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SRD5A1

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SRD5A1
Identifiers
AliasesSRD5A1, S5AR 1, steroid 5 alpha-reductase 1
External IDsOMIM: 184753; MGI: 98400; HomoloGene: 37426; GeneCards: SRD5A1; OMA:SRD5A1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

6715

78925

Ensembl

ENSG00000145545

ENSMUSG00000021594

UniProt

P18405

Q68FF9

RefSeq (mRNA)

NM_001047
NM_001324322
NM_001324323

NM_175283

RefSeq (protein)

NP_001038
NP_001311251
NP_001311252

NP_780492

Location (UCSC)Chr 5: 6.63 – 6.67 MbChr 13: 69.72 – 69.76 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

3-Oxo-5α-steroid 4-dehydrogenase 1 is an enzyme that in humans is encoded by the SRD5A1 gene.[5] 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.[6]

Function

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Main article: 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.[7][8][9]

Regulation

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The SRD5A1 gene is particularly susceptible to epigenetic regulation, and responsive to environmental stressors at key stages during postnatal development. This regulation leads to increased DNA methylation at the gene's intronic enhancer, and its reduced expression, which have lasting effects on reproductive function.[10][11]

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.[12]

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.[13]

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.[14]

Clinical significance

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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.[15]

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.[16]

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.[17]

Expression

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SRD5A1 gene expression in human tissues, sorted by fragments per kilobase of exon model per million reads mapped (FPKM).[18] The FPKM data is taken from a 2014 study.[19]

In humans, the protein isozyme encoded by the SRD5A1 gene is expressed in esophagus, liver, skin and 24 other tissues.[20][19]

See also

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000145545 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000021594 – 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. ^ Jenkins EP, Hsieh CL, Milatovich A, Normington K, Berman DM, Francke U, et al. (December 1991). "Characterization and chromosomal mapping of a human steroid 5 alpha-reductase gene and pseudogene and mapping of the mouse homologue". Genomics. 11 (4): 1102–1112. doi:10.1016/0888-7543(91)90038-G. PMID 1686016.
  6. ^ "Entrez Gene: SRD5A1 steroid-5-alpha-reductase, alpha polypeptide 1 (3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha 1)".
  7. ^ Nixon M, Upreti R, Andrew R (February 2012). "5α-Reduced glucocorticoids: a story of natural selection". The Journal of Endocrinology. 212 (2): 111–127. doi:10.1530/JOE-11-0318. PMID 21903862.
  8. ^ Azzouni F, Godoy A, Li Y, Mohler J (2012). "The 5 alpha-reductase isozyme family: a review of basic biology and their role in human diseases". Advances in Urology. 2012: 530121. doi:10.1155/2012/530121. PMC 3253436. PMID 22235201.
  9. ^ Han Y, Zhuang Q, Sun B, Lv W, Wang S, Xiao Q, et al. (January 2021). "Crystal structure of steroid reductase SRD5A reveals conserved steroid reduction mechanism". Nature Communications. 12 (1): 449. Bibcode:2021NatCo..12..449H. doi:10.1038/s41467-020-20675-2. PMC 7815742. PMID 33469028.
  10. ^ Bar-Sadeh B, Amichai OE, Pnueli L, Begum K, Leeman G, Emes RD, et al. (January 2022). "Epigenetic regulation of 5α reductase-1 underlies adaptive plasticity of reproductive function and pubertal timing". BMC Biology. 20 (1): 11. doi:10.1186/s12915-021-01219-6. PMC 8742331. PMID 34996447.
  11. ^ Bar-Sadeh B, Pnueli L, Keestra S, Bentley GR, Melamed P (August 2023). "Srd5a1 is Differentially Regulated and Methylated During Prepubertal Development in the Ovary and Hypothalamus". Journal of the Endocrine Society. 7 (10): bvad108. doi:10.1210/jendso/bvad108. PMC 10461783. PMID 37646011.
  12. ^ Yang L, Fox SA, Kirby JL, Troan BV, Hinton BT (April 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): 714–720. doi:10.1095/biolreprod.105.044354. PMID 16394217.
  13. ^ Fischer A, Gaedicke S, Frank J, Döring F, Rimbach G (October 2010). "Dietary vitamin E deficiency does not affect global and specific DNA methylation patterns in rat liver". The British Journal of Nutrition. 104 (7): 935–940. doi:10.1017/S0007114510001649. PMID 20447326.
  14. ^ Kayampilly PP, Wanamaker BL, Stewart JA, Wagner CL, Menon KM (October 2010). "Stimulatory effect of insulin on 5alpha-reductase type 1 (SRD5A1) expression through an Akt-dependent pathway in ovarian granulosa cells". Endocrinology. 151 (10): 5030–5037. doi:10.1210/en.2010-0444. PMC 2946143. PMID 20810561.
  15. ^ Tosi F, Negri C, Brun E, Castello R, Faccini G, Bonora E, et al. (February 2011). "Insulin enhances ACTH-stimulated androgen and glucocorticoid metabolism in hyperandrogenic women". European Journal of Endocrinology. 164 (2): 197–203. doi:10.1530/EJE-10-0782. PMID 21059865.
  16. ^ Vassiliadi DA, Barber TM, Hughes BA, McCarthy MI, Wass JA, Franks S, et al. (September 2009). "Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome". The Journal of Clinical Endocrinology and Metabolism. 94 (9): 3558–3566. doi:10.1210/jc.2009-0837. PMID 19567518.
  17. ^ Chang KH, Li R, Papari-Zareei M, Watumull L, Zhao YD, Auchus RJ, et al. (August 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): 13728–13733. Bibcode:2011PNAS..10813728C. doi:10.1073/pnas.1107898108. PMC 3158152. PMID 21795608.
  18. ^ "What the FPKM? A review of RNA-Seq expression units". The farrago. 2 May 2014. Archived from the original on 30 December 2019. Retrieved 2 November 2020.
  19. ^ a b Fagerberg L, Hallström BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J, et al. (February 2014). "Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics". Molecular & Cellular Proteomics. 13 (2): 397–406. doi:10.1074/mcp.M113.035600. PMC 3916642. PMID 24309898.
  20. ^ "SRD5A1 steroid 5 alpha-reductase 1 - Homo sapiens (human) - expression". Archived from the original on 28 January 2024. Retrieved 8 March 2024.

Further reading

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