SRD5A1
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3-oxo-5-alpha-steroid 4-dehydrogenase 1 is an enzyme that in humans is encoded by the SRD5A1 gene.[3]
Steroid 5-alpha-reductase (EC 1.3.99.5) catalyzes the conversion of testosterone into the more potent androgen, dihydrotestosterone (DHT). There are 2 isoforms of the enzyme: SRD5A1 and SRD5A2.[4]
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.[5]
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.[6]
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.[7]
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. [8]
PCOS is associated with enhanced androgen and cortisol metabolite excretion and increased 5 alpha-reductase activity that cannot be explained by obesity alone. Increased adrenal corticosteroid production represents an important pathogenic pathway in PCOS. [9]
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.[10]
See also
References
- ↑ "Human PubMed Reference:".
- ↑ "Mouse PubMed Reference:".
- ↑ Jenkins EP, Hsieh CL, Milatovich A, Normington K, Berman DM, Francke U, Russell DW (Dec 1991). "Characterization and chromosomal mapping of a human steroid 5 alpha-reductase gene and pseudogene and mapping of the mouse homologue". Genomics. 11 (4): 1102–12. doi:10.1016/0888-7543(91)90038-G. PMID 1686016.
- ↑ "Entrez Gene: SRD5A1 steroid-5-alpha-reductase, alpha polypeptide 1 (3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha 1)".
- ↑ Yang L, Fox SA, Kirby JL, Troan BV, Hinton BT (Apr 2006). "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): 714–20. doi:10.1095/biolreprod.105.044354. PMID 16394217.
- ↑ Fischer A, Gaedicke S, Frank J, Döring F, Rimbach G (Oct 2010). "Dietary vitamin E deficiency does not affect global and specific DNA methylation patterns in rat liver". The British Journal of Nutrition. 104 (7): 935–40. doi:10.1017/S0007114510001649. PMID 20447326.
- ↑ Kayampilly PP, Wanamaker BL, Stewart JA, Wagner CL, Menon KM (Oct 2010). "Stimulatory effect of insulin on 5alpha-reductase type 1 (SRD5A1) expression through an Akt-dependent pathway in ovarian granulosa cells". Endocrinology. 151 (10): 5030–7. doi:10.1210/en.2010-0444. PMC 2946143
. PMID 20810561. - ↑ Tosi F, Negri C, Brun E, Castello R, Faccini G, Bonora E, Muggeo M, Toscano V, Moghetti P (Feb 2011). "Insulin enhances ACTH-stimulated androgen and glucocorticoid metabolism in hyperandrogenic women". European Journal of Endocrinology / European Federation of Endocrine Societies. 164 (2): 197–203. doi:10.1530/EJE-10-0782. PMID 21059865.
- ↑ Vassiliadi DA, Barber TM, Hughes BA, McCarthy MI, Wass JA, Franks S, Nightingale P, Tomlinson JW, Arlt W, Stewart PM (Sep 2009). "Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome". The Journal of Clinical Endocrinology and Metabolism. 94 (9): 3558–66. doi:10.1210/jc.2009-0837. PMID 19567518.
- ↑ Chang KH, Li R, Papari-Zareei M, Watumull L, Zhao YD, Auchus RJ, Sharifi N (Aug 2011). "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): 13728–33. doi:10.1073/pnas.1107898108. PMC 3158152. PMID 21795608.
Further reading
- Jenkins EP, Andersson S, Imperato-McGinley J, Wilson JD, Russell DW (Jan 1992). "Genetic and pharmacological evidence for more than one human steroid 5 alpha-reductase". The Journal of Clinical Investigation. 89 (1): 293–300. doi:10.1172/JCI115574. PMC 442847. PMID 1345916.
- Andersson S, Russell DW (May 1990). "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): 3640–4. doi:10.1073/pnas.87.10.3640. PMC 53958. PMID 2339109.
- Moore RJ, Wilson JD (Feb 1972). "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): 958–67. PMID 4400474.
- Milewich L, Kaimal V, Toews GB (May 1983). "Androstenedione metabolism in human alveolar macrophages". The Journal of Clinical Endocrinology and Metabolism. 56 (5): 920–4. doi:10.1210/jcem-56-5-920. PMID 6833469.
- Thigpen AE, Silver RI, Guileyardo JM, Casey ML, McConnell JD, Russell DW (Aug 1993). "Tissue distribution and ontogeny of steroid 5 alpha-reductase isozyme expression". The Journal of Clinical Investigation. 92 (2): 903–10. doi:10.1172/JCI116665. PMC 294929. PMID 7688765.
- Antonipillai I, Wahe M, Yamamoto J, Horton R (Jan 1995). "Activin and inhibin have opposite effects on steroid 5 alpha-reductase activity in genital skin fibroblasts". Molecular and Cellular Endocrinology. 107 (1): 99–104. doi:10.1016/0303-7207(94)03430-2. PMID 7796940.
- Hirsch KS, Jones CD, Audia JE, Andersson S, McQuaid L, Stamm NB, Neubauer BL, Pennington P, Toomey RE, Russell DW (Jun 1993). "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): 5277–81. doi:10.1073/pnas.90.11.5277. PMC 46699. PMID 8389478.
- Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA (Apr 1996). "A "double adaptor" method for improved shotgun library construction". Analytical Biochemistry. 236 (1): 107–13. doi:10.1006/abio.1996.0138. PMID 8619474.
- Bonkhoff H, Stein U, Aumüller G, Remberger K (Oct 1996). "Differential expression of 5 alpha-reductase isoenzymes in the human prostate and prostatic carcinomas". The Prostate. 29 (4): 261–7. doi:10.1002/(SICI)1097-0045(199610)29:4<261::AID-PROS7>3.0.CO;2-E. PMID 8876709.
- Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA (Apr 1997). "Large-scale concatenation cDNA sequencing". Genome Research. 7 (4): 353–8. doi:10.1101/gr.7.4.353 (inactive 2015-10-29). PMC 139146. PMID 9110174.
- Ellis JA, Stebbing M, Harrap SB (Jun 1998). "Genetic analysis of male pattern baldness and the 5alpha-reductase genes". The Journal of Investigative Dermatology. 110 (6): 849–53. doi:10.1046/j.1523-1747.1998.00224.x. PMID 9620288.
- Zhou Z, Shackleton CH, Pahwa S, White PC, Speiser PW (Mar 1998). "Prominent sex steroid metabolism in human lymphocytes". Molecular and Cellular Endocrinology. 138 (1–2): 61–9. doi:10.1016/S0303-7207(98)00052-5. PMID 9685215.
- 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 (Aug 2000). "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): 9543–8. doi:10.1073/pnas.160270997. PMC 16901. PMID 10931946.
- Eminović I, Liović M, Prezelj J, Kocijancic A, Rozman D, Komel R (2002). "New steroid 5alpha-reductase type I (SRD5A1) homologous sequences on human chromosomes 6 and 8". Pflügers Archiv. 442 (6 Suppl 1): R187–9. doi:10.1007/s004240100019. PMID 11678334.
- Ellis JA, Wong ZY, Stebbing M, Harrap SB (Dec 2001). "Sex, genes and blood pressure". Clinical and Experimental Pharmacology & Physiology. 28 (12): 1053–5. doi:10.1046/j.1440-1681.2001.03579.x. PMID 11903314.
- Rodríguez-Dorantes M, Lizano-Soberón M, Camacho-Arroyo I, Calzada-León R, Morimoto S, Téllez-Ascencio N, Cerbón MA (Mar 2002). "Evidence that steroid 5alpha-reductase isozyme genes are differentially methylated in human lymphocytes". The Journal of Steroid Biochemistry and Molecular Biology. 80 (3): 323–30. doi:10.1016/S0960-0760(02)00023-7. PMID 11948017.
- Ha SJ, Kim JS, Myung JW, Lee HJ, Kim JW (Apr 2003). "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): 135–41. doi:10.1016/S0923-1811(02)00145-7. PMID 12670724.
- Habib FK, Ross M, Bayne CW, Bollina P, Grigor K, Chapman K (May 2003). "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): 1815–9. PMID 12738739.