Biology:3α-Hydroxysteroid dehydrogenase
 Generic protein structure example |
3α-Hydroxysteroid dehydrogenase (3α-HSD or aldo-keto reductase family 1 member C4) is an enzyme that in humans is encoded by the AKR1C4 gene.[1][2] It is known to be necessary for the synthesis of the endogenous neurosteroids allopregnanolone, THDOC, 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.[3]
Function
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.[2]
Clinical significance
Various antidepressants, including the SSRIs fluoxetine, fluvoxamine, sertraline, and paroxetine, the SNRI venlafaxine, and mirtazapine, have been found to activate certain 3α-HSD enzymes, 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).[4][5][6]
See also
- Steroidogenic enzyme
- 3α-hydroxysteroid dehydrogenase type 3
- 3β-Hydroxysteroid dehydrogenase
References
- ↑ "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): 588–90. January 1995. doi:10.1016/0888-7543(95)80066-U. PMID 7789999.
- ↑ 2.0 2.1 "Entrez Gene: AKR1C4 aldo-keto reductase family 1, member C4 (chlordecone reductase; 3-alpha hydroxysteroid dehydrogenase, type I; dihydrodiol dehydrogenase 4)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1109.
- ↑ "Human type 3 3alpha-hydroxysteroid dehydrogenase (aldo-keto reductase 1C2) and androgen metabolism in prostate cells". Endocrinology 144 (7): 2922–32. July 2003. doi:10.1210/en.2002-0032. PMID 12810547.
- ↑ "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): 13512–7. November 1999. doi:10.1073/pnas.96.23.13512. PMID 10557352. Bibcode: 1999PNAS...9613512G.
- ↑ "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): 438–50. September 2010. doi:10.1097/FBP.0b013e32833d8ba0. PMID 20716970.
- ↑ "Influence of mirtazapine on plasma concentrations of neuroactive steroids in major depression and on 3alpha-hydroxysteroid dehydrogenase activity". Molecular Psychiatry 11 (3): 261–72. March 2006. doi:10.1038/sj.mp.4001782. PMID 16344854.
External links
- Human AKR1C4 genome location and AKR1C4 gene details page in the UCSC Genome Browser.
Further reading
- "Human hepatic 3 alpha-hydroxysteroid dehydrogenase: possible identity with human hepatic chlordecone reductase". Biochemical and Biophysical Research Communications 187 (2): 760–6. September 1992. doi:10.1016/0006-291X(92)91260-W. PMID 1530633.
- "Isolation and characterization of cloned cDNAs encoding human liver chlordecone reductase". Biochemistry 29 (4): 1080–7. January 1990. doi:10.1021/bi00456a034. PMID 2187532.
- "Distribution of 3 alpha-hydroxysteroid dehydrogenase in rat brain and molecular cloning of multiple cDNAs encoding structurally related proteins in humans". The Journal of Steroid Biochemistry and Molecular Biology 53 (1–6): 41–6. June 1995. doi:10.1016/0960-0760(95)00019-V. PMID 7626489.
- "Substrate specificity, gene structure, and tissue-specific distribution of multiple human 3 alpha-hydroxysteroid dehydrogenases". The Journal of Biological Chemistry 270 (34): 20162–8. August 1995. doi:10.1074/jbc.270.34.20162. PMID 7650035.
- "Molecular cloning of two human liver 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase isoenzymes that are identical with chlordecone reductase and bile-acid binder". The Biochemical Journal 299 ( Pt 2) (2): 545–52. April 1994. doi:10.1042/bj2990545. PMID 8172617.
- "Molecular cloning of multiple cDNAs encoding human enzymes structurally related to 3 alpha-hydroxysteroid dehydrogenase". The Journal of Steroid Biochemistry and Molecular Biology 46 (6): 673–9. December 1993. doi:10.1016/0960-0760(93)90308-J. PMID 8274401.
- "Characterization of a novel variant (S145C/L311V) of 3alpha-hydroxysteroid/dihydrodiol dehydrogenase in human liver". Pharmacogenetics 9 (6): 763–71. December 1999. doi:10.1097/00008571-199912000-00011. PMID 10634139.
- "Close kinship of human 20alpha-hydroxysteroid dehydrogenase gene with three aldo-keto reductase genes". Genes to Cells 5 (2): 111–25. February 2000. doi:10.1046/j.1365-2443.2000.00310.x. PMID 10672042.
- "Human types 1 and 3 3 alpha-hydroxysteroid dehydrogenases: differential lability and tissue distribution". The Journal of Clinical Endocrinology and Metabolism 86 (2): 841–6. February 2001. doi:10.1210/jcem.86.2.7216. PMID 11158055.
- "Co-operative regulation of the transcription of human dihydrodiol dehydrogenase (DD)4/aldo-keto reductase (AKR)1C4 gene by hepatocyte nuclear factor (HNF)-4alpha/gamma and HNF-1alpha". The Biochemical Journal 355 (Pt 2): 537–44. April 2001. doi:10.1042/0264-6021:3550537. PMID 11284743.
- "Hepatocyte nuclear factor (HNF)-4 alpha/gamma, HNF-1 alpha, and vHNF-1 regulate the cell-specific expression of the human dihydrodiol dehydrogenase (DD)4/AKR1C4 gene". Archives of Biochemistry and Biophysics 405 (2): 185–90. September 2002. doi:10.1016/S0003-9861(02)00384-3. PMID 12220531.
- "Hepatocyte nuclear factor-4 alpha/gamma and hepatocyte nuclear factor-1 alpha as causal factors of interindividual difference in the expression of human dihydrodiol dehydrogenase 4 mRNA in human livers". Pharmacogenetics 13 (1): 49–53. January 2003. doi:10.1097/00008571-200301000-00007. PMID 12544512.
- "Influence of mirtazapine on plasma concentrations of neuroactive steroids in major depression and on 3alpha-hydroxysteroid dehydrogenase activity". Molecular Psychiatry 11 (3): 261–72. March 2006. doi:10.1038/sj.mp.4001782. PMID 16344854.
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