17β-Hydroxysteroid dehydrogenase explained

17β-Hydroxysteroid dehydrogenase
Ec Number:	1.1.1.51
Cas Number:	9015-81-0
Go Code:	0030283

17β-Hydroxysteroid dehydrogenases (17β-HSD, HSD17B), 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

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.^[8] Expressed primarily in the ovaries and placenta but also at lower levels in the breast epithelium.^[9] Major isoform of 17β-HSD in the granulosa cells of the ovaries.^[10] Mutations and associated deficiency have not been reported in humans.^[11] Knockout mice show altered ovarian sex steroid production, normal puberty, and severe subfertility due to defective luteinization and ovarian progesterone production.^[12]
• HSD17B2: Describable as "antiestrogenic" and "antiandrogenic".^[13] 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.^{[14] [15]} Said to be responsible for 17β-HSD activity in the endometrium and placenta.^[16] Mutations and associated congenital deficiency have not been reported in humans. However, local deficiency in expression of HSD17B2 has been associated with endometriosis.^[17]
• 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 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).^[18] 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.^[19] 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.^{[20] [21]}
• HSD17B9: Also known as retinol dehydrogenase 5 (RDH5). Involved in retinoid metabolism.^[22] Mutations are associated with fundus albipunctatus.^[23]
• HSD17B10: Also known as 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD). Substrates include steroids, neurosteroids, fatty acids, bile acids, isoleucine, and xenobiotics.^{[24] [25]} Mutations are associated with 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.^{[26] [27]}
• HSD17B12
• HSD17B13
• HSD17B14

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

Overview

Comparison and characteristics of human 17β-HSD isoenzymes^{[28] [29] [30] [31]}

	Gene name	Synonyms	Family	Size	Gene location	Cellular location	Substrate specificities	Preferred cofactor	Catalytic preference	Tissue distribution	Expression profile	Pathology
1				328	17q21.2		Estrogens	NADH, NADPH		Ovary, endometrium, breast, brain, prostate, placenta	Strongly restricted	Breast cancer, prostate cancer, endometriosis
2				387	16q23.3		Estrogens, androgens, progestogens	NAD^+		Liver, intestine, endometrium, placenta, pancreas, prostate, colon, bone	Selectively distributed	Breast cancer, prostate cancer, endometriosis, osteoporosis^[32]
3				310	9q22.32		Androgens	NADPH	Reduction	Testis, ovary, blood, saliva, skin, adipose tissue, brain, bone	Strongly restricted	deficiency, prostate cancer^[33]
4		,		736	5q23.1		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	deficiency, Perrault syndrome, prostate cancer
5		HSD17B5,,		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				317	12q13.3	Endosomes	Retinoids, androgens, estrogens	NAD^+	Oxidation	Liver, testis, lung, spleen, brain, ovary, kidney, adrenal, prostate	Selectively distributed	?
7				341	1q23.3	,	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				261	6p21.32		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		HSD17B9		318	12q13.2		Retinoids	NADH/NAD^+	Reduction / oxidation	Retina, liver, adipose tissue, blood, others	?	Fundus albipunctatus
10				261	Xp11.2		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	deficiency,, Alzheimer's disease
11				300	4q22.1	,	Estrogens, androgens	NAD^+	Oxidation	Liver, pancreas, intestine, kidney, adrenal gland, heart, lung, testis, ovary, placenta, sebaceous gland	Nearly ubiquitous	?
12				312	11p11.2		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				300	4q22.1	,	?	NAD^+?	Oxidation?	Liver, bone marrow, lung, ovary, testis, kidney, skeletal muscle, brain, bladder, nasal epithelia	Strongly restricted	?
14				270	19q13.33	Cytosol	Estrogens, androgens, fatty acids	NAD^+	Oxidation	Liver, kidney, brain, gallbladder, breast, adrenal, placenta	Widely distributed	Breast cancer (prognostic)
15	^[34] ^[35] ^[36]	, HSD17B15		318	14q23-24.3		Retinoids, androgens	NADPH	Reduction	Retina, prostate, brain, testis	?	Retinitis pigmentosa^[37]

Clinical significance

Mutations in HSD17B3 are responsible for type III deficiency.

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

• Steroidogenic enzyme
• 3α-Hydroxysteroid dehydrogenase

Notes and References

1. Dahm K, Breuer H . 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 . German . Hoppe-Seyler's Zeitschrift für Physiologische Chemie . 336 . 63–8 . 1964 . 14214322 . 10.1515/bchm2.1964.336.1.63 .
2. Lynn WS, Brown RH . The conversion of progesterone to androgens by testes . The Journal of Biological Chemistry . 232 . 2 . 1015–30 . June 1958 . 10.1016/S0021-9258(19)77419-5 . 13549484 . free .
3. Marcus PI, Talalay P . Induction and purification of alpha- and beta-hydroxysteroid dehydrogenases . The Journal of Biological Chemistry . 218 . 2 . 661–74 . February 1956 . 10.1016/S0021-9258(18)65833-8 . 13295221 . free .
4. Schultz RM, Groman EV, Engel LL . 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 . 10.1016/S0021-9258(17)40319-X . 193845 . free .
5. Talalay P, Dobson MM . Purification and properties of a beta-hydroxysteroid dehydrogenase . The Journal of Biological Chemistry . 205 . 2 . 823–37 . December 1953 . 10.1016/S0021-9258(18)49226-5 . 13129261 . free .
6. Labrie F, Luu-The V, Lin SX, Labrie C, Simard J, Breton R, Bélanger A . The key role of 17 beta-hydroxysteroid dehydrogenases in sex steroid biology . Steroids . 62 . 1 . 148–58 . January 1997 . 9029730 . 10.1016/S0039-128X(96)00174-2 . 54365519 .
7. Book: Charles G. D. . Brook . Daniel . Truong . Peter . Clayton . William . Carroll . Rosalind . Brown . Brook's Clinical Pediatric Endocrinology . 2011. John Wiley & Sons . 978-1-4443-1673-5 . 288.
8. Aka JA, Mazumdar M, Chen CQ, Poirier D, Lin SX . 17beta-hydroxysteroid dehydrogenase type 1 stimulates breast cancer by dihydrotestosterone inactivation in addition to estradiol production . Molecular Endocrinology . 24 . 4 . 832–45 . April 2010 . 20172961 . 5417535 . 10.1210/me.2009-0468 .
9. Hilborn E, Stål O, Jansson A . 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 . 28430630 . 5444764 . 10.18632/oncotarget.15547 .
10. Andersson S, Moghrabi N . Physiology and molecular genetics of 17 beta-hydroxysteroid dehydrogenases . Steroids . 62 . 1 . 143–7 . January 1997 . 9029729 . 10.1016/s0039-128x(96)00173-0. 54341481 .
11. Book: J. Larry . Jameson . Principles of Molecular Medicine. 13 July 1998. Springer Science & Business Media. 978-1-59259-726-0. 549.
12. Hakkarainen J, Jokela H, Pakarinen P, Heikelä H, Kätkänaho L, Vandenput L, Ohlsson C, Zhang FP, Poutanen M . 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 . 26018678 . 10.1096/fj.14-269035 . free.
13. Wang CT, Li CF, Wu WJ, Huang CN, Li CC, Li WM, Chan TC, Liang PI, Hsing CH, Liao KM . 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 . 27994658 . 5166531 . 10.7150/jca.16777 . HSD17B2 has both anti-estrogenic and anti-androgenic functions. .
14. Book: Shlomo. Melmed. Williams Textbook of Endocrinology. 2016. Elsevier Health Sciences. 978-0-323-29738-7. 904. 16 July 2017. 4 May 2024. https://web.archive.org/web/20240504042311/https://books.google.com/books?id=YZ8_CwAAQBAJ&pg=PA904#v=onepage&q&f=false. live.
15. Book: Jerome Frank. Strauss. Robert L.. Barbieri. Yen and Jaffe's Reproductive Endocrinology. 13 September 2013. Elsevier Health Sciences. 978-1-4557-2758-2. 82. 16 July 2017. 4 May 2024. https://web.archive.org/web/20240504042340/https://books.google.com/books?id=KZ95AAAAQBAJ&pg=PA82#v=onepage&q&f=false. live.
16. Book: J. Larry. Jameson. Leslie J.. De Groot. Endocrinology: Adult and Pediatric E-Book. 25 February 2015. Elsevier Health Sciences. 978-0-323-32195-2. 2078. 17 July 2017. 4 May 2024. https://web.archive.org/web/20240504042321/https://books.google.com/books?id=xmLeBgAAQBAJ&pg=PA2078#v=onepage&q&f=false. live.
17. 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 . 17Beta-hydroxysteroid dehydrogenase-2 deficiency and progesterone resistance in endometriosis . Seminars in Reproductive Medicine . 28 . 1 . 44–50 . January 2010 . 20108182 . 4511594 . 10.1055/s-0029-1242992 .
18. Pierce SB, Walsh T, Chisholm KM, Lee MK, Thornton AM, Fiumara A, Opitz JM, Levy-Lahad E, Klevit RE, King MC . 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 . 20673864 . 2917704 . 10.1016/j.ajhg.2010.07.007 .
19. 10.15347/WJM/2023.003 . free. Alternative androgen pathways . 2023 . Masiutin . Maxim . Yadav . Maneesh . WikiJournal of Medicine . 10 . X . 257943362.
20. Fomitcheva J, Baker ME, Anderson E, Lee GY, Aziz N . 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 . 9712896 . 10.1074/jbc.273.35.22664. free .
21. Kikuti YY, Tamiya G, Ando A, Chen L, Kimura M, Ferreira E, Tsuji K, Trowsdale J, Inoko H . 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 . 9205114 . 10.1006/geno.1997.4745 .
22. Lidén M, Tryggvason K, Eriksson U . Structure and function of retinol dehydrogenases of the short chain dehydrogenase/reductase family . Molecular Aspects of Medicine . 24 . 6 . 403–9 . December 2003 . 14585311 . 10.1016/s0098-2997(03)00036-0.
23. Skorczyk-Werner A, Pawłowski P, Michalczuk M, Warowicka A, Wawrocka A, Wicher K, Bakunowicz-Łazarczyk A, Krawczyński MR . 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 . 25820994 . 4543405 . 10.1007/s13353-015-0281-x .
24. Yang SY, He XY, Miller D . Hydroxysteroid (17β) dehydrogenase X in human health and disease . Mol. Cell. Endocrinol. . 343 . 1–2 . 1–6 . 2011 . 21708223 . 10.1016/j.mce.2011.06.011 . 8608312 .
25. Yang SY, He XY, Isaacs C, Dobkin C, Miller D, Philipp M . Roles of 17β-hydroxysteroid dehydrogenase type 10 in neurodegenerative disorders . J. Steroid Biochem. Mol. Biol. . 143 . 460–72 . 2014 . 25007702 . 10.1016/j.jsbmb.2014.07.001 . free .
26. 10.1016/j.mce.2018.10.014 . Role of HSD17B13 in the liver physiology and pathophysiology . 2019 . Molecular and Cellular Endocrinology . 489 . 119–125 . 30365983 . Su W, Mao Z, Liu Y, Zhang X, Zhang W, Gustafsson J, Guan Y .
27. 10.1186/s12944-021-01476-y. free . Identification of prognostic lipid droplet-associated genes in pancreatic cancer patients via bioinformatics analysis . 2021 . Lipids in Health and Disease . 20 . 1 . 58 . 34078402 . 8171034 . Bai R, Rebelo A, Kleeff J, Sunami Y .
28. Book: Hormones, Brain and Behavior. https://books.google.com/books?id=NT8oCwAAQBAJ&pg=RA3-PA69 . 9 November 2016 . Elsevier Science . 978-0-12-803608-2 . 69 . 4: Clinical Important Effects of Hormones on Brain and Behavior . Stafford . Lightman . 4.02: Disorders of Sexual Development in Males: Molecular Genetics, Epigenetics, Gender Identity, and Cognition . Yuan-Shan . Zhu . Julianne L. . Imperato-McGinley .
29. Moeller G, Adamski J . Integrated view on 17beta-hydroxysteroid dehydrogenases . Mol. Cell. Endocrinol. . 301 . 1–2 . 7–19 . 2009 . 19027824 . 10.1016/j.mce.2008.10.040 . 30321495 .
30. Mindnich R, Möller G, Adamski J . The role of 17 beta-hydroxysteroid dehydrogenases . Mol. Cell. Endocrinol. . 218 . 1–2 . 7–20 . 2004 . 15130507 . 10.1016/j.mce.2003.12.006 . 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 . 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 . 21193039 . 10.1016/j.jsbmb.2010.12.013 . 23767100 .
32. Soubhye J, Alard IC, van Antwerpen P, Dufrasne F . Type 2 17-β hydroxysteroid dehydrogenase as a novel target for the treatment of osteoporosis . Future Med Chem . 7 . 11 . 1431–56 . 2015 . 26230882 . 10.4155/fmc.15.74 .
33. Ning X, Yang Y, Deng H, Zhang Q, Huang Y, Su Z, Fu Y, Xiang Q, Zhang S . Development of 17β-hydroxysteroid dehydrogenase type 3 as a target in hormone-dependent prostate cancer therapy . Steroids . 121 . 10–16 . 2017 . 28267564 . 10.1016/j.steroids.2017.02.003 . 32062736 .
34. Samson M, Labrie F, and Luu-The V. Characterization of Type 15 17β-Hydroxysteroid Dehydrogenase. Steroid Hormone Biosynthesis & Metabolism (Translational). 23 June 2012.
35. Lin B, White JT, Ferguson C, Wang S, Vessella R, Bumgarner R, True LD, Hood L, Nelson PS . 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 . 2001 . 11245473 .
36. Kedishvili NY, Chumakova OV, Chetyrkin SV, Belyaeva OV, Lapshina EA, Lin DW, Matsumura M, Nelson PS . 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 . 2002 . 12036956 . 10.1074/jbc.M202588200 . free .
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 . New syndrome with retinitis pigmentosa is caused by nonsense mutations in retinol dehydrogenase RDH11 . Hum. Mol. Genet. . 23 . 21 . 5774–80 . 2014 . 24916380 . 4189905 . 10.1093/hmg/ddu291 .
38. Perspicace E, Cozzoli L, Gargano EM, Hanke N, Carotti A, Hartmann RW, Marchais-Oberwinkler S . 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 . 24974351 . 10.1016/j.ejmech.2014.06.036 .
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 . 10.1016/j.mce.2008.09.004 . 18835421 . 26950431 . 4 March 2022 . 4 March 2022 . https://web.archive.org/web/20220304221754/https://hal.archives-ouvertes.fr/hal-00532074/document . live .