17β-Hydroxysteroid dehydrogenase

Reactions

17β-HSDs have been known to catalyze the following redox reactions of sex steroids:

• 20α-Hydroxyprogesterone ↔ Progesterone
• ↔ Androstenediol
• Androstenedione ↔ Testosterone
• Dihydrotestosterone ↔ 5α-Androstanedione / 3α-Androstanediol / 3β-Androstanediol
• Estrone ↔ Estradiol
• 16α-Hydroxyestrone ↔ Estriol

Activity distribution

Genes

Genes coding for 17β-HSD include:

• HSD17B1: Referred to as "estrogenic". Major subtype for activation of estrogens from weaker forms (estrone to estradiol and 16α-hydroxyestrone to estriol). Catalyzes the final step in the biosynthesis of estrogens. Highly selective for estrogens; 100-fold higher affinity for estranes over androstanes. However, also catalyzes the conversion of DHEA into androstenediol. Recently, has been found to inactivate DHT into 3α- and 3β-androstanediol. Expressed primarily in the ovaries and placenta but also at lower levels in the breast epithelium. Major isoform of 17β-HSD in the granulosa cells of the ovaries. Mutations and associated deficiency have not been reported in humans. Knockout mice show altered ovarian sex steroid production, normal puberty, and severe subfertility due to defective luteinization and ovarian progesterone production.
• HSD17B2: Describable as "antiestrogenic" and "antiandrogenic". Major subtype for inactivation of estrogens and androgens into weaker forms (estradiol to estrone, testosterone to androstenedione, and androstenediol to DHEA). Also converts inactive 20α-hydroxyprogesterone into active progesterone. Preferential activity on androgens. Expressed widely in the body including in the liver, intestines, lungs, pancreas, kidneys, endometrium, prostate, breast epithelium, placenta, and bone. Said to be responsible for 17β-HSD activity in the endometrium and placenta. Mutations and associated congenital deficiency have not been reported in humans. However, local deficiency in expression of HSD17B2 has been associated with endometriosis.
• HSD17B3: Referred to as "androgenic". Major subtype in males for activation of androgens from weaker forms (androstenedione to testosterone and DHEA to androstenediol). Also activates estrogens from weaker forms to a lesser extent (estrone to estradiol). This is essential for testicular but not ovarian production of testosterone. Not expressed in the ovaries, where another 17β-HSD subtype, likely HSD17B5, is expressed instead. Mutations are associated with 17β-HSD type III deficiency. Males with this condition have pseudohermaphroditism, while females are normal with normal androgen and estrogen levels.
• HSD17B4: Also known as D-bifunctional protein (DBP). Involved in fatty acid β-oxidation and steroid metabolism (specifically estrone to estradiol, for instance in the uterus). Mutations are associated with DBP deficiency and Perrault syndrome (ovarian dysgenesis and deafness).
• HSD17B5: Also known as aldo-keto reductase 1C3 (AKR1C3), encoded by the AKR1C3 gene in humans. Has and activity in addition to 17β-HSD activity. Expressed in the adrenal cortex and may act as the "androgenic" 17β-HSD in ovarian thecal cells. Also expressed in the prostate gland, mammary gland, and Leydig cells.
• HSD17B6: Has activity and catalyzes conversion of the weak androgen androstanediol into the powerful androgen dihydrotestosterone in the prostate gland. Also involved into a backdoor pathway from 17α-hydroxyprogesterone to dihydrotestosterone by 3α-reduction of a metabolic intermediary, 17α-hydroxydihydroprogesterone, into another intermediary, 17α-hydroxyallopregnanolone. May be involved in the pathophysiology of .
• HSD17B7: Is involved in cholesterol metabolism but is also thought to activate estrogens (estrone to estradiol) and inactivate androgens (dihydrotestosterone to androstanediol). Expressed in the ovaries, breasts, placenta, testes, prostate gland, and liver.
• HSD17B8: Inactivates estradiol, testosterone, and dihydrotestosterone, though can also convert estrone into estradiol. Expressed in the ovaries, testes, liver, pancreas, kidneys, and other tissues.
• HSD17B9: Also known as retinol dehydrogenase 5 (RDH5). Involved in retinoid metabolism. Mutations are associated with fundus albipunctatus.
• HSD17B10: Also known as 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD). Substrates include steroids, neurosteroids, fatty acids, bile acids, isoleucine, and xenobiotics. Mutations are associated with 17β-HSD type X deficiency (also known as HSD10 disease or MHBD deficiency) and mental retardation, X-linked, syndromic 10 (MRXS10), which are characterized by neurodegeneration and mental retardation, respectively.
• HSD17B11: very little is known on the role/function of this iszyme.
• HSD17B12
• HSD17B13
• HSD17B14

At least 7 of the 14 isoforms of 17β-HSD are involved in interconversion of 17-ketosteroids and 17β-hydroxysteroids.

Overview

Clinical significance

Mutations in HSD17B3 are responsible for 17β-HSD type III deficiency.

Inhibitors of 17β-HSD type II are of interest for the potential treatment of osteoporosis.

Some inhibitors of 17β-HSD type I have been identified, for example esters of cinnamic acid and various flavones (e.g. fisetin).

References

References

1. (1964). "Anreicherung einer 17β-hydroxysteroid:NAD(P)-oxydoreduktase aus der Nebenniere der Ratte". Hoppe-Seyler's Zeitschrift für Physiologische Chemie.
2. (June 1958). "The conversion of progesterone to androgens by testes". The Journal of Biological Chemistry.
3. (February 1956). "Induction and purification of alpha- and beta-hydroxysteroid dehydrogenases". The Journal of Biological Chemistry.
4. (June 1977). "3(17)beta-Hydroxysteroid dehydrogenase of Pseudomonas testosteroni. A convenient purification and demonstration of multiple molecular forms". The Journal of Biological Chemistry.
5. (December 1953). "Purification and properties of a beta-hydroxysteroid dehydrogenase". The Journal of Biological Chemistry.
6. (January 1997). "The key role of 17 beta-hydroxysteroid dehydrogenases in sex steroid biology". Steroids.
7. (2011). "Brook's Clinical Pediatric Endocrinology". John Wiley & Sons.
8. (March 1992). "Distribution of 17 beta-hydroxysteroid dehydrogenase gene expression and activity in rat and human tissues". J. Steroid Biochem. Mol. Biol..
9. (6 December 2012). "Estrogens and Antiestrogens I: Physiology and Mechanisms of Action of Estrogens and Antiestrogens". Springer Science & Business Media.
10. (April 2010). "17beta-hydroxysteroid dehydrogenase type 1 stimulates breast cancer by dihydrotestosterone inactivation in addition to estradiol production". Molecular Endocrinology.
11. (May 2017). "Estrogen and androgen-converting enzymes 17β-hydroxysteroid dehydrogenase and their involvement in cancer: with a special focus on 17β-hydroxysteroid dehydrogenase type 1, 2, and breast cancer". Oncotarget.
12. (January 1997). "Physiology and molecular genetics of 17 beta-hydroxysteroid dehydrogenases". Steroids.
13. (13 July 1998). "Principles of Molecular Medicine". Springer Science & Business Media.
14. (September 2015). "Hydroxysteroid (17β)-dehydrogenase 1-deficient female mice present with normal puberty onset but are severely subfertile due to a defect in luteinization and progesterone production". FASEB Journal.
15. (2016). "High Expression of 17β-hydroxysteroid Dehydrogenase Type 2 is Associated with a Better Prognosis in Urothelial Carcinoma of the Urinary Tract". Journal of Cancer.
16. (2016). "Williams Textbook of Endocrinology". Elsevier Health Sciences.
17. (13 September 2013). "Yen and Jaffe's Reproductive Endocrinology". Elsevier Health Sciences.
18. (25 February 2015). "Endocrinology: Adult and Pediatric E-Book". Elsevier Health Sciences.
19. (January 2010). "17Beta-hydroxysteroid dehydrogenase-2 deficiency and progesterone resistance in endometriosis". Seminars in Reproductive Medicine.
20. (August 2010). "Mutations in the DBP-deficiency protein HSD17B4 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault Syndrome". American Journal of Human Genetics.
21. (2023). "Alternative androgen pathways". WikiJournal of Medicine.
22. (August 1998). "Characterization of Ke 6, a new 17beta-hydroxysteroid dehydrogenase, and its expression in gonadal tissues". The Journal of Biological Chemistry.
23. (June 1997). "Physical mapping 220 kb centromeric of the human MHC and DNA sequence analysis of the 43-kb segment including the RING1, HKE6, and HKE4 genes". Genomics.
24. (December 2003). "Structure and function of retinol dehydrogenases of the short chain dehydrogenase/reductase family". Molecular Aspects of Medicine.
25. (August 2015). "Fundus albipunctatus: review of the literature and report of a novel RDH5 gene mutation affecting the invariant tyrosine (p.Tyr175Phe)". Journal of Applied Genetics.
26. (2011). "Hydroxysteroid (17β) dehydrogenase X in human health and disease". Mol. Cell. Endocrinol..
27. (2014). "Roles of 17β-hydroxysteroid dehydrogenase type 10 in neurodegenerative disorders". J. Steroid Biochem. Mol. Biol..
28. (2019). "Role of HSD17B13 in the liver physiology and pathophysiology". Molecular and Cellular Endocrinology.
29. (2021). "Identification of prognostic lipid droplet-associated genes in pancreatic cancer patients via bioinformatics analysis". Lipids in Health and Disease.
30. (9 November 2016). "Hormones, Brain and Behavior". Elsevier Science.
31. (2009). "Integrated view on 17beta-hydroxysteroid dehydrogenases". Mol. Cell. Endocrinol..
32. (2004). "The role of 17 beta-hydroxysteroid dehydrogenases". Mol. Cell. Endocrinol..
33. (2011). "17β-Hydroxysteroid dehydrogenases (17β-HSDs) as therapeutic targets: protein structures, functions, and recent progress in inhibitor development". J. Steroid Biochem. Mol. Biol..
34. (2015). "Type 2 17-β hydroxysteroid dehydrogenase as a novel target for the treatment of osteoporosis". Future Med Chem.
35. (2017). "Development of 17β-hydroxysteroid dehydrogenase type 3 as a target in hormone-dependent prostate cancer therapy". Steroids.
36. (23 June 2012). "Characterization of Type 15 17β-Hydroxysteroid Dehydrogenase". Steroid Hormone Biosynthesis & Metabolism (Translational).
37. (2001). "Prostate short-chain dehydrogenase reductase 1 (PSDR1): a new member of the short-chain steroid dehydrogenase/reductase family highly expressed in normal and neoplastic prostate epithelium". Cancer Res..
38. (2002). "Evidence that the human gene for prostate short-chain dehydrogenase/reductase (PSDR1) encodes a novel retinal reductase (RalR1)". J. Biol. Chem..
39. (2014). "New syndrome with retinitis pigmentosa is caused by nonsense mutations in retinol dehydrogenase RDH11". Hum. Mol. Genet..
40. (August 2014). "Novel, potent and selective 17β-hydroxysteroid dehydrogenase type 2 inhibitors as potential therapeutics for osteoporosis with dual human and mouse activities". European Journal of Medicinal Chemistry.
41. (March 2009). "Flavonoids and cinnamic acid derivatives as inhibitors of 17beta-hydroxysteroid dehydrogenase type 1". Molecular and Cellular Endocrinology.