17β-Hydroxysteroid dehydrogenase

17β-Hydroxysteroid dehydrogenase
Identifiers
EC number 1.1.1.51
CAS number 9015-81-0
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / 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). 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: 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. 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.[21][22]
  • HSD17B9: Also known as retinol dehydrogenase 5 (RDH5). Involved in retinoid metabolism.[23] Mutations are associated with fundus albipunctatus.[24]
  • HSD17B10: Also known as 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD). Substrates include steroids, neurosteroids, fatty acids, bile acids, isoleucine, and xenobiotics.[25][26] 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.[25][26]
  • 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[27][28][29][30]
#Gene nameSynonymsFamilySize (AA)Gene locationCellular locationSubstrate specificitiesPreferred cofactorCatalytic preferenceTissue distributionExpression profilePathology
1HSD17B1SDR32817q21.2CytosolEstrogensNADH, NADPHReductionOvary, endometrium, breast, brain, prostate, placentaStrongly restrictedBreast cancer, prostate cancer, endometriosis
2HSD17B2SDR38716q23.3EREstrogens, androgens, progestogensNAD+OxidationLiver, intestine, endometrium, placenta, pancreas, prostate, colon, boneSelectively distributedBreast cancer, prostate cancer, endometriosis, osteoporosis[31]
3HSD17B3SDR3109q22.32ERAndrogensNADPHReductionTestis, ovary, blood, saliva, skin, adipose tissue, brain, boneStrongly restricted17β-HSD3 deficiency, prostate cancer[32]
4HSD17B4DBP, MFP2SDR7365q23.1PXSFatty acids, bile acids, estrogens, androgensNAD+OxidationLiver, heart, prostate, testis, lung, skeletal muscle, kidney, pancreas, thymus, ovary, intestine, placenta, brain, spleen, colon, lymphocytesUbiquitousDBP deficiency, Perrault syndrome, prostate cancer
5AKR1C3HSD17B5, PGFSAKR32310p15.1Nucleus, cytosolAndrogens, progestogens, estrogens, prostaglandinsNADPHReductionProstate, mammary gland, liver, kidney, lung, heart, small intestine, colon, uterus, testis, brain, skeletal muscle, adipose tissueNearly ubiquitousBreast cancer, prostate cancer
6HSD17B6SDR31712q13.3EndosomesRetinoids, androgens, estrogensNAD+OxidationLiver, testis, lung, spleen, brain, ovary, kidney, adrenal, prostateSelectively distributed?
7HSD17B7SDR3411q23.3PM, ERCholesterol, estrogens, androgens, progestogensNADPHReductionOvary, corpus luteum, uterus, placenta, liver, breast, testis, brain, adrenal gland, small intestine, lung, thymus, prostate, adipose tissue, othersWidely distributedBreast cancer
8HSD17B8SDR2616p21.32MCFatty acids, estrogens, androgensNAD+OxidationProstate, placenta, kidney, brain, cerebellum, heart, lung, small intestine, ovary, testis, adrenal, stomachWidely distributedPolycystic kidney disease
9RDH5HSD17B931812q13.2ERRetinoidsNADH/NAD+Reduction / oxidationRetina, liver, adipose tissue, blood, others?Fundus albipunctatus
10HSD17B10MHBDSDR261Xp11.2MCFatty acids, bile acids, estrogens, androgens, progestogens, corticosteroidsNAD+OxidationLiver, small intestine, colon, kidney, heart, brain, placenta, lung, ovary, testis, spleen, thymus, prostate, peripheral blood leukocytesNearly ubiquitous17β-HSD10 deficiency, MRXS10, Alzheimer's disease
11HSD17B11SDR3004q22.1ER, EPEstrogens, androgensNAD+OxidationLiver, pancreas, intestine, kidney, adrenal gland, heart, lung, testis, ovary, placenta, sebaceous glandNearly ubiquitous?
12HSD17B12SDR31211p11.2ERFatty acids, estrogens, androgensNADPHReductionHeart, 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, vaginaUbiquitous?
13HSD17B13SDR3004q22.1ER, EP?NAD+?Oxidation?Liver, bone marrow, lung, ovary, testis, kidney, skeletal muscle, brain, bladder, nasal epitheliaStrongly restricted?
14HSD17B14SDR27019q13.33CytosolEstrogens, androgens, fatty acidsNAD+OxidationLiver, kidney, brain, gallbladder, breast, adrenal, placentaWidely distributedBreast cancer (prognostic)
15RDH11[33][34][35]PSDR1, HSD17B15SDR31814q23-24.3ERRetinoids, androgensNADPHReductionRetina, prostate, brain, testis?Retinitis pigmentosa[36]

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.[31][37]

Some inhibitors of 17β-HSD type I have been identified, for example esters of cinnamic acid and various flavones (e.g. fisetin).[38]

See also

References

  1. ↑ Dahm K, Breuer H (1964). "Anreicherung einer 17β-hydroxysteroid:NAD(P)-oxydoreduktase aus der Nebenniere der Ratte" [Precipitation of a 17-Beta-Hydroxysteroid:Nad(P) Oxidoreductase from the Rat Adrenal Gland]. Hoppe-Seyler's Zeitschrift für Physiologische Chemie (in German). 336: 63–8. doi:10.1515/bchm2.1964.336.1.63. PMID 14214322.
  2. ↑ Lynn WS, Brown RH (June 1958). "The conversion of progesterone to androgens by testes". The Journal of Biological Chemistry. 232 (2): 1015–30. PMID 13549484.
  3. ↑ Marcus PI, Talalay P (February 1956). "Induction and purification of alpha- and beta-hydroxysteroid dehydrogenases". The Journal of Biological Chemistry. 218 (2): 661–74. PMID 13295221.
  4. ↑ Schultz RM, Groman EV, Engel LL (June 1977). "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. PMID 193845.
  5. ↑ Talalay P, Dobson MM (December 1953). "Purification and properties of a beta-hydroxysteroid dehydrogenase". The Journal of Biological Chemistry. 205 (2): 823–37. PMID 13129261.
  6. ↑ Labrie F, Luu-The V, Lin SX, Labrie C, Simard J, Breton R, Bélanger A (January 1997). "The key role of 17 beta-hydroxysteroid dehydrogenases in sex steroid biology". Steroids. 62 (1): 148–58. doi:10.1016/S0039-128X(96)00174-2. PMID 9029730.
  7. ↑ Brook CG, Truong D, Clayton P, Carroll W, Brown R (22 September 2011). Brook's Clinical Pediatric Endocrinology. John Wiley & Sons. p. 288. ISBN 978-1-4443-1673-5. Retrieved 29 April 2012.
  8. ↑ Martel C, Rhéaume E, Takahashi M, Trudel C, Couët J, Luu-The V, Simard J, Labrie F (March 1992). "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. 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.
  10. 1 2 3 4 Hilborn E, Stål O, Jansson A (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. 8 (18): 30552–30562. doi:10.18632/oncotarget.15547. PMC 5444764. PMID 28430630.
  11. ↑ Aka JA, Mazumdar M, Chen CQ, Poirier D, Lin SX (April 2010). "17beta-hydroxysteroid dehydrogenase type 1 stimulates breast cancer by dihydrotestosterone inactivation in addition to estradiol production". Molecular Endocrinology. 24 (4): 832–45. doi:10.1210/me.2009-0468. PMC 5417535. PMID 20172961.
  12. 1 2 3 4 5 6 7 8 Strauss JF, Barbieri RL (13 September 2013). Yen and Jaffe's Reproductive Endocrinology. Elsevier Health Sciences. pp. 82–. ISBN 978-1-4557-2758-2.
  13. ↑ Andersson S, Moghrabi N (January 1997). "Physiology and molecular genetics of 17 beta-hydroxysteroid dehydrogenases". Steroids. 62 (1): 143–7. doi:10.1016/s0039-128x(96)00173-0. PMID 9029729.
  14. 1 2 Jameson JL (13 July 1998). Principles of Molecular Medicine. Springer Science & Business Media. pp. 549–. ISBN 978-1-59259-726-0.
  15. ↑ Hakkarainen J, Jokela H, Pakarinen P, Heikelä H, Kätkänaho L, Vandenput L, Ohlsson C, Zhang FP, Poutanen M (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. 29 (9): 3806–16. doi:10.1096/fj.14-269035. PMID 26018678.
  16. ↑ Wang CT, Li CF, Wu WJ, Huang CN, Li CC, Li WM, Chan TC, Liang PI, Hsing CH, Liao KM (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. 7 (15): 2221–2230. doi:10.7150/jca.16777. PMC 5166531. PMID 27994658. HSD17B2 has both anti-estrogenic and anti-androgenic functions.
  17. 1 2 Melmed S (2016). Williams Textbook of Endocrinology. Elsevier Health Sciences. pp. 904–. ISBN 978-0-323-29738-7.
  18. ↑ Jameson JL, De Groot LJ (25 February 2015). Endocrinology: Adult and Pediatric E-Book. Elsevier Health Sciences. pp. 2078–. ISBN 978-0-323-32195-2.
  19. ↑ Bulun SE, Cheng YH, Pavone ME, Yin P, Imir G, Utsunomiya H, Thung S, Xue Q, Marsh EE, Tokunaga H, Ishikawa H, Kurita T, Su EJ (January 2010). "17Beta-hydroxysteroid dehydrogenase-2 deficiency and progesterone resistance in endometriosis". Seminars in Reproductive Medicine. 28 (1): 44–50. doi:10.1055/s-0029-1242992. PMC 4511594. PMID 20108182.
  20. 1 2 Pierce SB, Walsh T, Chisholm KM, Lee MK, Thornton AM, Fiumara A, Opitz JM, Levy-Lahad E, Klevit RE, King MC (August 2010). "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. doi:10.1016/j.ajhg.2010.07.007. PMC 2917704. PMID 20673864.
  21. ↑ Fomitcheva J, Baker ME, Anderson E, Lee GY, Aziz N (August 1998). "Characterization of Ke 6, a new 17beta-hydroxysteroid dehydrogenase, and its expression in gonadal tissues". The Journal of Biological Chemistry. 273 (35): 22664–71. doi:10.1074/jbc.273.35.22664. PMID 9712896.
  22. ↑ Kikuti YY, Tamiya G, Ando A, Chen L, Kimura M, Ferreira E, Tsuji K, Trowsdale J, Inoko H (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. 42 (3): 422–35. doi:10.1006/geno.1997.4745. PMID 9205114.
  23. ↑ Lidén M, Tryggvason K, Eriksson U (December 2003). "Structure and function of retinol dehydrogenases of the short chain dehydrogenase/reductase family". Molecular Aspects of Medicine. 24 (6): 403–9. doi:10.1016/s0098-2997(03)00036-0. PMID 14585311.
  24. ↑ Skorczyk-Werner A, Pawłowski P, Michalczuk M, Warowicka A, Wawrocka A, Wicher K, Bakunowicz-Łazarczyk A, Krawczyński MR (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. 56 (3): 317–27. doi:10.1007/s13353-015-0281-x. PMC 4543405. PMID 25820994.
  25. 1 2 Yang SY, He XY, Miller D (2011). "Hydroxysteroid (17β) dehydrogenase X in human health and disease". Mol. Cell. Endocrinol. 343 (1–2): 1–6. doi:10.1016/j.mce.2011.06.011. PMID 21708223.
  26. 1 2 Yang SY, He XY, Isaacs C, Dobkin C, Miller D, Philipp M (2014). "Roles of 17β-hydroxysteroid dehydrogenase type 10 in neurodegenerative disorders". J. Steroid Biochem. Mol. Biol. 143: 460–72. doi:10.1016/j.jsbmb.2014.07.001. PMID 25007702.
  27. ↑ Zhu Y, Imperato-McGinley JL (9 November 2016). "4.02: Disorders of Sexual Development in Males: Molecular Genetics, Epigenetics, Gender Identity, and Cognition". In Lightman S. Hormones, Brain and Behavior. 4: Clinical Important Effects of Hormones on Brain and Behavior. Elsevier Science. p. 69. ISBN 978-0-12-803608-2.
  28. ↑ Moeller G, Adamski J (2009). "Integrated view on 17beta-hydroxysteroid dehydrogenases". Mol. Cell. Endocrinol. 301 (1–2): 7–19. doi:10.1016/j.mce.2008.10.040. PMID 19027824.
  29. ↑ Mindnich R, Möller G, Adamski J (2004). "The role of 17 beta-hydroxysteroid dehydrogenases". Mol. Cell. Endocrinol. 218 (1–2): 7–20. doi:10.1016/j.mce.2003.12.006. PMID 15130507.
  30. ↑ Marchais-Oberwinkler S, Henn C, Möller G, Klein T, Negri M, Oster A, Spadaro A, Werth R, Wetzel M, Xu K, Frotscher M, Hartmann RW, Adamski J (2011). "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. doi:10.1016/j.jsbmb.2010.12.013. PMID 21193039.
  31. 1 2 Soubhye J, Alard IC, van Antwerpen P, Dufrasne F (2015). "Type 2 17-β hydroxysteroid dehydrogenase as a novel target for the treatment of osteoporosis". Future Med Chem. 7 (11): 1431–56. doi:10.4155/fmc.15.74. PMID 26230882.
  32. ↑ Ning X, Yang Y, Deng H, Zhang Q, Huang Y, Su Z, Fu Y, Xiang Q, Zhang S (2017). "Development of 17β-hydroxysteroid dehydrogenase type 3 as a target in hormone-dependent prostate cancer therapy". Steroids. 121: 10–16. doi:10.1016/j.steroids.2017.02.003. PMID 28267564.
  33. ↑ Samson M, Labrie F, and Luu-The V (23 June 2012). "Characterization of Type 15 17β-Hydroxysteroid Dehydrogenase". Steroid Hormone Biosynthesis & Metabolism (Translational). doi:10.1210/endo-meetings.2012.NRSH.11.SAT-534.
  34. ↑ Lin B, White JT, Ferguson C, Wang S, Vessella R, Bumgarner R, True LD, Hood L, Nelson PS (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. 61 (4): 1611–8. PMID 11245473.
  35. ↑ Kedishvili NY, Chumakova OV, Chetyrkin SV, Belyaeva OV, Lapshina EA, Lin DW, Matsumura M, Nelson PS (2002). "Evidence that the human gene for prostate short-chain dehydrogenase/reductase (PSDR1) encodes a novel retinal reductase (RalR1)". J. Biol. Chem. 277 (32): 28909–15. doi:10.1074/jbc.M202588200. PMID 12036956.
  36. ↑ Xie YA, Lee W, Cai C, Gambin T, Nõupuu K, Sujirakul T, Ayuso C, Jhangiani S, Muzny D, Boerwinkle E, Gibbs R, Greenstein VC, Lupski JR, Tsang SH, Allikmets R (2014). "New syndrome with retinitis pigmentosa is caused by nonsense mutations in retinol dehydrogenase RDH11". Hum. Mol. Genet. 23 (21): 5774–80. doi:10.1093/hmg/ddu291. PMC 4189905. PMID 24916380.
  37. ↑ Perspicace E, Cozzoli L, Gargano EM, Hanke N, Carotti A, Hartmann RW, Marchais-Oberwinkler S (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. 83: 317–37. doi:10.1016/j.ejmech.2014.06.036. PMID 24974351.
  38. ↑ Brozic P, Kocbek P, Sova M, Kristl J, Martens S, Adamski J, Gobec S, Lanisnik Rizner T (March 2009). "Flavonoids and cinnamic acid derivatives as inhibitors of 17beta-hydroxysteroid dehydrogenase type 1". Molecular and Cellular Endocrinology. 301 (1–2): 229–34. doi:10.1016/j.mce.2008.09.004. PMID 18835421.

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