SRD5A1

Steroid-5-alpha-reductase, alpha polypeptide 1 (3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha 1)
Identifiers
Symbols SRD5A1;
External IDs OMIM: 184753 MGI: 98400 HomoloGene: 37426 GeneCards: SRD5A1 Gene
EC number 1.3.99.5
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 6715 78925
Ensembl ENSG00000145545 ENSMUSG00000021594
UniProt P18405 n/a
RefSeq (mRNA) NM_001047.2 NM_175283.3
RefSeq (protein) NP_001038.1 NP_780492.2
Location (UCSC) Chr 5:
6.63 – 6.67 Mb		 Chr 13:
69.71 – 69.75 Mb
PubMed search [1] [2]

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

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.[2]

Contents

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.[3]

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.[4]

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.[5]

Clinical signficance

Hyperinsulemia 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. [6]

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. [7]

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.[8]

See also

References

  1. ^ Jenkins EP, Hsieh CL, Milatovich A, Normington K, Berman DM, Francke U, Russell DW (Mar 1992). "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. 
  2. ^ "Entrez Gene: SRD5A1 steroid-5-alpha-reductase, alpha polypeptide 1 (3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha 1)". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6715. 
  3. ^ Yang, L.; Fox, S. A.; Kirby, J. L.; Troan, B. V.; Hinton, B. T. (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.  edit
  4. ^ Fischer, A.; Gaedicke, S.; Frank, J.; Döring, F.; Rimbach, G. (2010). "Dietary vitamin E deficiency does not affect global and specific DNA methylation patterns in rat liver". British Journal of Nutrition 104 (7): 935–940. doi:10.1017/S0007114510001649. PMID 20447326.  edit
  5. ^ Kayampilly, P. P.; Wanamaker, B. L.; Stewart, J. A.; Wagner, C. L.; Menon, K. M. J. (2010). "Stimulatory Effect of Insulin on 5α-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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2946143.  edit
  6. ^ Tosi F, Negri C, Brun E, et al. (February 2011). "Insulin enhances ACTH-stimulated androgen and glucocorticoid metabolism in hyperandrogenic women". Eur. J. Endocrinol. 164 (2): 197–203. doi:10.1530/EJE-10-0782. PMID 21059865. 
  7. ^ Vassiliadi DA, Barber TM, Hughes BA, et al. (September 2009). "Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome". J. Clin. Endocrinol. Metab. 94 (9): 3558–66. doi:10.1210/jc.2009-0837. PMID 19567518. 
  8. ^ Chang, K. -H.; Li, R.; Papari-Zareei, M.; Watumull, L.; Zhao, Y. D.; Auchus, R. J.; Sharifi, N. (2011). "Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer". Proceedings of the National Academy of Sciences 108 (33): 13728–13733. doi:10.1073/pnas.1107898108. PMC 3158152. PMID 21795608. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3158152.  edit

Further reading

1.3.1: NAD/NADP acceptor
1.3.3: Oxygen acceptor
1.3.5: Quinone
1.3.99: Other acceptors
B enzm: 1.1/2/3/4/5/6/7/8/10/11/13/14/15-18, 2.1/2/3/4/5/6/7/8, 2.7.10, 2.7.11-12, 3.1/2/3/4/5/6/7, 3.1.3.48, 3.4.21/22/23/24, 4.1/2/3/4/5/6, 5.1/2/3/4/99, 6.1-3/4/5-6
Mevalonate pathway
Geranyl-
To cholesterol
To Bile acids
Steroidogenesis
Other/ungrouped

M: MET

mt, k, c/g/r/p/y/i, f/h/s/l/o/e, a/u, n, m

k, cgrp/y/i, f/h/s/l/o/e, au, n, m, epon

m(A16/C10),i(k, c/g/r/p/y/i, f/h/s/o/e, a/u, n, m)

M: END

anat/phys/devp/horm

noco(d)/cong/tumr, sysi/epon

proc, drug (A10/H1/H2/H3/H5)