The CYP17A1 gene resides on chromosome 10 at the band 10q24.3 and contains 8 exons.[5] The cDNA of this gene spans a length of 1527 bp.[8] This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are generally regarded as monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids, and other lipids, including the remarkable carbon-carbon bond scission catalyzed by this enzyme.
CYP17A1 is a 57.4 kDa protein that belongs to the cytochrome P450 family.[10][11] The protein encoded by its cDNA is composed of 508 amino acid residues. As an enzyme, CYP17A1 possesses an active site that associates with a heme prosthetic group to catalyze biosynthetic reactions.[8] Based on its known structures while bound to two steroidal inhibitors, abiraterone and galeterone, CYP17A1 possesses the canonical cytochrome P450 fold present in other complex P450 enzymes that participate in steroidogenesis or cholesterol metabolism, though it orients the steroid ligands toward the F and G helices, perpendicular to the heme group, rather than the β1 sheet.[12][13]
Furthermore, the 17,20-lyase activity is dependent on cytochrome P450 oxidoreductase (POR) cytochrome b5 (CYB5) and phosphorylation.[16][17][18] Cytochrome b5 acts as a facilitator for 17,20 lyase activity of CYP17A1 and can donate a second electron to some P450s. In humans the production of testosterone via pregnenolone to17-OHPreg and DHEA by the CYP17A1 requires POR.[19][20] Human CYP17A1 protein is phosphorylated on serine and threonine residues by a cAMP-dependent protein kinase. Phosphorylation of the protein increases 17,20-lyase activity, while dephosphorylation virtually eliminates this activity.[18]
In humans, the CYP17A1 gene is largely associated with endocrine effects and steroid hormone metabolism.[22][23][24] Furthermore, mutations in the CYP17A1 gene are associated with rare forms of congenital adrenal hyperplasia, in particular 17α-hydroxylase deficiency/17,20-lyase deficiency and isolated 17,20-lyase deficiency. Overall, CYP17A1 is an important target for inhibition in the treatment of prostate cancer because it produces androgen that is required for tumor cell growth.[25][26] The decreased enzyme activity of CYP17A1 is related to infertility due to hypogonadotropic hypogonadism. In females, folliculogenesis is arrested, while in males, testicular atrophy with interstitial cell proliferation and arrested spermatogenesis. Although generally anovulatory, there are some case reports of women with 17α-hydroxylase deficiency who underwent spontaneous menarche with cyclic menses.[27]
A multi-locus genetic risk score study based on a combination of 27 loci, including the CYP17A1 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).[9]
Currently,[when?] the FDA has approved only one CYP17A1 inhibitor, abiraterone, which contains a steroidal scaffold that is similar to the endogenous CYP17A1 substrates. Abiraterone is structurally similar to the substrates of other cytochrome P450 enzymes involved in steroidogenesis, and interference can pose a liability in terms of side effects. Using nonsteroidal scaffolds is expected to enable the design of compounds that interact more selectively with CYP17A1.[26] Potent inhibitors of the CYP17A1 enzyme provide a last line defense against ectopic androgenesis in advanced prostate cancer.[28]
The drug abiraterone acetate, which is used to treat castration-resistant prostate cancer, blocks the biosynthesis of androgens by inhibiting the CYP17A1 enzyme. Abiraterone acetate binds in the active site of the enzyme[29] and coordinates the heme iron through its pyridine nitrogen, mimicking the substrate.[30]
Ketoconazole is an older CYP17A1 inhibitor that is now little used. However, ketoconazole competitively inhibits CYP17A1, therefore its effectiveness will depend on the concentration of ketoconazole. This is in contrast to the abiraterone acetate, that permanently (rather than competitively) disables CYP17A1, once it binds to it.
Seviteronel (VT-464) is a novel CYP17A1 inhibitor which is aimed to avoid co-administration of glucocortoid therapy.[32] In the 2010s it underwent various phases of clinical studies and preclinical models as a drug against prostate cancer or breast cancer.[33][34]
Steroidogenesis
Steroidogenesis, showing, at left side, both reactions of 17α-hydroxylase, and both actions of 17, 20 lyase.
^ abBoulpaep EL, Boron, WF (2005). Medical physiology: a cellular and molecular approach. St. Louis, Mo: Elsevier Saunders. p. 1180. ISBN1-4160-2328-3.
^Ma YN, Cao CY, Wang QW, Gui WJ, Zhu GN (October 2016). "Effects of azocyclotin on gene transcription and steroid metabolome of hypothalamic-pituitary-gonad axis, and their consequences on reproduction in zebrafish (Danio rerio)". Aquatic Toxicology. 179: 55–64. doi:10.1016/j.aquatox.2016.08.006. PMID27571716.
^Kostin VA, Zolottsev VA, Kuzikov AV, Masamrekh RA, Shumyantseva VV, Veselovsky AV, Stulov SV, Novikov RA, Timofeev VP, Misharin AY (November 2016). "Oxazolinyl derivatives of [17(20)E]-21-norpregnene differing in the structure of A and B rings. Facile synthesis and inhibition of CYP17A1 catalytic activity". Steroids. 115: 114–122. doi:10.1016/j.steroids.2016.06.002. PMID27505042. S2CID205256638.
^Bird IM, Abbott DH (October 2016). "The hunt for a selective 17,20 lyase inhibitor; learning lessons from nature". The Journal of Steroid Biochemistry and Molecular Biology. 163: 136–46. doi:10.1016/j.jsbmb.2016.04.021. PMC5046225. PMID27154414. VT464 is another recently developed compound proposed to act as a selective lyase inhibitor, and more complete data is available in the public domain to support this claim. A review of preliminary data released suggest the IC50 for Human CYP17 lyase activity is ten times lower than for hydroxylase 15 and in nonhuman primates VT464 was able to suppress circulating testosterone as effectively as abiraterone, but with minimally depressed cortisol (remaining at 82% control compared to only 9% with aberaterone), and without associated increases in pregnenolone, progesterone and mineralocorticoids otherwise observed with abiraterone. Like Galaterone, VT464 is also in use in clinical trials without co-administration of prednisone. Together with the clear lack of suppression of circulating cortisol in nonhuman primates, these data argue that VT464 may indeed be a selective 17,20 lyase inhibitor.
Haider SM, Patel JS, Poojari CS, Neidle S (July 2010). "Molecular modeling on inhibitor complexes and active-site dynamics of cytochrome P450 C17, a target for prostate cancer therapy". Journal of Molecular Biology. 400 (5): 1078–98. doi:10.1016/j.jmb.2010.05.069. PMID20595043.
