Biology:17β-Hydroxysteroid dehydrogenase

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Short description: Class of enzymes
17β-Hydroxysteroid dehydrogenase
Identifiers
EC number1.1.1.51
CAS number9015-81-0
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO

17β-Hydroxysteroid dehydrogenases (17β-HSD, HSD17B) (EC 1.1.1.51), also 17-ketosteroid reductases (17-KSR), are a group of alcohol oxidoreductases which catalyze the reduction of 17-ketosteroids and the dehydrogenation of 17β-hydroxysteroids in steroidogenesis and steroid metabolism.[1][2][3][4][5] This includes interconversion of DHEA and androstenediol, androstenedione and testosterone, and estrone and estradiol.[6][7]

The major reactions catalyzed by 17β-HSD (e.g., the conversion of androstenedione to testosterone) are in fact hydrogenation (reduction) rather than dehydrogenation (oxidation) reactions.

Reactions

Steroidogenesis. 17β-HSD visible in bottom-left region.

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

Activity distribution

Distribution of 17β-HSD activities for formation of estradiol versus estrone in human tissues.[8][9]

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.[10] Recently, has been found to inactivate DHT into 3α- and 3β-androstanediol.[10][11] Expressed primarily in the ovaries and placenta but also at lower levels in the breast epithelium.[12][10] Major isoform of 17β-HSD in the granulosa cells of the ovaries.[13] Mutations and associated deficiency have not been reported in humans.[14] Knockout mice show altered ovarian sex steroid production, normal puberty, and severe subfertility due to defective luteinization and ovarian progesterone production.[15]
  • HSD17B2: Describable as "antiestrogenic" and "antiandrogenic".[16] 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.[10][17][12] Said to be responsible for 17β-HSD activity in the endometrium and placenta.[18] Mutations and associated congenital deficiency have not been reported in humans.[14] However, local deficiency in expression of HSD17B2 has been associated with endometriosis.[19]
  • 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.[17][12]
  • 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).[20] Mutations are associated with DBP deficiency and Perrault syndrome (ovarian dysgenesis and deafness).[20]
  • HSD17B5: Also known as aldo-keto reductase 1C3 (AKR1C3). Has 3α-HSD and 20α-HSD 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.[12]
  • HSD17B6: Has 3α-HSD 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.[21] May be involved in the pathophysiology of PCOS.[12]
  • HSD17B7: Is involved in cholesterol metabolism but is also thought to activate estrogens (estrone to estradiol) and inactivate androgens (dihydrotestosterone to androstanediol).[12] Expressed in the ovaries, breasts, placenta, testes, prostate gland, and liver.[12]
  • HSD17B8: Inactivates estradiol, testosterone, and dihydrotestosterone, though can also convert estrone into estradiol. Expressed in the ovaries, testes, liver, pancreas, kidneys, and other tissues.[22][23]
  • HSD17B9: Also known as retinol dehydrogenase 5 (RDH5). Involved in retinoid metabolism.[24] Mutations are associated with fundus albipunctatus.[25]
  • HSD17B10: Also known as 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD). Substrates include steroids, neurosteroids, fatty acids, bile acids, isoleucine, and xenobiotics.[26][27] 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.[26][27]
  • HSD17B11
  • HSD17B12
  • HSD17B13
  • HSD17B14

At least 7 of the 14 isoforms of 17β-HSD are involved in interconversion of 17-ketosteroids and 17β-hydroxysteroids.[12]

Overview

Comparison and characteristics of human 17β-HSD isoenzymes[28][29][30][31]
# Gene name Synonyms Family Size (AA) Gene location Cellular location Substrate specificities Preferred cofactor Catalytic preference Tissue distribution Expression profile Pathology
1 HSD17B1 SDR 328 17q21.2 Cytosol Estrogens NADH, NADPH Reduction Ovary, endometrium, breast, brain, prostate, placenta Strongly restricted Breast cancer, prostate cancer, endometriosis
3 HSD17B3 SDR 310 9q22.32 ER Androgens NADPH Reduction Testis, ovary, blood, saliva, skin, adipose tissue, brain, bone Strongly restricted 17β-HSD3 deficiency, prostate cancer[32]
4 HSD17B4 DBP, MFP2 SDR 736 5q23.1 PXS Fatty acids, bile acids, estrogens, androgens NAD+ Oxidation Liver, heart, prostate, testis, lung, skeletal muscle, kidney, pancreas, thymus, ovary, intestine, placenta, brain, spleen, colon, lymphocytes Ubiquitous DBP deficiency, Perrault syndrome, prostate cancer
5 AKR1C3 HSD17B5, PGFS AKR 323 10p15.1 Nucleus, cytosol Androgens, progestogens, estrogens, prostaglandins NADPH Reduction Prostate, mammary gland, liver, kidney, lung, heart, small intestine, colon, uterus, testis, brain, skeletal muscle, adipose tissue Nearly ubiquitous Breast cancer, prostate cancer
6 HSD17B6 SDR 317 12q13.3 Endosomes Retinoids, androgens, estrogens NAD+ Oxidation Liver, testis, lung, spleen, brain, ovary, kidney, adrenal, prostate Selectively distributed ?
7 HSD17B7 SDR 341 1q23.3 PM, ER Cholesterol, estrogens, androgens, progestogens NADPH Reduction Ovary, corpus luteum, uterus, placenta, liver, breast, testis, brain, adrenal gland, small intestine, lung, thymus, prostate, adipose tissue, others Widely distributed Breast cancer
8 HSD17B8 SDR 261 6p21.32 MC Fatty acids, estrogens, androgens NAD+ Oxidation Prostate, placenta, kidney, brain, cerebellum, heart, lung, small intestine, ovary, testis, adrenal, stomach Widely distributed Polycystic kidney disease
9 RDH5 HSD17B9 318 12q13.2 ER Retinoids NADH/NAD+ Reduction / oxidation Retina, liver, adipose tissue, blood, others ? Fundus albipunctatus
10 HSD17B10 MHBD SDR 261 Xp11.2 MC Fatty acids, bile acids, estrogens, androgens, progestogens, corticosteroids NAD+ Oxidation Liver, small intestine, colon, kidney, heart, brain, placenta, lung, ovary, testis, spleen, thymus, prostate, peripheral blood leukocytes Nearly ubiquitous 17β-HSD10 deficiency, MRXS10, Alzheimer's disease
11 HSD17B11 SDR 300 4q22.1 ER, EP Estrogens, androgens NAD+ Oxidation Liver, pancreas, intestine, kidney, adrenal gland, heart, lung, testis, ovary, placenta, sebaceous gland Nearly ubiquitous ?
12 HSD17B12 SDR 312 11p11.2 ER Fatty acids, estrogens, androgens NADPH Reduction Heart, skeletal muscle, liver, kidney, adrenal gland, testis, placenta, cerebellum, pancreas, stomach, small intestine, large intestine, trachea, lung, thyroid, esophagus, prostate, aorta, urinary bladder, spleen, skin, brain, ovary, breast, uterus, vagina Ubiquitous ?
13 HSD17B13 SDR 300 4q22.1 ER, EP ? NAD+? Oxidation? Liver, bone marrow, lung, ovary, testis, kidney, skeletal muscle, brain, bladder, nasal epithelia Strongly restricted ?
14 HSD17B14 SDR 270 19q13.33 Cytosol Estrogens, androgens, fatty acids NAD+ Oxidation Liver, kidney, brain, gallbladder, breast, adrenal, placenta Widely distributed Breast cancer (prognostic)

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.[33][34]

Some inhibitors of 17β-HSD type I have been identified, for example esters of cinnamic acid and various flavones (e.g. fisetin).[35]

See also

References

  1. ↑ "Anreicherung einer 17β-hydroxysteroid:NAD(P)-oxydoreduktase aus der Nebenniere der Ratte" (in German). Hoppe-Seyler's Zeitschrift für Physiologische Chemie 336: 63–8. 1964. doi:10.1515/bchm2.1964.336.1.63. PMID 14214322. 
  2. ↑ "The conversion of progesterone to androgens by testes". The Journal of Biological Chemistry 232 (2): 1015–30. June 1958. doi:10.1016/S0021-9258(19)77419-5. PMID 13549484. 
  3. ↑ "Induction and purification of alpha- and beta-hydroxysteroid dehydrogenases". The Journal of Biological Chemistry 218 (2): 661–74. February 1956. doi:10.1016/S0021-9258(18)65833-8. PMID 13295221. 
  4. ↑ "3(17)beta-Hydroxysteroid dehydrogenase of Pseudomonas testosteroni. A convenient purification and demonstration of multiple molecular forms". The Journal of Biological Chemistry 252 (11): 3775–83. June 1977. doi:10.1016/S0021-9258(17)40319-X. PMID 193845. 
  5. ↑ "Purification and properties of a beta-hydroxysteroid dehydrogenase". The Journal of Biological Chemistry 205 (2): 823–37. December 1953. doi:10.1016/S0021-9258(18)49226-5. PMID 13129261. 
  6. ↑ "The key role of 17 beta-hydroxysteroid dehydrogenases in sex steroid biology". Steroids 62 (1): 148–58. January 1997. doi:10.1016/S0039-128X(96)00174-2. PMID 9029730. 
  7. ↑ Brook, Charles G. D.; Truong, Daniel; Clayton, Peter; Carroll, William; Brown, Rosalind (2011). Brook's Clinical Pediatric Endocrinology. John Wiley & Sons. p. 288. ISBN 978-1-4443-1673-5. https://books.google.com/books?id=Y8nhO6D0k4cC&pg=PA288. 
  8. ↑ "Distribution of 17 beta-hydroxysteroid dehydrogenase gene expression and activity in rat and human tissues". J. Steroid Biochem. Mol. Biol. 41 (3–8): 597–603. March 1992. doi:10.1016/0960-0760(92)90390-5. PMID 1314080. 
  9. ↑ Michael Oettel; Ekkehard Schillinger (6 December 2012). Estrogens and Antiestrogens I: Physiology and Mechanisms of Action of Estrogens and Antiestrogens. Springer Science & Business Media. p. 226. ISBN 978-3-642-58616-3. https://books.google.com/books?id=0BfrCAAAQBAJ&pg=PA226. 
  10. ↑ 10.0 10.1 10.2 10.3 "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 8 (18): 30552–30562. May 2017. doi:10.18632/oncotarget.15547. PMID 28430630. 
  11. ↑ "17beta-hydroxysteroid dehydrogenase type 1 stimulates breast cancer by dihydrotestosterone inactivation in addition to estradiol production". Molecular Endocrinology 24 (4): 832–45. April 2010. doi:10.1210/me.2009-0468. PMID 20172961. 
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 12.6 12.7 Strauss, Jerome Frank; Barbieri, Robert L. (13 September 2013). Yen and Jaffe's Reproductive Endocrinology. Elsevier Health Sciences. p. 82. ISBN 978-1-4557-2758-2. https://books.google.com/books?id=KZ95AAAAQBAJ&pg=PA82. 
  13. ↑ "Physiology and molecular genetics of 17 beta-hydroxysteroid dehydrogenases". Steroids 62 (1): 143–7. January 1997. doi:10.1016/s0039-128x(96)00173-0. PMID 9029729. 
  14. ↑ 14.0 14.1 Jameson, J. Larry (13 July 1998). Principles of Molecular Medicine. Springer Science & Business Media. p. 549. ISBN 978-1-59259-726-0. https://books.google.com/books?id=UhjyBwAAQBAJ&pg=PA549. 
  15. ↑ "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 29 (9): 3806–16. September 2015. doi:10.1096/fj.14-269035. PMID 26018678. 
  16. ↑ "High Expression of 17β-hydroxysteroid Dehydrogenase Type 2 is Associated with a Better Prognosis in Urothelial Carcinoma of the Urinary Tract". Journal of Cancer 7 (15): 2221–2230. 2016. doi:10.7150/jca.16777. PMID 27994658. "HSD17B2 has both anti-estrogenic and anti-androgenic functions.". 
  17. ↑ 17.0 17.1 Melmed, Shlomo (2016). Williams Textbook of Endocrinology. Elsevier Health Sciences. p. 904. ISBN 978-0-323-29738-7. https://books.google.com/books?id=YZ8_CwAAQBAJ&pg=PA904. 
  18. ↑ Jameson, J. Larry; De Groot, Leslie J. (25 February 2015). Endocrinology: Adult and Pediatric E-Book. Elsevier Health Sciences. p. 2078. ISBN 978-0-323-32195-2. https://books.google.com/books?id=xmLeBgAAQBAJ&pg=PA2078. 
  19. ↑ "17Beta-hydroxysteroid dehydrogenase-2 deficiency and progesterone resistance in endometriosis". Seminars in Reproductive Medicine 28 (1): 44–50. January 2010. doi:10.1055/s-0029-1242992. PMID 20108182. 
  20. ↑ 20.0 20.1 "Mutations in the DBP-deficiency protein HSD17B4 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault Syndrome". American Journal of Human Genetics 87 (2): 282–8. August 2010. doi:10.1016/j.ajhg.2010.07.007. PMID 20673864. 
  21. ↑ Masiutin, Maxim; Yadav, Maneesh (2023). "Alternative androgen pathways". WikiJournal of Medicine 10: X. doi:10.15347/WJM/2023.003. 
  22. ↑ "Characterization of Ke 6, a new 17beta-hydroxysteroid dehydrogenase, and its expression in gonadal tissues". The Journal of Biological Chemistry 273 (35): 22664–71. August 1998. doi:10.1074/jbc.273.35.22664. PMID 9712896. 
  23. ↑ "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 42 (3): 422–35. June 1997. doi:10.1006/geno.1997.4745. PMID 9205114. 
  24. ↑ "Structure and function of retinol dehydrogenases of the short chain dehydrogenase/reductase family". Molecular Aspects of Medicine 24 (6): 403–9. December 2003. doi:10.1016/s0098-2997(03)00036-0. PMID 14585311. 
  25. ↑ "Fundus albipunctatus: review of the literature and report of a novel RDH5 gene mutation affecting the invariant tyrosine (p.Tyr175Phe)". Journal of Applied Genetics 56 (3): 317–27. August 2015. doi:10.1007/s13353-015-0281-x. PMID 25820994. 
  26. ↑ 26.0 26.1 "Hydroxysteroid (17β) dehydrogenase X in human health and disease". Mol. Cell. Endocrinol. 343 (1–2): 1–6. 2011. doi:10.1016/j.mce.2011.06.011. PMID 21708223. 
  27. ↑ 27.0 27.1 "Roles of 17β-hydroxysteroid dehydrogenase type 10 in neurodegenerative disorders". J. Steroid Biochem. Mol. Biol. 143: 460–72. 2014. doi:10.1016/j.jsbmb.2014.07.001. PMID 25007702. 
  28. ↑ Zhu, Yuan-Shan; Imperato-McGinley, Julianne L. (9 November 2016). "4.02: Disorders of Sexual Development in Males: Molecular Genetics, Epigenetics, Gender Identity, and Cognition". Hormones, Brain and Behavior. 4: Clinical Important Effects of Hormones on Brain and Behavior. Elsevier Science. pp. 69. ISBN 978-0-12-803608-2. https://books.google.com/books?id=NT8oCwAAQBAJ&pg=RA3-PA69. 
  29. ↑ "Integrated view on 17beta-hydroxysteroid dehydrogenases". Mol. Cell. Endocrinol. 301 (1–2): 7–19. 2009. doi:10.1016/j.mce.2008.10.040. PMID 19027824. 
  30. ↑ "The role of 17 beta-hydroxysteroid dehydrogenases". Mol. Cell. Endocrinol. 218 (1–2): 7–20. 2004. doi:10.1016/j.mce.2003.12.006. PMID 15130507. 
  31. ↑ "17β-Hydroxysteroid dehydrogenases (17β-HSDs) as therapeutic targets: protein structures, functions, and recent progress in inhibitor development". J. Steroid Biochem. Mol. Biol. 125 (1–2): 66–82. 2011. doi:10.1016/j.jsbmb.2010.12.013. PMID 21193039. 
  32. ↑ "Development of 17β-hydroxysteroid dehydrogenase type 3 as a target in hormone-dependent prostate cancer therapy". Steroids 121: 10–16. 2017. doi:10.1016/j.steroids.2017.02.003. PMID 28267564. 
  33. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named pmid26230882
  34. ↑ "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 83: 317–37. August 2014. doi:10.1016/j.ejmech.2014.06.036. PMID 24974351. 
  35. ↑ "Flavonoids and cinnamic acid derivatives as inhibitors of 17beta-hydroxysteroid dehydrogenase type 1". Molecular and Cellular Endocrinology 301 (1–2): 229–34. March 2009. doi:10.1016/j.mce.2008.09.004. PMID 18835421. https://hal.archives-ouvertes.fr/hal-00532074/document. 

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