. 1994 Jul;79(1):160-4. [Content Brief]

[5]. Francis K Yoshimoto, et al. Mechanism of 17α,20-Lyase and New Hydroxylation Reactions of Human Cytochrome P450 17A1: 18O LABELING AND OXYGEN SURROGATE EVIDENCE FOR A ROLE OF A PERFERRYL OXYGEN. J Biol Chem. 2016 Aug 12;291(33):17143-64. [Content Brief]

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