CYP17A1
| Steroid 17-alpha-hydroxylase/17,20 lyase | |||
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| Sources:Amigo / QuickGO | |||
17α-hydroxypregnenolone to split the side-chain off the steroid nucleus (the 17,20-lyase activity, EC 1.14.14.32).[7]
StructureGeneThe CYP17A1 gene resides on chromosome 10 at the band 10q24.3 and contains 8 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.
The CYP17A1 gene may also contain variants associated with increased risk of coronary artery disease.[9][non-primary source needed] ProteinCYP17A1 is a 57.4 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]
Expressionluteinized granulosa cells in ovarian follicles.[14] In addition to classical steroidogenic tissue, CYP17A1 has also been detected in the heart, kidney, and adipose tissue.[14] In the fetus, CYP17A1 has been reported in the kidney, thymus, and spleen.[14]
FunctionCYP17A1 is a member of the 17α-hydroxypregnenolone to dehydroepiandrosterone (DHEA).[15] Mutations in this gene are associated with isolated steroid-17α-hydroxylase deficiency, 17α-hydroxylase/17,20-lyase deficiency, pseudohermaphroditism, and adrenal hyperplasia.[5]
Furthermore, the 17,20-lyase activity is dependent on cytochrome cAMP-dependent protein kinase. Phosphorylation of the protein increases 17,20-lyase activity, while dephosphorylation virtually eliminates this activity.[18]
Clinical significanceMutations in this gene are associated with rare forms of congenital adrenal hyperplasia, specifically 17α-hydroxylase deficiency/17,20-lyase deficiency and isolated 17,20-lyase deficiency.[21] 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] Clinical markerA 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] As a drug targetCYP17A1 inhibitorsCurrently,[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 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]
Since 2014, castration-resistant prostate cancer.[31]
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
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