View source for SRD5A1

{{Infobox gene}}

'''3-oxo-5α-steroid 4-dehydrogenase 1''' is an [[enzyme]] that in humans is encoded by the ''SRD5A1'' [[gene]].<ref name="pmid1686016">{{cite journal | vauthors = Jenkins EP, Hsieh CL, Milatovich A, Normington K, Berman DM, Francke U, Russell DW | title = Characterization and chromosomal mapping of a human steroid 5 alpha-reductase gene and pseudogene and mapping of the mouse homologue | journal = Genomics | volume = 11 | issue = 4 | pages = 1102–12 | date = Dec 1991 | pmid = 1686016 | pmc =  | doi = 10.1016/0888-7543(91)90038-G }}</ref> It is one of three forms of [[5α-reductase]].

Steroid 5α-reductase (EC 1.3.99.5) catalyzes the conversion of [[testosterone]] into the more potent [[androgen]], [[dihydrotestosterone]] (DHT). There are 3 isoforms of the [[enzyme]]: SRD5A1, [[SRD5A2]], and [[SRD5A3]].<ref name="entrez">{{cite web | title = Entrez Gene: SRD5A1 steroid-5-alpha-reductase, alpha polypeptide 1 (3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha 1)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6715| accessdate = }}</ref><ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=79644|title=SRD5A3 steroid 5 alpha-reductase 3 [Homo sapiens (human)] - Gene - NCBI|website=www.ncbi.nlm.nih.gov|access-date=2018-04-26}}</ref>

== Regulation ==

[[ETV4]] family members bind to ETS DNA-binding sites and both regulate their own expression and the transcription of a subset of genes that are dependent upon testicular luminal fluid factors, including Ggt_pr4, SRD5A1, and Gpx5.<ref>{{cite journal | vauthors = Yang L, Fox SA, Kirby JL, Troan BV, Hinton BT | title = Putative regulation of expression of members of the Ets variant 4 transcription factor family and their downstream targets in the rat epididymis | journal = Biology of Reproduction | volume = 74 | issue = 4 | pages = 714–20 | date = Apr 2006 | pmid = 16394217 | pmc =  | doi = 10.1095/biolreprod.105.044354 }}</ref>

6-month dietary [[vitamin E]] (VE) deficiency in rats resulted in a twofold increase in the mRNA level of SRD5A1 gene and a twofold decrease in the mRNA level of GCLM gene but is not directly mediated by changes in promoter DNA methylation.<ref>{{cite journal | vauthors = Fischer A, Gaedicke S, Frank J, Döring F, Rimbach G | title = Dietary vitamin E deficiency does not affect global and specific DNA methylation patterns in rat liver | journal = The British Journal of Nutrition | volume = 104 | issue = 7 | pages = 935–40 | date = Oct 2010 | pmid = 20447326 | pmc =  | doi = 10.1017/S0007114510001649 }}</ref>

Insulin increases the expression of 5α-reductase type 1 mRNA via [[Akt/PKB signaling pathway|Akt signalling]] suggest that elevated levels of 5α-reduced androgens seen in hyperinsulinemic conditions might be explained on the basis of a stimulatory effect of insulin on 5α-reductase in granulosa cells leading to impaired follicle growth and ovulation.<ref>{{cite journal | vauthors = Kayampilly PP, Wanamaker BL, Stewart JA, Wagner CL, Menon KM | title = Stimulatory effect of insulin on 5alpha-reductase type 1 (SRD5A1) expression through an Akt-dependent pathway in ovarian granulosa cells | journal = Endocrinology | volume = 151 | issue = 10 | pages = 5030–7 | date = Oct 2010 | pmid = 20810561 | pmc = 2946143 | doi = 10.1210/en.2010-0444 }}</ref>

== Clinical significance ==
[[Hyperinsulinemia]] acutely enhances [[ACTH]] effects on both the androgen and glucocorticoid pathways leading to changes in steroid metabolites molar ratios that suggest insulin stimulation of 5 α-reductase activity. <ref>{{cite journal | vauthors = Tosi F, Negri C, Brun E, Castello R, Faccini G, Bonora E, Muggeo M, Toscano V, Moghetti P | title = Insulin enhances ACTH-stimulated androgen and glucocorticoid metabolism in hyperandrogenic women | journal = European Journal of Endocrinology / European Federation of Endocrine Societies | volume = 164 | issue = 2 | pages = 197–203 | date = Feb 2011 | pmid = 21059865 | doi = 10.1530/EJE-10-0782 }}</ref>

[[PCOS]] is associated with enhanced androgen and cortisol metabolite excretion and increased 5α-reductase activity that cannot be explained by obesity alone. Increased adrenal corticosteroid production represents an important pathogenic pathway in PCOS.<ref>{{cite journal | vauthors = Vassiliadi DA, Barber TM, Hughes BA, McCarthy MI, Wass JA, Franks S, Nightingale P, Tomlinson JW, Arlt W, Stewart PM | title = Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 94 | issue = 9 | pages = 3558–66 | date = Sep 2009 | pmid = 19567518 | doi = 10.1210/jc.2009-0837 }}</ref>

Progression to [[castration-resistant prostate cancer]] (CRPC) is accompanied by increased expression of SRD5A1 over [[SRD5A2]], which is otherwise the dominant isoenzyme expressed in the prostate. The dominant route of DHT synthesis in human CRPC bypasses testosterone, and instead requires 5α-reduction of [[androstenedione]] by SRD5A1 to [[5α-androstanedione]], which is then converted to [[Dihydrotestosterone|DHT]] fuelling cancer growth.<ref>{{cite journal | vauthors = Chang KH, Li R, Papari-Zareei M, Watumull L, Zhao YD, Auchus RJ, Sharifi N | title = Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 33 | pages = 13728–33 | date = Aug 2011 | pmid = 21795608 | pmc = 3158152 | doi = 10.1073/pnas.1107898108 | bibcode = 2011PNAS..10813728C }}</ref>

==See also==
* [[Steroidogenic enzyme]]
* [[5α-Reductase]]

== References ==
{{Reflist}}

== Further reading ==
{{refbegin | 2}}
* {{cite journal | vauthors = Jenkins EP, Andersson S, Imperato-McGinley J, Wilson JD, Russell DW | title = Genetic and pharmacological evidence for more than one human steroid 5 alpha-reductase | journal = The Journal of Clinical Investigation | volume = 89 | issue = 1 | pages = 293–300 | date = Jan 1992 | pmid = 1345916 | pmc = 442847 | doi = 10.1172/JCI115574 }}
* {{cite journal | vauthors = Andersson S, Russell DW | title = Structural and biochemical properties of cloned and expressed human and rat steroid 5 alpha-reductases | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 87 | issue = 10 | pages = 3640–4 | date = May 1990 | pmid = 2339109 | pmc = 53958 | doi = 10.1073/pnas.87.10.3640 | bibcode = 1990PNAS...87.3640A }}
* {{cite journal | vauthors = Moore RJ, Wilson JD | title = Localization of the reduced nicotinamide adenine dinucleotide phosphate: 4 -3-ketosteroid 5 -oxidoreductase in the nuclear membrane of the rat ventral prostate | journal = The Journal of Biological Chemistry | volume = 247 | issue = 3 | pages = 958–67 | date = Feb 1972 | pmid = 4400474 | doi =  }}
* {{cite journal | vauthors = Milewich L, Kaimal V, Toews GB | title = Androstenedione metabolism in human alveolar macrophages | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 56 | issue = 5 | pages = 920–4 | date = May 1983 | pmid = 6833469 | doi = 10.1210/jcem-56-5-920 }}
* {{cite journal | vauthors = Thigpen AE, Silver RI, Guileyardo JM, Casey ML, McConnell JD, Russell DW | title = Tissue distribution and ontogeny of steroid 5 alpha-reductase isozyme expression | journal = The Journal of Clinical Investigation | volume = 92 | issue = 2 | pages = 903–10 | date = Aug 1993 | pmid = 7688765 | pmc = 294929 | doi = 10.1172/JCI116665 }}
* {{cite journal | vauthors = Antonipillai I, Wahe M, Yamamoto J, Horton R | title = Activin and inhibin have opposite effects on steroid 5 alpha-reductase activity in genital skin fibroblasts | journal = Molecular and Cellular Endocrinology | volume = 107 | issue = 1 | pages = 99–104 | date = Jan 1995 | pmid = 7796940 | doi = 10.1016/0303-7207(94)03430-2 }}
* {{cite journal | vauthors = Hirsch KS, Jones CD, Audia JE, Andersson S, McQuaid L, Stamm NB, Neubauer BL, Pennington P, Toomey RE, Russell DW | title = LY191704: a selective, nonsteroidal inhibitor of human steroid 5 alpha-reductase type 1 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 11 | pages = 5277–81 | date = Jun 1993 | pmid = 8389478 | pmc = 46699 | doi = 10.1073/pnas.90.11.5277 | bibcode = 1993PNAS...90.5277H }}
* {{cite journal | vauthors = Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA | title = A "double adaptor" method for improved shotgun library construction | journal = Analytical Biochemistry | volume = 236 | issue = 1 | pages = 107–13 | date = Apr 1996 | pmid = 8619474 | doi = 10.1006/abio.1996.0138 }}
* {{cite journal | vauthors = Bonkhoff H, Stein U, Aumüller G, Remberger K | title = Differential expression of 5 alpha-reductase isoenzymes in the human prostate and prostatic carcinomas | journal = The Prostate | volume = 29 | issue = 4 | pages = 261–7 | date = Oct 1996 | pmid = 8876709 | doi = 10.1002/(SICI)1097-0045(199610)29:4<261::AID-PROS7>3.0.CO;2-E }}
* {{cite journal | vauthors = Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA | title = Large-scale concatenation cDNA sequencing | journal = Genome Research | volume = 7 | issue = 4 | pages = 353–8 | date = Apr 1997 | pmid = 9110174 | pmc = 139146 | doi = 10.1101/gr.7.4.353 }}
* {{cite journal | vauthors = Ellis JA, Stebbing M, Harrap SB | title = Genetic analysis of male pattern baldness and the 5alpha-reductase genes | journal = The Journal of Investigative Dermatology | volume = 110 | issue = 6 | pages = 849–53 | date = Jun 1998 | pmid = 9620288 | doi = 10.1046/j.1523-1747.1998.00224.x }}
* {{cite journal | vauthors = Zhou Z, Shackleton CH, Pahwa S, White PC, Speiser PW | title = Prominent sex steroid metabolism in human lymphocytes | journal = Molecular and Cellular Endocrinology | volume = 138 | issue = 1–2 | pages = 61–9 | date = Mar 1998 | pmid = 9685215 | doi = 10.1016/S0303-7207(98)00052-5 }}
* {{cite journal | vauthors = Hu RM, Han ZG, Song HD, Peng YD, Huang QH, Ren SX, Gu YJ, Huang CH, Li YB, Jiang CL, Fu G, Zhang QH, Gu BW, Dai M, Mao YF, Gao GF, Rong R, Ye M, Zhou J, Xu SH, Gu J, Shi JX, Jin WR, Zhang CK, Wu TM, Huang GY, Chen Z, Chen MD, Chen JL | title = Gene expression profiling in the human hypothalamus-pituitary-adrenal axis and full-length cDNA cloning | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 17 | pages = 9543–8 | date = Aug 2000 | pmid = 10931946 | pmc = 16901 | doi = 10.1073/pnas.160270997 | bibcode = 2000PNAS...97.9543H }}
* {{cite journal | vauthors = Eminović I, Liović M, Prezelj J, Kocijancic A, Rozman D, Komel R | title = New steroid 5alpha-reductase type I (SRD5A1) homologous sequences on human chromosomes 6 and 8 | journal = Pflügers Archiv | volume = 442 | issue = 6 Suppl 1 | pages = R187–9 | year = 2002 | pmid = 11678334 | doi = 10.1007/s004240100019 }}
* {{cite journal | vauthors = Ellis JA, Wong ZY, Stebbing M, Harrap SB | title = Sex, genes and blood pressure | journal = Clinical and Experimental Pharmacology & Physiology | volume = 28 | issue = 12 | pages = 1053–5 | date = Dec 2001 | pmid = 11903314 | doi = 10.1046/j.1440-1681.2001.03579.x }}
* {{cite journal | vauthors = Rodríguez-Dorantes M, Lizano-Soberón M, Camacho-Arroyo I, Calzada-León R, Morimoto S, Téllez-Ascencio N, Cerbón MA | title = Evidence that steroid 5alpha-reductase isozyme genes are differentially methylated in human lymphocytes | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 80 | issue = 3 | pages = 323–30 | date = Mar 2002 | pmid = 11948017 | doi = 10.1016/S0960-0760(02)00023-7 }}
* {{cite journal | vauthors = Ha SJ, Kim JS, Myung JW, Lee HJ, Kim JW | title = Analysis of genetic polymorphisms of steroid 5alpha-reductase type 1 and 2 genes in Korean men with androgenetic alopecia | journal = Journal of Dermatological Science | volume = 31 | issue = 2 | pages = 135–41 | date = Apr 2003 | pmid = 12670724 | doi = 10.1016/S0923-1811(02)00145-7 }}
* {{cite journal | vauthors = Habib FK, Ross M, Bayne CW, Bollina P, Grigor K, Chapman K | title = The loss of 5alpha-reductase type I and type II mRNA expression in metastatic prostate cancer to bone and lymph node metastasis | journal = Clinical Cancer Research | volume = 9 | issue = 5 | pages = 1815–9 | date = May 2003 | pmid = 12738739 | doi =  }}
{{refend}}

{{CH-CH oxidoreductases}}
{{Cholesterol and steroid metabolism enzymes}}