Aldo-keto reductase family 1 member C4, also known as 3α-Hydroxysteroid dehydrogenase type 1 (3α-HSD1),[5][6][7] is an enzyme that in humans is encoded by the AKR1C4 gene.[8][9][10] It is known to be necessary for the synthesis of the endogenous neurosteroids allopregnanolone, tetrahydrodeoxycorticosterone, and 3α-androstanediol. It is also known to catalyze the reversible conversion of 3α-androstanediol (5α-androstane-3α,17β-diol) to dihydrotestosterone (DHT, 5α-androstan-17β-ol-3-one) and vice versa.[11]

AKR1C4
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesAKR1C4, 3-alpha-HSD, C11, CDR, CHDR, DD-4, DD4, HAKRA, aldo-keto reductase family 1, member C4, aldo-keto reductase family 1 member C4
External IDsOMIM: 600451; MGI: 1933427; HomoloGene: 84695; GeneCards: AKR1C4; OMA:AKR1C4 - orthologs
EC number1.1.1.225
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001818

NM_030611

RefSeq (protein)

NP_001809

NP_085114

Location (UCSC)Chr 10: 5.2 – 5.22 MbChr 13: 4.48 – 4.51 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Function

edit

This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. These enzymes catalyze the conversion of aldehydes and ketones to their corresponding alcohols by utilizing NADH and/or NADPH as cofactors. The enzymes display overlapping but distinct substrate specificity. This enzyme catalyzes the bioreduction of chlordecone, a toxic organochlorine pesticide, to chlordecone alcohol in liver. This gene shares high sequence identity with three other gene members and is clustered with those three genes at 10p15-p14 on chromosome 10.[10]

Clinical significance

edit

Various antidepressants, including the SSRIs fluoxetine, fluvoxamine, sertraline, and paroxetine, the SNRI venlafaxine, and mirtazapine, have been found to activate certain isoforms of the 3α-hydroxysteroid dehydrogenase, resulting in a selective facilitation of 5α-dihydroprogesterone conversion into allopregnanolone. This action has been implicated in their effectiveness in affective disorders, and has resulted in them being described as selective brain steroidogenic stimulants (SBSSs).[12][13][14]

Isozymes

edit
HGNC Gene Symbol Enzyme Name Aliases[15]
AKR1C1 aldo-keto reductase family 1 member C1; 20α-hydroxysteroid dehydrogenase
AKR1C2 aldo-keto reductase family 1 member C2; 3α-hydroxysteroid dehydrogenase type 3
AKR1C3 aldo-keto reductase family 1 member C3; 3α-hydroxysteroid dehydrogenase type 2; 17β-hydroxysteroid dehydrogenase type 5; HSD17B5
AKR1C4 aldo-keto reductase family 1 member C4; 3α-hydroxysteroid dehydrogenase type 1

See also

edit

References

edit
  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000198610Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000021210Ensembl, 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. ^ Li T, Zhang W, Lin SX (February 2020). "Steroid enzyme and receptor expression and regulations in breast tumor samples - A statistical evaluation of public data". The Journal of Steroid Biochemistry and Molecular Biology. 196: 105494. doi:10.1016/j.jsbmb.2019.105494. PMID 31610224.
  6. ^ Longone P, Rupprecht R, Manieri GA, Bernardi G, Romeo E, Pasini A (March 2008). "The complex roles of neurosteroids in depression and anxiety disorders". Neurochemistry International. 52 (4–5): 596–601. doi:10.1016/j.neuint.2007.10.001. PMID 17996986.
  7. ^ Savchuk I, Morvan ML, Antignac JP, Gemzell-Danielsson K, Le Bizec B, Söder O, et al. (December 2018). "The human genital tubercle is steroidogenic organ at early pregnancy". Molecular and Cellular Endocrinology. 477: 148–155. doi:10.1016/j.mce.2018.06.012. PMID 29928928.
  8. ^ Masiutin MM, Yadav MK (3 April 2023). "Alternative androgen pathways" (PDF). WikiJournal of Medicine. 10: 29. doi:10.15347/WJM/2023.003. S2CID 257943362.  This article incorporates text from this source, which is available under the CC BY 4.0 license.
  9. ^ Khanna M, Qin KN, Klisak I, Belkin S, Sparkes RS, Cheng KC (January 1995). "Localization of multiple human dihydrodiol dehydrogenase (DDH1 and DDH2) and chlordecone reductase (CHDR) genes in chromosome 10 by the polymerase chain reaction and fluorescence in situ hybridization". Genomics. 25 (2): 588–590. doi:10.1016/0888-7543(95)80066-U. PMID 7789999.
  10. ^ a b EntrezGene 1109 AKR1C4 aldo-keto reductase family 1 member C4 [ Homo sapiens (human) ]
  11. ^ Rizner TL, Lin HK, Peehl DM, Steckelbroeck S, Bauman DR, Penning TM (July 2003). "Human type 3 3alpha-hydroxysteroid dehydrogenase (aldo-keto reductase 1C2) and androgen metabolism in prostate cells". Endocrinology. 144 (7): 2922–2932. doi:10.1210/en.2002-0032. PMID 12810547.
  12. ^ Griffin LD, Mellon SH (November 1999). "Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes". Proceedings of the National Academy of Sciences of the United States of America. 96 (23): 13512–13517. Bibcode:1999PNAS...9613512G. doi:10.1073/pnas.96.23.13512. PMC 23979. PMID 10557352.
  13. ^ Pinna G (September 2010). "In a mouse model relevant for post-traumatic stress disorder, selective brain steroidogenic stimulants (SBSS) improve behavioral deficits by normalizing allopregnanolone biosynthesis". Behavioural Pharmacology. 21 (5–6): 438–450. doi:10.1097/FBP.0b013e32833d8ba0. PMC 2942072. PMID 20716970.
  14. ^ Schüle C, Romeo E, Uzunov DP, Eser D, di Michele F, Baghai TC, et al. (March 2006). "Influence of mirtazapine on plasma concentrations of neuroactive steroids in major depression and on 3alpha-hydroxysteroid dehydrogenase activity". Molecular Psychiatry. 11 (3): 261–272. doi:10.1038/sj.mp.4001782. PMID 16344854. S2CID 21473462.
  15. ^ Dufort I, Labrie F, Luu-The V (February 2001). "Human types 1 and 3 3 alpha-hydroxysteroid dehydrogenases: differential lability and tissue distribution". J Clin Endocrinol Metab. 86 (2): 841–6. doi:10.1210/jcem.86.2.7216. PMID 11158055. human types 1 and 3 3α-HSD, 20α-HSD, and type 5 17β-HSD were named AKR1C4, AKR1C2, AKR1C1, and AKR1C3, respectively

Further reading

edit
edit