3α-Hydroxysteroid dehydrogenase explained

Ec Number:1.1.1.50

3α-Hydroxysteroid dehydrogenase (3α-HSD) is an enzyme (1.1.1.50)[1] [2] that plays a role in the metabolism of steroids and non-steroidal compounds in humans and other species, such as bacteria,[3] [4] fungi, plants,[5] [6] and so on. This enzyme catalyzes the chemical reaction of conversion of 3-ketosteroids into 3α-hydroxysteroids.[7] The enzyme has various protein isoforms (isozymes).[8]

3α-Hydroxysteroid dehydrogenase in humans

In humans, 3α-hydroxysteroid dehydrogenase is encoded by the multiple different genes, so that each gene encodes a particular isoform.[8] [9] [10] The most studied isoforms are type 1 (AKR1C4), type 2 (AKR1C3) and type 3 (AKR1C2). Each of these isoforms shares higher than 70% sequence homology and common properties. They are monomeric soluble proteins consisting of about 320 amino acid residues with molecular weights about 34±37 kilodaltons; although these isoforms are highly similar in their sequence, they exhibit unique reactivity profiles.[6] [1] [2] Albeit other isoforms may also exists in humans;[9] [11] still, RNA expression analysis indicates that human type 1 isozyme (AKR1C4) is expressed exclusively in the liver, whereas type 3 (AKR1C2) is more widely expressed and is found, besides the liver, also in the adrenal glads, testis, brain, prostate, and HaCaT keratinocytes.[1] [2] The 3α-hydroxysteroid dehydrogenase activity has also been detected in retinol dehydrogenases found in microsomal fractions of rat and human tissues, the membrane-bound proteins which are members of the short-chain dehydrogenase/reductase family. The 3α-hydroxysteroid dehydrogenase activities of these retinol dehydrogenases enzymes are almost exclusively oxidative in intact mammalian cells and are nicotinamide adenine dinucleotide (NAD)±specific.[12] [13] NAD is a coenzyme found in all living cells and is required for the metabolic processes that make life possible; specifically, NAD is involved in redox reactions, carrying electrons from one reaction to another; the coenzyme exists in two forms: NAD+ (oxidized form) and NADH (reduced form), so that NAD plays a role in the production of energy through the electron transport chain, as well as in the synthesis of nucleic acids.[14] [15] In context of 3α-hydroxysteroid dehydrogenase enzymes, the notion that these enzymes are NAD±specific mean that they require NAD in either its oxidized or reduced form to function properly; still, the activity of these enzymes is almost exclusively oxidative in intact mammalian cells, relying on NAD as a coenzyme for their action, whereas in other (non-mammalian) organisms it can be in reduced form.[16] [17] In humans, the genes for the protein isoforms of the 3α-hydroxysteroid dehydrogenase enzyme share a common gene structure that is characteristic of the aldo-keto-reductase family members and contain at least nine conserved exon-intron boundaries.[18] [19]

Regardless of a particular isoform, the 3α-hydroxysteroid dehydrogenase enzyme in humans is known to be necessary for the synthesis of many important endogenous neurosteroids, such as allopregnanolone, tetrahydrodeoxycorticosterone, and 5α-androstane-3α,17β-diol, also known as 3α-androstanediol, and abbreviated as 3α-diol. The activity of this enzyme towards 3α-diol is important not only in the conventional pathways of androgen biosynthesis, but also in the androgen backdoor patthway.[20] [21] [22] An important emzyme activity in humans is the transformation of the one of the most potent natural androgens, 5α-dihydrotestosterone into 3α-diol, a compound having much lower biological activity towards the androgen receptor.[20] [1] [2] This enzyme in humans, in its various protein isoforms, are also known to be involved in the metabolism of glucocorticoids, progestins, prostaglandins, bile acid precursors, and xenobiotics, thus playing a role in the control of a series of active steroid levels in target tissues.

3α-Hydroxysteroid dehydrogenase in other species

In non-human species, 3α-hydroxysteroid dehydrogenases contribute to steroidogenesis as part of the NADPH/NAD±dependent oxidoreductase family; so that these enzymes facilitate the conversion between ketones and their corresponding secondary alcohols across various positions on steroidal substrates (3α-, 3β-, 11β-, 17β-, 20α-, and 20β-positions of the stroid nucleus), and also play a dual role in both the synthesis and deactivation of steroids, and some also participate in the metabolism of a range of non-steroidal molecules. Within target tissues, these dehydrogenases transform inactive steroid hormones into their active counterparts and vice versa, so that these reactions regulates the activation of steroid hormone receptors and influences non-genomic signaling pathways; as such,3α-hydroxysteroid dehydrogenases serve as regulators, enabling the pre-receptor modulation of steroid hormone activities in these organisms.[3]

References

  1. Web site: Ec 1.1.1.50 . May 12, 2024 . April 5, 2023 . https://web.archive.org/web/20230405065826/https://iubmb.qmul.ac.uk/enzyme/EC1/1/1/50.html . live .
  2. Web site: Information on EC 1.1.1.50 - 3alpha-hydroxysteroid 3-dehydrogenase (Si-specific) - BRENDA Enzyme Database . May 12, 2024 . April 4, 2023 . https://web.archive.org/web/20230404090036/https://www.brenda-enzymes.info/enzyme.php?ecno=1.1.1.50 . live .
  3. August 22, 2011. 10.1016/j.jsbmb.2011.08.002. 21884790 . Hydroxysteroid dehydrogenases (HSDS) in bacteria – A bioinformatic perspective . Kisiela . Michael . Skarka . Adam . Ebert . Bettina . Maser . Edmund . The Journal of Steroid Biochemistry and Molecular Biology . 129 . 1–2 . 31–46 .
  4. Doden HL, Ridlon JM . Microbial Hydroxysteroid Dehydrogenases: From Alpha to Omega . Microorganisms . 9 . 3 . February 24, 2021 . 469 . 33668351 . 7996314 . 10.3390/microorganisms9030469 . free .
  5. February 24, 2023. 10.3389/fmicb.2023.1140662. free . Biological synthesis of ursodeoxycholic acid . Song . Peng . Zhang . Xue . Feng . Wei . Xu . Wei . Wu . Chaoyun . Xie . Shaoqing . Yu . Sisi . Fu . Rongzhao . Frontiers in Microbiology . 14 . 36910199 . 9998936 .
  6. 10.1093/pcp/pcz049. March 20, 2019 . Identification of a 3β-Hydroxysteroid Dehydrogenase/ 3-Ketosteroid Reductase Involved in α-Tomatine Biosynthesis in Tomato . Lee . Hyoung Jae . Nakayasu . Masaru . Akiyama . Ryota . Kobayashi . Midori . Miyachi . Haruka . Sugimoto . Yukihiro . Umemoto . Naoyuki . Saito . Kazuki . Muranaka . Toshiya . Mizutani . Masaharu . Plant and Cell Physiology . 60 . 6 . 1304–1315 . 30892648 .
  7. 10.1016/S0969-2126(00)00064-2 . The refined three-dimensional structure of 3α,20β-hydroxysteroid dehydrogenase and possible roles of the residues conserved in short-chain dehydrogenases . 1994 . Ghosh . Debashis . Wawrzak . Zdzislaw . Weeks . Charles M. . Duax . William L. . Erman . Mary . Structure . 2 . 7 . 629–640 . 7922040 .
  8. 10.1093/oxfordjournals.jbchem.a022211. November 1, 1998 . Identification of a Principal mRNA Species for Human 3 -Hydroxysteroid Dehydrogenase Isoform (AKR1C3) That Exhibits High Prostaglandin D2 11-Ketoreductase Activity . Matsuura . K. . Shiraishi . H. . Hara . A. . Sato . K. . Deyashiki . Y. . Ninomiya . M. . Sakai . S. . Journal of Biochemistry . 124 . 5 . 940–946 . 9792917 .
  9. 10.1210/en.2002-0032. 12810547 . Human Type 3 3α-Hydroxysteroid Dehydrogenase (Aldo-Keto Reductase 1C2) and Androgen Metabolism in Prostate Cells . 2003 . RižNer . Tea Lanišnik . Lin . Hsueh K. . Peehl . Donna M. . Steckelbroeck . Stephan . Bauman . David R. . Penning . Trevor M. . Endocrinology . 144 . 7 . 2922–2932 .
  10. 10.1210/jcem.86.3.7325. March 1, 2001 . Characterization of the 5α-Reductase-3α-Hydroxysteroid Dehydrogenase Complex in the Human Brain. Steckelbroeck . Stephan . Watzka . Mathias . Reichelt . Robert . Hans . Volkmar H. J. . Stoffel-Wagner . Birgit . Heidrich . Dagmar D. . Schramm . Johannes . Bidlingmaier . Frank . Klingmüller . Dietrich . The Journal of Clinical Endocrinology & Metabolism . 86 . 3 . 1324–1331 . 11238528 .
  11. 10.1042/0264-6021:3510067 . Human 3α-hydroxysteroid dehydrogenase isoforms (AKR1C1‒AKR1C4) of the aldo-keto reductase superfamily: Functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones . 2000 . Penning . Trevor M. . Burczynski . Michael E. . Jez . Joseph M. . Hung . Chien-Fu . Lin . Hseuh-Kung . Ma . Haiching . Moore . Margaret . Palackal . Nisha . Ratnam . Kapila . Biochemical Journal . 351 . Pt 1 . 67–77 . 10998348 . 1221336 .
  12. Book: 10.1007/978-1-4615-5871-2_54. 978-1-4615-5871-2 . Hydroxysteroid Dehydrogenases . Enzymology and Molecular Biology of Carbonyl Metabolism 6 . Advances in Experimental Medicine and Biology . 1996 . Penning . Trevor M. . 414 . 475–490 .
  13. 10.1023/A:1010291527744 . 2001 . Degtiar . W. G. . Kushlinsky . N. E. . 3α-Hydroxysteroid Dehydrogenase in Animal and Human Tissues . Biochemistry (Moscow) . 66 . 3 . 256–266 . 11333148 .
  14. 10.1126/science.aac4854 . NAD + in aging, metabolism, and neurodegeneration . 2015 . Verdin . Eric . Science . 350 . 6265 . 1208–1213 . 26785480 .
  15. January 1, 2021. 10.1038/s41392-020-00354-w . NAD+ metabolism, stemness, the immune response, and cancer . Navas . Lola E. . Carnero . Amancio . Signal Transduction and Targeted Therapy . 6 . 1 . 2 . 33384409 . 7775471 .
  16. 10.1210/jcem.86.2.7216. February 1, 2001 . Human Types 1 and 3 3α-Hydroxysteroid Dehydrogenases: Differential Lability and Tissue Distribution1 . Dufort . Isabelle . Labrie . Fernand . Luu-The . Van . The Journal of Clinical Endocrinology & Metabolism . 86 . 2 . 841–846 . 11158055 .
  17. April 10, 2012. 10.1371/journal.pbio.1001305. free . A Novel 3-Hydroxysteroid Dehydrogenase That Regulates Reproductive Development and Longevity . Wollam . Joshua . Magner . Daniel B. . Magomedova . Lilia . Rass . Elisabeth . Shen . Yidong . Rottiers . Veerle . Habermann . Bianca . Cummins . Carolyn L. . Antebi . Adam . PLOS Biology . 10 . 4 . e1001305 . 22505847 . 3323522 .
  18. 10.1210/er.2018-00089. August 20, 2018 . Structural and Functional Biology of Aldo-Keto Reductase Steroid-Transforming Enzymes . Penning . Trevor M. . Wangtrakuldee . Phumvadee . Auchus . Richard J. . Endocrine Reviews . 40 . 2 . 447–475 . 30137266 . 6405412 .
  19. June 15, 2023. 10.3389/fpls.2023.1159394. free . Genome-wide analysis revealed the stepwise origin and functional diversification of HSDS from lower to higher plant species . Saleem . Noor . Aziz . Usman . Ali . Muhammad . Liu . Xiangling . Alwutayd . Khairiah Mubarak . Alshegaihi . Rana M. . Niedbała . Gniewko . Elkelish . Amr . Zhang . Meng . Frontiers in Plant Science . 14 . 37396629 . 10311447 .
  20. 10.15347/WJM/2023.003 . free . Alternative androgen pathways . April 3, 2023 . Maxim. Masiutin. Maneesh . Yadav . WikiJournal of Medicine . 10 . 29 . 257943362 . May 12, 2024 . October 24, 2023 . https://web.archive.org/web/20231024051038/https://upload.wikimedia.org/wikiversity/en/a/a7/Alternative_androgens_pathways.pdf . live .
  21. 10.1016/j.tem.2004.09.004 . The backdoor pathway to dihydrotestosterone . 2004 . Auchus . Richard J. . Trends in Endocrinology & Metabolism . 15 . 9 . 432–438 . 15519890 .
  22. April 3, 2019. 10.1371/journal.pbio.3000198. free . The "backdoor pathway" of androgen synthesis in human male sexual development . Miller . Walter L. . Auchus . Richard J. . PLOS Biology . 17 . 4 . e3000198 . 30943210 . 6464227 .

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "3α-Hydroxysteroid dehydrogenase".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.