fbpx
Wikipedia

17β-Hydroxysteroid dehydrogenase

October 21, 2023

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]

17β-Hydroxysteroid dehydrogenase
Identifiers
EC no.1.1.1.51
CAS no.9015-81-0
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins

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 Edit

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

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

Activity distribution Edit

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

Genes Edit

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-HSDTooltip 3α-hydroxysteroid dehydrogenase and 20α-HSDTooltip 20α-hydroxysteroid dehydrogenase 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-HSDTooltip 3α-hydroxysteroid dehydrogenase 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 PCOSTooltip polycystic ovary syndrome.[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 Edit

Comparison and characteristics of human 17β-HSD isoenzymes[28][29][30][31]
# Gene name Synonyms Family Size (AATooltip Amino acids) Gene location Cellular location Substrate specificities Preferred cofactor Catalytic preference Tissue distribution Expression profile Pathology
1 HSD17B1 SDRTooltip Short-chain dehydrogenase 328 17q21.2 Cytosol Estrogens NADH, NADPH Reduction Ovary, endometrium, breast, brain, prostate, placenta Strongly restricted Breast cancer, prostate cancer, endometriosis
2 HSD17B2 SDR 387 16q23.3 ERTooltip Endoplasmic reticulum Estrogens, androgens, progestogens NAD+ Oxidation Liver, intestine, endometrium, placenta, pancreas, prostate, colon, bone Selectively distributed Breast cancer, prostate cancer, endometriosis, osteoporosis[32]
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[33]
4 HSD17B4 DBP, MFP2 SDR 736 5q23.1 PXSTooltip Peroxisomes 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 AKR1C3Tooltip Aldo-keto reductase family 1 member C3 HSD17B5, PGFS AKRTooltip Aldo-keto reductase 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 PMTooltip Plasma membrane, 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 MCTooltip Mitochondria 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 RDH5Tooltip Retinol dehydrogenase 5 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, MRXS10Tooltip Mental retardation, X-linked, syndromic 10, Alzheimer's disease
11 HSD17B11 SDR 300 4q22.1 ER, EPTooltip Extracellular space 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)
15 RDH11Tooltip Retinol dehydrogenase 11[34][35][36] PSDR1, HSD17B15 SDR 318 14q23-24.3 ER Retinoids, androgens NADPH Reduction Retina, prostate, brain, testis ? Retinitis pigmentosa[37]

Clinical significance Edit

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.[32][38]

Some inhibitors of 17β-HSD type I have been identified, for example esters of cinnamic acid and various flavones (e.g. fisetin).[39]

See also Edit

References Edit

  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. doi:10.1016/S0021-9258(19)77419-5. 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. doi:10.1016/S0021-9258(18)65833-8. 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. doi:10.1016/S0021-9258(17)40319-X. 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. doi:10.1016/S0021-9258(18)49226-5. 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. S2CID 54365519.
  7. ^ Brook CG, Truong D, Clayton P, Carroll W, Brown R (2011). Brook's Clinical Pediatric Endocrinology. John Wiley & Sons. p. 288. ISBN 978-1-4443-1673-5.
  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. doi:10.1016/0960-0760(92)90390-5. PMID 1314080. S2CID 54325300.
  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. ^ a b c d 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. ^ a b c d e f g h Strauss JF, Barbieri RL (13 September 2013). Yen and Jaffe's Reproductive Endocrinology. Elsevier Health Sciences. p. 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. S2CID 54341481.
  14. ^ a b Jameson JL (13 July 1998). Principles of Molecular Medicine. Springer Science & Business Media. p. 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. ^ a b Melmed S (2016). Williams Textbook of Endocrinology. Elsevier Health Sciences. p. 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. p. 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. ^ a b 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. ^ Masiutin, Maxim; Yadav, Maneesh (2023). "Alternative androgen pathways". WikiJournal of Medicine. 10: X. doi:10.15347/WJM/2023.003. S2CID 257943362.
  22. ^ 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.
  23. ^ 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.
  24. ^ 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.
  25. ^ 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.
  26. ^ a b 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. S2CID 8608312.
  27. ^ a b 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.
  28. ^ 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 (ed.). Hormones, Brain and Behavior. Vol. 4: Clinical Important Effects of Hormones on Brain and Behavior. Elsevier Science. p. 69. ISBN 978-0-12-803608-2.
  29. ^ 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. S2CID 30321495.
  30. ^ 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. S2CID 26877571.
  31. ^ 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. S2CID 23767100.
  32. ^ a b 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.
  33. ^ 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. S2CID 32062736.
  34. ^ Samson M, Labrie F, and Luu-The V (23 June 2012). "Characterization of Type 15 17β-Hydroxysteroid Dehydrogenase". Steroid Hormone Biosynthesis & Metabolism (Translational).
  35. ^ 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.
  36. ^ 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.
  37. ^ 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.
  38. ^ 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.
  39. ^ 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. S2CID 26950431.

External links Edit

October 21, 2023
17β, hydroxysteroid, dehydrogenase, 17β, hsd17b, also, ketosteroid, reductases, group, alcohol, oxidoreductases, which, catalyze, reduction, ketosteroids, dehydrogenation, 17β, hydroxysteroids, steroidogenesis, steroid, metabolism, this, includes, interconvers. 17b Hydroxysteroid dehydrogenases 17b 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 17b 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 17b Hydroxysteroid dehydrogenaseIdentifiersEC no 1 1 1 51CAS no 9015 81 0DatabasesIntEnzIntEnz viewBRENDABRENDA entryExPASyNiceZyme viewKEGGKEGG entryMetaCycmetabolic pathwayPRIAMprofilePDB structuresRCSB PDB PDBe PDBsumGene OntologyAmiGO QuickGOSearchPMCarticlesPubMedarticlesNCBIproteinsThe major reactions catalyzed by 17b HSD e g the conversion of androstenedione to testosterone are in fact hydrogenation reduction rather than dehydrogenation oxidation reactions Contents 1 Reactions 1 1 Activity distribution 2 Genes 2 1 Overview 3 Clinical significance 4 See also 5 References 6 External linksReactions Edit nbsp Steroidogenesis 17b HSD visible in bottom left region 17b HSDs have been known to catalyze the following redox reactions of sex steroids 20a Hydroxyprogesterone Progesterone DHEATooltip Dehydroepiandrosterone Androstenediol Androstenedione Testosterone Dihydrotestosterone 5a Androstanedione 3a Androstanediol 3b Androstanediol Estrone Estradiol 16a Hydroxyestrone EstriolActivity distribution Edit nbsp Distribution of 17b HSD activities for formation of estradiol versus estrone in human tissues 8 9 Genes EditGenes coding for 17b HSD include HSD17B1 Referred to as estrogenic Major subtype for activation of estrogens from weaker forms estrone to estradiol and 16a 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 3a and 3b androstanediol 10 11 Expressed primarily in the ovaries and placenta but also at lower levels in the breast epithelium 12 10 Major isoform of 17b 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 20a 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 17b 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 17b HSD subtype likely HSD17B5 is expressed instead Mutations are associated with 17b 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 b 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 3a HSDTooltip 3a hydroxysteroid dehydrogenase and 20a HSDTooltip 20a hydroxysteroid dehydrogenase activity in addition to 17b HSD activity Expressed in the adrenal cortex and may act as the androgenic 17b HSD in ovarian thecal cells Also expressed in the prostate gland mammary gland and Leydig cells 12 HSD17B6 Has 3a HSDTooltip 3a hydroxysteroid dehydrogenase 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 17a hydroxyprogesterone to dihydrotestosterone by 3a reduction of a metabolic intermediary 17a hydroxydihydroprogesterone into another intermediary 17a hydroxyallopregnanolone 21 May be involved in the pathophysiology of PCOSTooltip polycystic ovary syndrome 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 17b 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 HSD17B14At least 7 of the 14 isoforms of 17b HSD are involved in interconversion of 17 ketosteroids and 17b hydroxysteroids 12 Overview Edit Comparison and characteristics of human 17b HSD isoenzymes 28 29 30 31 Gene name Synonyms Family Size AATooltip Amino acids Gene location Cellular location Substrate specificities Preferred cofactor Catalytic preference Tissue distribution Expression profile Pathology1 HSD17B1 SDRTooltip Short chain dehydrogenase 328 17q21 2 Cytosol Estrogens NADH NADPH Reduction Ovary endometrium breast brain prostate placenta Strongly restricted Breast cancer prostate cancer endometriosis2 HSD17B2 SDR 387 16q23 3 ERTooltip Endoplasmic reticulum Estrogens androgens progestogens NAD Oxidation Liver intestine endometrium placenta pancreas prostate colon bone Selectively distributed Breast cancer prostate cancer endometriosis osteoporosis 32 3 HSD17B3 SDR 310 9q22 32 ER Androgens NADPH Reduction Testis ovary blood saliva skin adipose tissue brain bone Strongly restricted 17b HSD3 deficiency prostate cancer 33 4 HSD17B4 DBP MFP2 SDR 736 5q23 1 PXSTooltip Peroxisomes 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 cancer5 AKR1C3Tooltip Aldo keto reductase family 1 member C3 HSD17B5 PGFS AKRTooltip Aldo keto reductase 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 cancer6 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 PMTooltip Plasma membrane 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 cancer8 HSD17B8 SDR 261 6p21 32 MCTooltip Mitochondria Fatty acids estrogens androgens NAD Oxidation Prostate placenta kidney brain cerebellum heart lung small intestine ovary testis adrenal stomach Widely distributed Polycystic kidney disease9 RDH5Tooltip Retinol dehydrogenase 5 HSD17B9 318 12q13 2 ER Retinoids NADH NAD Reduction oxidation Retina liver adipose tissue blood others Fundus albipunctatus10 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 17b HSD10 deficiency MRXS10Tooltip Mental retardation X linked syndromic 10 Alzheimer s disease11 HSD17B11 SDR 300 4q22 1 ER EPTooltip Extracellular space 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 15 RDH11Tooltip Retinol dehydrogenase 11 34 35 36 PSDR1 HSD17B15 SDR 318 14q23 24 3 ER Retinoids androgens NADPH Reduction Retina prostate brain testis Retinitis pigmentosa 37 Clinical significance EditMutations in HSD17B3 are responsible for 17b HSD type III deficiency Inhibitors of 17b HSD type II are of interest for the potential treatment of osteoporosis 32 38 Some inhibitors of 17b HSD type I have been identified for example esters of cinnamic acid and various flavones e g fisetin 39 See also EditSteroidogenic enzymeReferences Edit Dahm K Breuer H 1964 Anreicherung einer 17b 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 fur Physiologische Chemie in German 336 63 8 doi 10 1515 bchm2 1964 336 1 63 PMID 14214322 Lynn WS Brown RH June 1958 The conversion of progesterone to androgens by testes The Journal of Biological Chemistry 232 2 1015 30 doi 10 1016 S0021 9258 19 77419 5 PMID 13549484 Marcus PI Talalay P February 1956 Induction and purification of alpha and beta hydroxysteroid dehydrogenases The Journal of Biological Chemistry 218 2 661 74 doi 10 1016 S0021 9258 18 65833 8 PMID 13295221 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 doi 10 1016 S0021 9258 17 40319 X PMID 193845 Talalay P Dobson MM December 1953 Purification and properties of a beta hydroxysteroid dehydrogenase The Journal of Biological Chemistry 205 2 823 37 doi 10 1016 S0021 9258 18 49226 5 PMID 13129261 Labrie F Luu The V Lin SX Labrie C Simard J Breton R Belanger 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 S2CID 54365519 Brook CG Truong D Clayton P Carroll W Brown R 2011 Brook s Clinical Pediatric Endocrinology John Wiley amp Sons p 288 ISBN 978 1 4443 1673 5 Martel C Rheaume E Takahashi M Trudel C Couet 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 doi 10 1016 0960 0760 92 90390 5 PMID 1314080 S2CID 54325300 Michael Oettel Ekkehard Schillinger 6 December 2012 Estrogens and Antiestrogens I Physiology and Mechanisms of Action of Estrogens and Antiestrogens Springer Science amp Business Media p 226 ISBN 978 3 642 58616 3 a b c d Hilborn E Stal O Jansson A May 2017 Estrogen and androgen converting enzymes 17b hydroxysteroid dehydrogenase and their involvement in cancer with a special focus on 17b hydroxysteroid dehydrogenase type 1 2 and breast cancer Oncotarget 8 18 30552 30562 doi 10 18632 oncotarget 15547 PMC 5444764 PMID 28430630 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 a b c d e f g h Strauss JF Barbieri RL 13 September 2013 Yen and Jaffe s Reproductive Endocrinology Elsevier Health Sciences p 82 ISBN 978 1 4557 2758 2 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 S2CID 54341481 a b Jameson JL 13 July 1998 Principles of Molecular Medicine Springer Science amp Business Media p 549 ISBN 978 1 59259 726 0 Hakkarainen J Jokela H Pakarinen P Heikela H Katkanaho L Vandenput L Ohlsson C Zhang FP Poutanen M September 2015 Hydroxysteroid 17b 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 Wang CT Li CF Wu WJ Huang CN Li CC Li WM Chan TC Liang PI Hsing CH Liao KM 2016 High Expression of 17b 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 a b Melmed S 2016 Williams Textbook of Endocrinology Elsevier Health Sciences p 904 ISBN 978 0 323 29738 7 Jameson JL De Groot LJ 25 February 2015 Endocrinology Adult and Pediatric E Book Elsevier Health Sciences p 2078 ISBN 978 0 323 32195 2 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 a b 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 Masiutin Maxim Yadav Maneesh 2023 Alternative androgen pathways WikiJournal of Medicine 10 X doi 10 15347 WJM 2023 003 S2CID 257943362 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 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 Liden 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 Skorczyk Werner A Pawlowski P Michalczuk M Warowicka A Wawrocka A Wicher K Bakunowicz Lazarczyk A Krawczynski 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 a b Yang SY He XY Miller D 2011 Hydroxysteroid 17b 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 S2CID 8608312 a b Yang SY He XY Isaacs C Dobkin C Miller D Philipp M 2014 Roles of 17b 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 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 ed Hormones Brain and Behavior Vol 4 Clinical Important Effects of Hormones on Brain and Behavior Elsevier Science p 69 ISBN 978 0 12 803608 2 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 S2CID 30321495 Mindnich R Moller 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 S2CID 26877571 Marchais Oberwinkler S Henn C Moller G Klein T Negri M Oster A Spadaro A Werth R Wetzel M Xu K Frotscher M Hartmann RW Adamski J 2011 17b Hydroxysteroid dehydrogenases 17b 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 S2CID 23767100 a b Soubhye J Alard IC van Antwerpen P Dufrasne F 2015 Type 2 17 b 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 Ning X Yang Y Deng H Zhang Q Huang Y Su Z Fu Y Xiang Q Zhang S 2017 Development of 17b 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 S2CID 32062736 Samson M Labrie F and Luu The V 23 June 2012 Characterization of Type 15 17b Hydroxysteroid Dehydrogenase Steroid Hormone Biosynthesis amp Metabolism Translational 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 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 Xie YA Lee W Cai C Gambin T Noupuu 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 Perspicace E Cozzoli L Gargano EM Hanke N Carotti A Hartmann RW Marchais Oberwinkler S August 2014 Novel potent and selective 17b 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 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 S2CID 26950431 External links Edit3 or 17 beta hydroxysteroid dehydrogenase at the U S National Library of Medicine Medical Subject Headings MeSH Portal nbsp Biology Retrieved from https en wikipedia org w index php title 17b Hydroxysteroid dehydrogenase amp oldid 1172337616, wikipedia, wiki, book, books, library,

article

, read, download, free, free download, mp3, video, mp4, 3gp, jpg, jpeg, gif, png, picture, music, song, movie, book, game, games.