3α-Hydroxysteroid dehydrogenase

3α-Hydroxysteroid dehydrogenase
Identifiers
EC no.	1.1.1.50
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Search PMC articles PubMed articles NCBI proteins

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][8] The enzyme has various protein isoforms (isozymes).^[9]

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.^[9][10][11] 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;^[10][12] 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.^[13][14] 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.^[15][16] 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.^[17][18]

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.^[7][19][20]

HGNC Gene Symbol	Enzyme Name Aliases[7]
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

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.^{[21][22][23][7]} 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.^[21][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.^[7]

3α-Hydroxysteroid dehydrogenase in other species

The carbon atom numbering in a hypothetical steroid nucleus can be demonstrated by a structure of 24-ethyl-lanostane, a prototypical steroid with 32 carbon atoms. Its core ring system (ABCD), composed of 17 carbon atoms, is shown with IUPAC-approved ring lettering and carbon atom numbering.^[24]

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

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3. Kisiela, Michael; Skarka, Adam; Ebert, Bettina; Maser, Edmund (August 22, 2011). "Hydroxysteroid dehydrogenases (HSDS) in bacteria – A bioinformatic perspective". The Journal of Steroid Biochemistry and Molecular Biology. 129 (1–2): 31–46. doi:10.1016/j.jsbmb.2011.08.002. PMID 21884790.
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8. Ghosh, Debashis; Wawrzak, Zdzislaw; Weeks, Charles M.; Duax, William L.; Erman, Mary (1994). "The refined three-dimensional structure of 3α,20β-hydroxysteroid dehydrogenase and possible roles of the residues conserved in short-chain dehydrogenases". Structure. 2 (7): 629–640. doi:10.1016/S0969-2126(00)00064-2. PMID 7922040.
9. Matsuura, K.; Shiraishi, H.; Hara, A.; Sato, K.; Deyashiki, Y.; Ninomiya, M.; Sakai, S. (November 1, 1998). "Identification of a Principal mRNA Species for Human 3 -Hydroxysteroid Dehydrogenase Isoform (AKR1C3) That Exhibits High Prostaglandin D2 11-Ketoreductase Activity". Journal of Biochemistry. 124 (5): 940–946. doi:10.1093/oxfordjournals.jbchem.a022211. PMID 9792917.
10. RižNer, Tea Lanišnik; Lin, Hsueh K.; Peehl, Donna M.; Steckelbroeck, Stephan; Bauman, David R.; Penning, Trevor M. (2003). "Human Type 3 3α-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.
11. Steckelbroeck, Stephan; Watzka, Mathias; Reichelt, Robert; Hans, Volkmar H. J.; Stoffel-Wagner, Birgit; Heidrich, Dagmar D.; Schramm, Johannes; Bidlingmaier, Frank; Klingmüller, Dietrich (March 1, 2001). "Characterization of the 5α-Reductase-3α-Hydroxysteroid Dehydrogenase Complex in the Human Brain". The Journal of Clinical Endocrinology & Metabolism. 86 (3): 1324–1331. doi:10.1210/jcem.86.3.7325. PMID 11238528.
12. Penning, Trevor M.; Burczynski, Michael E.; Jez, Joseph M.; Hung, Chien-Fu; Lin, Hseuh-Kung; Ma, Haiching; Moore, Margaret; Palackal, Nisha; Ratnam, Kapila (2000). "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". Biochemical Journal. 351 (Pt 1): 67–77. doi:10.1042/0264-6021:3510067. PMC 1221336. PMID 10998348.
13. Penning, Trevor M. (1996). "Hydroxysteroid Dehydrogenases". Enzymology and Molecular Biology of Carbonyl Metabolism 6. Advances in Experimental Medicine and Biology. Vol. 414. pp. 475–490. doi:10.1007/978-1-4615-5871-2_54. ISBN 978-1-4615-5871-2.
14. Degtiar, W. G.; Kushlinsky, N. E. (2001). "3α-Hydroxysteroid Dehydrogenase in Animal and Human Tissues". Biochemistry (Moscow). 66 (3): 256–266. doi:10.1023/A:1010291527744. PMID 11333148.
15. Verdin, Eric (2015). "NAD ⁺ in aging, metabolism, and neurodegeneration". Science. 350 (6265): 1208–1213. doi:10.1126/science.aac4854. PMID 26785480.
16. Navas, Lola E.; Carnero, Amancio (January 1, 2021). "NAD+ metabolism, stemness, the immune response, and cancer". Signal Transduction and Targeted Therapy. 6 (1): 2. doi:10.1038/s41392-020-00354-w. PMC 7775471. PMID 33384409.
17. Dufort, Isabelle; Labrie, Fernand; Luu-The, Van (February 1, 2001). "Human Types 1 and 3 3α-Hydroxysteroid Dehydrogenases: Differential Lability and Tissue Distribution1". The Journal of Clinical Endocrinology & Metabolism. 86 (2): 841–846. doi:10.1210/jcem.86.2.7216. PMID 11158055.
18. Wollam, Joshua; Magner, Daniel B.; Magomedova, Lilia; Rass, Elisabeth; Shen, Yidong; Rottiers, Veerle; Habermann, Bianca; Cummins, Carolyn L.; Antebi, Adam (April 10, 2012). "A Novel 3-Hydroxysteroid Dehydrogenase That Regulates Reproductive Development and Longevity". PLOS Biology. 10 (4): e1001305. doi:10.1371/journal.pbio.1001305. PMC 3323522. PMID 22505847.
19. Penning, Trevor M.; Wangtrakuldee, Phumvadee; Auchus, Richard J. (August 20, 2018). "Structural and Functional Biology of Aldo-Keto Reductase Steroid-Transforming Enzymes". Endocrine Reviews. 40 (2): 447–475. doi:10.1210/er.2018-00089. PMC 6405412. PMID 30137266.
20. Saleem, Noor; Aziz, Usman; Ali, Muhammad; Liu, Xiangling; Alwutayd, Khairiah Mubarak; Alshegaihi, Rana M.; Niedbała, Gniewko; Elkelish, Amr; Zhang, Meng (June 15, 2023). "Genome-wide analysis revealed the stepwise origin and functional diversification of HSDS from lower to higher plant species". Frontiers in Plant Science. 14. doi:10.3389/fpls.2023.1159394. PMC 10311447. PMID 37396629.
21. Masiutin, Maxim; Yadav, Maneesh (April 3, 2023). "Alternative androgen pathways" (PDF). WikiJournal of Medicine. 10: 29. doi:10.15347/WJM/2023.003. S2CID 257943362. Archived (PDF) from the original on October 24, 2023. Retrieved May 12, 2024. This article incorporates text from this source, which is available under the CC BY 4.0 license.
22. Auchus, Richard J. (2004). "The backdoor pathway to dihydrotestosterone". Trends in Endocrinology & Metabolism. 15 (9): 432–438. doi:10.1016/j.tem.2004.09.004. PMID 15519890.
23. Miller, Walter L.; Auchus, Richard J. (April 3, 2019). "The "backdoor pathway" of androgen synthesis in human male sexual development". PLOS Biology. 17 (4): e3000198. doi:10.1371/journal.pbio.3000198. PMC 6464227. PMID 30943210.
24. "IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989". Eur J Biochem. 186 (3): 430. 1989. doi:10.1111/j.1432-1033.1989.tb15228.x. PMID 2606099. p. 430: 3S-1.1. Numbering and ring letters. Steroids are numbered and rings are lettered as in formula 1