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CYP17A1

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Steroid 17- Alpha -hydroxylase/17,20 lyase
Identifiers
EC no.1.14.14.19
CAS no.9029-67-8
Alt. namesP450c17, CYP17A1, steroid 17- Alpha -hydroxylase/17,20 lyase, CYPXVII, cytochrome P450 17A1, cytochrome p450 XVIIA1, cytochrome P450-C17, cytochrome P450, family 17, subfamily A, polypeptide 1, steroid 17- Alpha -monooxygenase, cytochrome P450c17, 4.1.2.30, 17- Alpha -hydroxyprogesterone aldolase, cytochrome P450, subfamily XVII (steroid 17- Alpha -hydroxylase), steroid 17 Alpha -hydroxylase/17,20 lyase, IPR033282
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDBstructuresRCSB PDBPDBePDBsum
Search
PMCarticles
PubMedarticles
NCBIproteins
CYP17A1
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesCYP17A1,CPT7, CYP17, P450C17, S17AH, cytochrome P450 family 17 subfamily A member 1
External IDsOMIM:609300;MGI:88586;HomoloGene:73875;GeneCards:CYP17A1;OMA:CYP17A1 - orthologs
EC number1.14.14.32 1.14.14.19, 1.14.14.32
Orthologs
SpeciesHumanMouse
Entrez

1586

13074

Ensembl

ENSG00000148795

ENSMUSG00000003555

UniProt

P05093

P27786

RefSeq (mRNA)

NM_000102

NM_007809

RefSeq (protein)

NP_000093

NP_031835

Location (UCSC)Chr 10: 102.83 – 102.84 MbChr 19: 46.66 – 46.66 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Cytochrome P450 17A1(steroid 17α-monooxygenase,17α-hydroxylase,17- Alpha -hydroxylase,17,20-lyase,17,20-desmolase) is anenzymeof thehydroxylasetype that in humans is encoded by theCYP17A1geneonchromosome 10.[5]It is ubiquitously expressed in many tissues and cell types, including thezona reticularisandzona fasciculata(but notzona glomerulosa) of theadrenal cortexas well asgonadaltissues.[6][7]It has both 17α-hydroxylase and 17,20-lyase activities, and is a key enzyme in the steroidogenic pathway that producesprogestins,mineralocorticoids,glucocorticoids,androgens,andestrogens.More specifically, the enzyme acts uponpregnenoloneandprogesteroneto add ahydroxyl(-OH) group at carbon 17 position (C17) of the steroid D ring (the 17α-hydroxylase activity,EC1.14.14.19), or acts upon17α-hydroxyprogesteroneand17α-hydroxypregnenoloneto split the side-chain off the steroid nucleus (the 17,20-lyaseactivity,EC1.14.14.32).[7]

Structure

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Gene

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TheCYP17A1gene resides on chromosome 10 at the band 10q24.3 and contains 8exons.[5]ThecDNAof this gene spans a length of 1527bp.[8]This gene encodes a member of thecytochrome P450superfamily of enzymes. The cytochrome P450 proteins are generally regarded asmonooxygenasesthat catalyze many reactions involved in drug metabolism and synthesis ofcholesterol,steroids,and otherlipids,including the remarkable carbon-carbon bond scission catalyzed by this enzyme.

TheCYP17A1gene may also contain variants associated with increased risk ofcoronary artery disease.[9][non-primary source needed]

Protein

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CYP17A1 is a 57.4kDaprotein that belongs to the cytochrome P450 family.[10][11]The protein encoded by its cDNA is composed of 508amino acid residues.As an enzyme, CYP17A1 possesses anactive sitethat associates with ahemeprosthetic group to catalyze biosynthetic reactions.[8]Based on its known structures while bound to twosteroidalinhibitors,abirateroneandgaleterone,CYP17A1 possesses the canonical cytochrome P450 fold present in other complex P450 enzymes that participate insteroidogenesisorcholesterolmetabolism, though it orients the steroid ligands toward the F and G helices, perpendicular to the heme group, rather than the β1 sheet.[12][13]

Expression

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Expressionof CYP17A1 has been found in all of the traditionalsteroidogenictissuesexcept theplacenta,including thezona reticularisandzona fasciculataof theadrenal cortex,theLeydig cellsof thetestes,thethecal cellsof theovaries,and, more recently, inluteinizedgranulosa cellsinovarian follicles.[14]In addition to classical steroidogenic tissue, CYP17A1 has also been detected in theheart,kidney,andadipose tissue.[14]In thefetus,CYP17A1 has been reported in the kidney,thymus,andspleen.[14]

Function

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CYP17A1 is a member of thecytochrome P450superfamily of enzymes localized in theendoplasmic reticulum.Proteins in this family are monooxygenases that catalyze synthesis ofcholesterol,steroidsand other lipids and are involved in drug metabolism.[5]CYP17A1 has both 17α-hydroxylase activity (EC1.14.14.19) and 17,20-lyase activity (EC1.14.14.32). The 17α-hydroxylase activity of CYP17A1 is required for the generation ofglucocorticoidssuch as cortisol, but both the hydroxylase and 17,20-lyase activities of CYP17A1 are required for the production ofandrogenicandoestrogenicsex steroids by converting17α-hydroxypregnenolonetodehydroepiandrosterone (DHEA).[15]Mutations in this gene are associated with isolated steroid-17α-hydroxylase deficiency, 17α-hydroxylase/17,20-lyase deficiency,pseudohermaphroditism,andadrenal hyperplasia.[5]

Furthermore, the 17,20-lyase activity is dependent on cytochromeP450 oxidoreductase(POR) cytochrome b5 (CYB5) andphosphorylation.[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 oftestosteronevia pregnenolone to17-OHPreg and DHEA by the CYP17A1 requires POR.[19][20]Human CYP17A1 protein isphosphorylatedon serine and threonine residues by acAMP-dependent protein kinase.Phosphorylation of the protein increases 17,20-lyase activity, while dephosphorylation virtually eliminates this activity.[18]

Clinical significance

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Mutations in this gene are associated with rare forms ofcongenital adrenal hyperplasia,specifically17α-hydroxylase deficiency/17,20-lyase deficiencyandisolated 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 ofcongenital 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]

See also:Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency

Clinical marker

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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]

As a drug target

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CYP17A1 inhibitors

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Main article:CYP17A1 inhibitor

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. Usingnonsteroidalscaffolds 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 drugabiraterone acetate,which is used to treatcastration-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 thehemeiron through its pyridine nitrogen, mimicking the substrate.[30]

Since 2014,galeteronehas been inphase IIIclinical trialsforcastration-resistant prostate cancer.[31]

Ketoconazoleis an olderCYP17A1 inhibitorthat is now little used. However, ketoconazole competitively inhibits CYP17A1, therefore its effectiveness will depend on the concentration of ketoconazole. This is in contrast to theabiraterone acetate,that permanently (rather than competitively) disables CYP17A1, once it binds to it.

Seviteronel(VT-464) is a novelCYP17A1 inhibitorwhich 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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Steroidogenesis,showing, at left side, both reactions of 17α-hydroxylase, and both actions of 17, 20 lyase.

Additional images

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See also

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References

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  1. ^abcGRCh38: Ensembl release 89: ENSG00000148795–Ensembl,May 2017
  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000003555–Ensembl,May 2017
  3. ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^abcd"CYP17A1 cytochrome P450 family 17 subfamily A member 1 [Homo sapiens (human)] - Gene - NCBI".ncbi.nlm.nih.gov.Archivedfrom the original on 2015-06-23.Retrieved2016-09-27.
  6. ^"BioGPS - your Gene Portal System".biogps.org.Archivedfrom the original on 2011-08-20.Retrieved2016-10-11.
  7. ^abBoulpaep EL, Boron, WF (2005).Medical physiology: a cellular and molecular approach.St. Louis, Mo: Elsevier Saunders. p. 1180.ISBN1-4160-2328-3.
  8. ^abVasaitis TS, Bruno RD, Njar VC (May 2011)."CYP17 inhibitors for prostate cancer therapy".The Journal of Steroid Biochemistry and Molecular Biology.125(1–2): 23–31.doi:10.1016/j.jsbmb.2010.11.005.PMC3047603.PMID21092758.
  9. ^abMega JL, Stitziel NO, Smith JG, Chasman DI, Caulfield M, Devlin JJ, et al. (June 2015)."Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials".Lancet.385(9984): 2264–2271.doi:10.1016/S0140-6736(14)61730-X.PMC4608367.PMID25748612.
  10. ^"CYP17A1 - Steroid 17- Alpha -hydroxylase/17,20 lyase - Homo sapiens (Human) - CYP17A1 gene & protein".uniprot.org.Archivedfrom the original on 2016-10-12.Retrieved2016-10-11.
  11. ^Estrada DF, Laurence JS, Scott EE (February 2016)."Cytochrome P450 17A1 Interactions with the FMN Domain of Its Reductase as Characterized by NMR".The Journal of Biological Chemistry.291(8): 3990–4003.doi:10.1074/jbc.M115.677294.PMC4759177.PMID26719338.
  12. ^DeVore NM, Scott EE (January 2012)."Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001".Nature.482(7383): 116–119.Bibcode:2012Natur.482..116D.doi:10.1038/nature10743.PMC3271139.PMID22266943.
  13. ^Petrunak EM, DeVore NM, Porubsky PR, Scott EE (November 2014)."Structures of human steroidogenic cytochrome P450 17A1 with substrates".The Journal of Biological Chemistry.289(47): 32952–32964.doi:10.1074/jbc.M114.610998.PMC4239641.PMID25301938.
  14. ^abcStorbeck KH, Swart P, Africander D, Conradie R, Louw R, Swart AC (April 2011). "16α-hydroxyprogesterone: origin, biosynthesis and receptor interaction".Molecular and Cellular Endocrinology.336(1–2): 92–101.doi:10.1016/j.mce.2010.11.016.PMID21095220.S2CID5503049.
  15. ^DeVore NM, Scott EE (January 2012)."Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001".Nature.482(7383): 116–119.Bibcode:2012Natur.482..116D.doi:10.1038/nature10743.PMC3271139.PMID22266943.
  16. ^Udhane SS, Dick B, Hu Q, Hartmann RW, Pandey AV (September 2016)."Specificity of anti-prostate cancer CYP17A1 inhibitors on androgen biosynthesis".Biochemical and Biophysical Research Communications.477(4): 1005–1010.doi:10.1016/j.bbrc.2016.07.019.PMID27395338.
  17. ^Pandey AV, Miller WL (April 2005)."Regulation of 17,20 lyase activity by cytochrome b5 and by serine phosphorylation of P450c17".The Journal of Biological Chemistry.280(14): 13265–13271.doi:10.1074/jbc.M414673200.PMID15687493.
  18. ^abZhang LH, Rodriguez H, Ohno S, Miller WL (November 1995)."Serine phosphorylation of human P450c17 increases 17,20-lyase activity: implications for adrenarche and the polycystic ovary syndrome".Proceedings of the National Academy of Sciences of the United States of America.92(23): 10619–10623.Bibcode:1995PNAS...9210619Z.doi:10.1073/pnas.92.23.10619.PMC40663.PMID7479852.
  19. ^Fukami M, Homma K, Hasegawa T, Ogata T (April 2013)."Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development".Developmental Dynamics.242(4): 320–329.doi:10.1002/dvdy.23892.PMID23073980.S2CID44702659.
  20. ^Masiutin M, Yadav M (2023)."Alternative androgen pathways".WikiJournal of Medicine.10:X.doi:10.15347/WJM/2023.003.S2CID257943362.
  21. ^"Entrez Gene: CYP17A1 cytochrome P450, family 17, subfamily A, polypeptide 1".Archivedfrom the original on 2010-03-07.Retrieved2017-08-30.
  22. ^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.
  23. ^Legendre A, Elie C, Ramambason C, Manens L, Souidi M, Froment P, et al. (August 2016)."Endocrine effects of lifelong exposure to low-dose depleted uranium on testicular functions in adult rat"(PDF).Toxicology.368–369: 58–68.Bibcode:2016Toxgy.368...58L.doi:10.1016/j.tox.2016.08.014.PMID27544493.Archived(PDF)from the original on 2024-02-02.Retrieved2024-02-02.
  24. ^Yadav R, Petrunak EM, Estrada DF, Scott EE (February 2017)."Structural insights into the function of steroidogenic cytochrome P450 17A1".Molecular and Cellular Endocrinology.441:68–75.doi:10.1016/j.mce.2016.08.035.PMC5235955.PMID27566228.
  25. ^Kostin VA, Zolottsev VA, Kuzikov AV, Masamrekh RA, Shumyantseva VV, Veselovsky AV, et al. (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.
  26. ^abBonomo S, Hansen CH, Petrunak EM, Scott EE, Styrishave B, Jørgensen FS, et al. (July 2016)."Promising Tools in Prostate Cancer Research: Selective Non-Steroidal Cytochrome P450 17A1 Inhibitors".Scientific Reports.6:29468.Bibcode:2016NatSR...629468B.doi:10.1038/srep29468.PMC4942611.PMID27406023.
  27. ^Acién P, Acién M (November 2020)."Disorders of Sex Development: Classification, Review, and Impact on Fertility".Journal of Clinical Medicine.9(11): 3555.doi:10.3390/jcm9113555.PMC7694247.PMID33158283.
  28. ^Bordeau BM, Ciulla DA, Callahan BP (September 2016)."Hedgehog Proteins Consume Steroidal CYP17A1 Antagonists: Potential Therapeutic Significance in Advanced Prostate Cancer".ChemMedChem.11(18): 1983–1986.doi:10.1002/cmdc.201600238.PMC5588864.PMID27435344.
  29. ^Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, et al. (April 2018)."Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency".Pharmaceuticals.11(2): 37.doi:10.3390/ph11020037.PMC6027421.PMID29710837.
  30. ^PDB:3ruk​;DeVore NM, Scott EE (January 2012)."Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001".Nature.482(7383): 116–119.Bibcode:2012Natur.482..116D.doi:10.1038/nature10743.PMC3271139.PMID22266943.
  31. ^"Tokai Pharmaceuticals' Reformulated Galeterone Demonstrates Robust PSA Reductions in Advanced Prostate Cancer Patients"(Press release). Tokai Pharmaceuticals. January 29, 2014.[permanent dead link]
  32. ^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.163:136–146.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.
  33. ^Madan RA, Schmidt KT, Karzai F, Peer CJ, Cordes LM, Chau CH, et al. (August 2020)."Phase 2 Study of Seviteronel (INO-464) in Patients With Metastatic Castration-Resistant Prostate Cancer After Enzalutamide Treatment".Clinical Genitourinary Cancer.18(4): 258–267.e1.doi:10.1016/j.clgc.2019.11.002.PMC7415516.PMID32327394.
  34. ^Peer CJ, Schmidt KT, Kindrick JD, Eisner JR, Brown VV, Baskin-Bey E, et al. (October 2019)."A population pharmacokinetic analysis of the oral CYP17 lyase and androgen receptor inhibitor seviteronel in patients with advanced/metastatic castration-resistant prostate cancer or breast cancer".Cancer Chemotherapy and Pharmacology.84(4): 759–770.doi:10.1007/s00280-019-03908-0.PMC8132106.PMID31367790.S2CID199056344.

Further reading

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