SRD5A1 explained

3-Oxo-5α-steroid 4-dehydrogenase 1 is an enzyme that in humans is encoded by the SRD5A1 gene.^[1] It is one of three forms of steroid 5α-reductase.

Steroid 5α-reductase (EC 1.3.99.5) catalyzes, among other reactions, the conversion of testosterone into the more potent androgen, 5α-dihydrotestosterone (DHT). The SRD5A1, SRD5A2, and SRD5A3 genes in humans all encode 5α-reductase isozymes.^[2]

Function

See main article: article and 5α-Reductase.

The 3-oxo-5α-steroid 4-dehydrogenase 1 enzyme is involved in bile acid biosynthesis, androgen and estrogen metabolism. For instance, the enzyme catalyzes the conversion of testosterone into the more potent androgen, 5α-dihydrotestosterone. It can also catalyze the conversion of progesterone, corticosterone or other steroids, to its corresponding 5α-3-oxo-steroids. This chemical reaction is called 5α-reduction, i.e. the reduction of the Δ5-4 double bond in steroids by catalyzing direct hydride transfer from NADPH to the carbon 5 position of the steroid substrate.^{[3] [4] [5]}

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.^[6]

Six-month dietary vitamin E 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.^[7]

Insulin increases the expression of 5α-reductase type 1 mRNA via 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.^[8]

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 5α-reductase activity.^[9]

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.^[10]

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 DHT fuelling cancer growth.^[11]

Expression

In humans, the protein isozyme encoded by the SRD5A1 gene is expressed in esophagus, liver, skin and 24 other tissues.^{[12] [13]}

See also

• Steroidogenic enzyme
• 5α-Reductase

Further reading

• Jenkins EP, Andersson S, Imperato-McGinley J, Wilson JD, Russell DW . Genetic and pharmacological evidence for more than one human steroid 5 alpha-reductase . The Journal of Clinical Investigation . 89 . 1 . 293–300 . January 1992 . 1345916 . 442847 . 10.1172/JCI115574 .
• Andersson S, Russell DW . Structural and biochemical properties of cloned and expressed human and rat steroid 5 alpha-reductases . Proceedings of the National Academy of Sciences of the United States of America . 87 . 10 . 3640–3644 . May 1990 . 2339109 . 53958 . 10.1073/pnas.87.10.3640 . free . 1990PNAS...87.3640A .
• Moore RJ, Wilson JD . Localization of the reduced nicotinamide adenine dinucleotide phosphate: 4 -3-ketosteroid 5 -oxidoreductase in the nuclear membrane of the rat ventral prostate . The Journal of Biological Chemistry . 247 . 3 . 958–967 . February 1972 . 4400474 . 10.1016/S0021-9258(19)45700-1 . free .
• Milewich L, Kaimal V, Toews GB . Androstenedione metabolism in human alveolar macrophages . The Journal of Clinical Endocrinology and Metabolism . 56 . 5 . 920–924 . May 1983 . 6833469 . 10.1210/jcem-56-5-920 .
• Thigpen AE, Silver RI, Guileyardo JM, Casey ML, McConnell JD, Russell DW . Tissue distribution and ontogeny of steroid 5 alpha-reductase isozyme expression . The Journal of Clinical Investigation . 92 . 2 . 903–910 . August 1993 . 7688765 . 294929 . 10.1172/JCI116665 .
• Antonipillai I, Wahe M, Yamamoto J, Horton R . Activin and inhibin have opposite effects on steroid 5 alpha-reductase activity in genital skin fibroblasts . Molecular and Cellular Endocrinology . 107 . 1 . 99–104 . January 1995 . 7796940 . 10.1016/0303-7207(94)03430-2 . 21654090 .
• Hirsch KS, Jones CD, Audia JE, Andersson S, McQuaid L, Stamm NB, Neubauer BL, Pennington P, Toomey RE, Russell DW . 6 . LY191704: a selective, nonsteroidal inhibitor of human steroid 5 alpha-reductase type 1 . Proceedings of the National Academy of Sciences of the United States of America . 90 . 11 . 5277–5281 . June 1993 . 8389478 . 46699 . 10.1073/pnas.90.11.5277 . free . 1993PNAS...90.5277H .
• Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA . A "double adaptor" method for improved shotgun library construction . Analytical Biochemistry . 236 . 1 . 107–113 . April 1996 . 8619474 . 10.1006/abio.1996.0138 .
• Bonkhoff H, Stein U, Aumüller G, Remberger K . Differential expression of 5 alpha-reductase isoenzymes in the human prostate and prostatic carcinomas . The Prostate . 29 . 4 . 261–267 . October 1996 . 8876709 . 10.1002/(SICI)1097-0045(199610)29:4<261::AID-PROS7>3.0.CO;2-E . 29826751 .
• Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA . 6 . Large-scale concatenation cDNA sequencing . Genome Research . 7 . 4 . 353–358 . April 1997 . 9110174 . 139146 . 10.1101/gr.7.4.353 .
• Ellis JA, Stebbing M, Harrap SB . Genetic analysis of male pattern baldness and the 5alpha-reductase genes . The Journal of Investigative Dermatology . 110 . 6 . 849–853 . June 1998 . 9620288 . 10.1046/j.1523-1747.1998.00224.x . free .
• Zhou Z, Shackleton CH, Pahwa S, White PC, Speiser PW . Prominent sex steroid metabolism in human lymphocytes . Molecular and Cellular Endocrinology . 138 . 1–2 . 61–69 . March 1998 . 9685215 . 10.1016/S0303-7207(98)00052-5 . 20490901 . free .
• 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 . 6 . Gene expression profiling in the human hypothalamus-pituitary-adrenal axis and full-length cDNA cloning . Proceedings of the National Academy of Sciences of the United States of America . 97 . 17 . 9543–9548 . August 2000 . 10931946 . 16901 . 10.1073/pnas.160270997 . free . 2000PNAS...97.9543H .
• Eminović I, Liović M, Prezelj J, Kocijancic A, Rozman D, Komel R . New steroid 5alpha-reductase type I (SRD5A1) homologous sequences on human chromosomes 6 and 8 . Pflügers Archiv . 442 . 6 Suppl 1 . R187–R189 . 2002 . 11678334 . 10.1007/s004240100019 . 21081236 .
• Ellis JA, Wong ZY, Stebbing M, Harrap SB . Sex, genes and blood pressure . Clinical and Experimental Pharmacology & Physiology . 28 . 12 . 1053–1055 . December 2001 . 11903314 . 10.1046/j.1440-1681.2001.03579.x . 23923031 .
• Rodríguez-Dorantes M, Lizano-Soberón M, Camacho-Arroyo I, Calzada-León R, Morimoto S, Téllez-Ascencio N, Cerbón MA . Evidence that steroid 5alpha-reductase isozyme genes are differentially methylated in human lymphocytes . The Journal of Steroid Biochemistry and Molecular Biology . 80 . 3 . 323–330 . March 2002 . 11948017 . 10.1016/S0960-0760(02)00023-7 . 20292300 .
• Ha SJ, Kim JS, Myung JW, Lee HJ, Kim JW . Analysis of genetic polymorphisms of steroid 5alpha-reductase type 1 and 2 genes in Korean men with androgenetic alopecia . Journal of Dermatological Science . 31 . 2 . 135–141 . April 2003 . 12670724 . 10.1016/S0923-1811(02)00145-7 .
• Habib FK, Ross M, Bayne CW, Bollina P, Grigor K, Chapman K . The loss of 5alpha-reductase type I and type II mRNA expression in metastatic prostate cancer to bone and lymph node metastasis . Clinical Cancer Research . 9 . 5 . 1815–1819 . May 2003 . 12738739 .

Notes and References

1. Jenkins EP, Hsieh CL, Milatovich A, Normington K, Berman DM, Francke U, Russell DW . Characterization and chromosomal mapping of a human steroid 5 alpha-reductase gene and pseudogene and mapping of the mouse homologue . Genomics . 11 . 4 . 1102–1112 . December 1991 . 1686016 . 10.1016/0888-7543(91)90038-G .
2. Web site: Entrez Gene: SRD5A1 steroid-5-alpha-reductase, alpha polypeptide 1 (3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha 1).
3. Nixon M, Upreti R, Andrew R . 5α-Reduced glucocorticoids: a story of natural selection . The Journal of Endocrinology . 212 . 2 . 111–127 . February 2012 . 21903862 . 10.1530/JOE-11-0318 . free .
4. Azzouni F, Godoy A, Li Y, Mohler J . The 5 alpha-reductase isozyme family: a review of basic biology and their role in human diseases . Advances in Urology . 2012 . 530121 . 2012 . 22235201 . 3253436 . 10.1155/2012/530121 . free .
5. Han Y, Zhuang Q, Sun B, Lv W, Wang S, Xiao Q, Pang B, Zhou Y, Wang F, Chi P, Wang Q, Li Z, Zhu L, Li F, Deng D, Chiang YC, Li Z, Ren R . 6 . Crystal structure of steroid reductase SRD5A reveals conserved steroid reduction mechanism . Nature Communications . 12 . 1 . 449 . January 2021 . 33469028 . 7815742 . 10.1038/s41467-020-20675-2 . 2021NatCo..12..449H .
6. Yang L, Fox SA, Kirby JL, Troan BV, Hinton BT . Putative regulation of expression of members of the Ets variant 4 transcription factor family and their downstream targets in the rat epididymis . Biology of Reproduction . 74 . 4 . 714–720 . April 2006 . 16394217 . 10.1095/biolreprod.105.044354 . free .
7. Fischer A, Gaedicke S, Frank J, Döring F, Rimbach G . Dietary vitamin E deficiency does not affect global and specific DNA methylation patterns in rat liver . The British Journal of Nutrition . 104 . 7 . 935–940 . October 2010 . 20447326 . 10.1017/S0007114510001649 . free .
8. Kayampilly PP, Wanamaker BL, Stewart JA, Wagner CL, Menon KM . Stimulatory effect of insulin on 5alpha-reductase type 1 (SRD5A1) expression through an Akt-dependent pathway in ovarian granulosa cells . Endocrinology . 151 . 10 . 5030–5037 . October 2010 . 20810561 . 2946143 . 10.1210/en.2010-0444 .
9. Tosi F, Negri C, Brun E, Castello R, Faccini G, Bonora E, Muggeo M, Toscano V, Moghetti P . 6 . Insulin enhances ACTH-stimulated androgen and glucocorticoid metabolism in hyperandrogenic women . European Journal of Endocrinology . 164 . 2 . 197–203 . February 2011 . 21059865 . 10.1530/EJE-10-0782 . free .
10. Vassiliadi DA, Barber TM, Hughes BA, McCarthy MI, Wass JA, Franks S, Nightingale P, Tomlinson JW, Arlt W, Stewart PM . 6 . Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome . The Journal of Clinical Endocrinology and Metabolism . 94 . 9 . 3558–3566 . September 2009 . 19567518 . 10.1210/jc.2009-0837 . free .
11. Chang KH, Li R, Papari-Zareei M, Watumull L, Zhao YD, Auchus RJ, Sharifi N . Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer . Proceedings of the National Academy of Sciences of the United States of America . 108 . 33 . 13728–13733 . August 2011 . 21795608 . 3158152 . 10.1073/pnas.1107898108 . free . 2011PNAS..10813728C .
12. Web site: SRD5A1 steroid 5 alpha-reductase 1 - Homo sapiens (human) - expression . 8 March 2024 . 28 January 2024 . https://web.archive.org/web/20240128105529/https://www.ncbi.nlm.nih.gov/gene/6715#gene-expression . live .
13. Fagerberg L, Hallström BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J, Habuka M, Tahmasebpoor S, Danielsson A, Edlund K, Asplund A, Sjöstedt E, Lundberg E, Szigyarto CA, Skogs M, Takanen JO, Berling H, Tegel H, Mulder J, Nilsson P, Schwenk JM, Lindskog C, Danielsson F, Mardinoglu A, Sivertsson A, von Feilitzen K, Forsberg M, Zwahlen M, Olsson I, Navani S, Huss M, Nielsen J, Ponten F, Uhlén M . 6 . Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics . Molecular & Cellular Proteomics . 13 . 2 . 397–406 . February 2014 . 24309898 . 3916642 . 10.1074/mcp.M113.035600 . free .