17β-Hydroxysteroid dehydrogenase

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
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PMCarticles
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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
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-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
Comparison and characteristics of human 17β-HSD isoenzymes[28][29][30][31]
#Gene nameSynonymsFamilySize (AATooltip Amino acids)Gene locationCellular locationSubstrate specificitiesPreferred cofactorCatalytic preferenceTissue distributionExpression profilePathology
1HSD17B1SDRTooltip Short-chain dehydrogenase32817q21.2CytosolEstrogensNADH, NADPHReductionOvary, endometrium, breast, brain, prostate, placentaStrongly restrictedBreast cancer, prostate cancer, endometriosis
2HSD17B2SDR38716q23.3ERTooltip Endoplasmic reticulumEstrogens, androgens, progestogensNAD+OxidationLiver, intestine, endometrium, placenta, pancreas, prostate, colon, boneSelectively distributedBreast cancer, prostate cancer, endometriosis, osteoporosis[32]
3HSD17B3SDR3109q22.32ERAndrogensNADPHReductionTestis, ovary, blood, saliva, skin, adipose tissue, brain, boneStrongly restricted17β-HSD3 deficiency, prostate cancer[33]
4HSD17B4DBP, MFP2SDR7365q23.1PXSTooltip PeroxisomesFatty 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
5AKR1C3Tooltip Aldo-keto reductase family 1 member C3HSD17B5, PGFSAKRTooltip Aldo-keto reductase32310p15.1Nucleus, 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 ?
7HSD17B7SDR3411q23.3PMTooltip Plasma membrane, ERCholesterol, estrogens, androgens, progestogensNADPHReductionOvary, corpus luteum, uterus, placenta, liver, breast, testis, brain, adrenal gland, small intestine, lung, thymus, prostate, adipose tissue, othersWidely distributedBreast cancer
8HSD17B8SDR2616p21.32MCTooltip MitochondriaFatty acids, estrogens, androgensNAD+OxidationProstate, placenta, kidney, brain, cerebellum, heart, lung, small intestine, ovary, testis, adrenal, stomachWidely distributedPolycystic kidney disease
9RDH5Tooltip Retinol dehydrogenase 5HSD17B931812q13.2ERRetinoidsNADH/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, MRXS10Tooltip Mental retardation, X-linked, syndromic 10, Alzheimer's disease
11HSD17B11SDR3004q22.1ER, EPTooltip Extracellular spaceEstrogens, 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)
15RDH11Tooltip Retinol dehydrogenase 11[34][35][36]PSDR1, HSD17B15SDR31814q23-24.3ERRetinoids, androgensNADPHReductionRetina, prostate, brain, testis ?Retinitis pigmentosa[37]

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.[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

References
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