The eukaryotic class II cytochrome P450 enzyme CYP17 is an endoplasmic reticulum membrane bound multifunctional protein with 17a-hydroxylase and C17,20-lyase activities, both engaged on a single active site (Fig. 2) [23-28].
Alike other cytochrome P450 enzymes, this cysteinato-heme enzyme functions as a mono-oxygenase by activating and cleaving molecular dioxygen so that one of the atoms is inserted into its substrate while the other gives rise to a water molecule [29, 30]. P450 reductase transfer of electrons in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) is a requisite for both catalytic activities [29, 30]. Its natural substrates are pregnenolone (Preg) and progesterone (Prog) which are first hydroxylated at the 17 position and then their side chain is cleaved to afford 17-keto derivatives (dehydroepiandrosterone, DHEA and androstenedione, AD respectively), which are androgen precursors. The andro-gens (testosterone, T and dihydrotestosterone, DHT) that result from further metabolization of both DHEA and AD, bind to the AR and initiate transcription, triggering the synthesis of specific proteins and also cell proliferation [31, 32]. Apart from male physiology, androgens are involved in PC development and progression, as at least 80% of human PCs respond favorably to androgen ablation therapy [33-35]. This dependence of PC on androgen signalling has been known for about 70 years [36, 37] and the use of strategies that effectively lower the levels of circulating androgens in PC patients has been the mainstay of PC therapy for several decades.
CYP17 is localized to the adrenals, testes, placenta and ovaries and plays a fundamental role in the synthesis of not only sex steroids but also corticosteroids. The testes are responsible for about 90-95% of the circulating androgens and the adrenals for the remaining 5-10% . Human CYP17 is expressed from a single gene mapped to a specific sub-band of chromosome 10 at q24.3, in steroidogenic tissue [39-41]. This bifunctionality of the product of a single gene has been explained by modulation of the enzyme's C17,20-lyase activity by several factors such as the presence of the electron carrier P450 oxidoreductase (POR) [42, 43], cytochrome b5 (cyt. b5) [44-48], the phosphorylation of serine/threonine residues [44, 49-51], and single amino acid mutations [52-55]. The effective ratio of C17,20-lyase to 17a-hydroxylase activities is under tight control during development in the human adrenal cortex, and becomes greatly elevated in adrenarche, where a rise in DHEA body concentrations is observed without concomitant increase in glucocorticoid or mineralocorticoid production . Thus, production of the mineralocorticoid aldosterone occurs in the adrenal zona glomerulosa where CYP17 is absent. In the zona reticularis and in the gonads, the presence of both activities drives the production of sex steroids, whereas overexpression of 17a-hydroxylase activity is fundamental for the production of glucorticoids in the zona fasciculata.
The crystal structure of CYP17 remains yet to be determined since purification from its membrane environment and subsequent reconstitution of activity in vitro has proved to be a difficult task [26, 29, 30]. However, the availability of some cytochrome P450 crystal structures, such as the ones from prokaryotic P450cam [57, 58], P450BM3 [59-61], and P450 CY-PeryF , as well as the eukaryotic CYP3A4  and AYP2C9  among others , has been a valuable tool in building homology models. In addition, the high-resolution crystal structures of mammalian P450s that are significantly homologous to CYP17 and complexed to a variety of ligands  have now been uploaded onto the Protein Data Bank (PDB). A very recent model has been developed based on these crystal structures from closely related mammalian cytochrome P450s . In another approach, a truncated, His-tagged version of human CYP17 was generated from a synthetic complimentary DNA and expressed in E. coli . These models were used to dock known CYP17 inhibitors to the active site.
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