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. This includes interconversion of DHEA and androstenediol, androstenedione and testosterone, and estrone and estradiol.

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

Reactions

17β-HSDs 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. Expressed primarily in the ovaries and placenta but also at lower levels in the breast epithelium. Major isoform of 17β-HSD in the granulosa cells of the ovaries. Mutations and associated deficiency have not been reported in humans. Knockout mice show altered ovarian sex steroid production, normal puberty, and severe subfertility due to defective luteinization and ovarian progesterone production. HSD17B2: Describable as "antiestrogenic" and "antiandrogenic". 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. Said to be responsible for 17β-HSD activity in the endometrium and placenta. Mutations and associated congenital deficiency have not been reported in humans. However, local deficiency in expression of HSD17B2 has been associated with endometriosis. 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). 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. 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. HSD17B9: Also known as retinol dehydrogenase 5 (RDH5). Involved in retinoid metabolism. Mutations are associated with fundus albipunctatus. HSD17B10: Also known as 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD). Substrates include steroids, neurosteroids, fatty acids, bile acids, isoleucine, and xenobiotics. 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. 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 # Gene name Synonyms Family Size () Gene location Cellular location Substrate specificities Preferred cofactor Catalytic preference Tissue distribution Expression profile Pathology 1 HSD17B1 328 17q21.2 Cytosol Estrogens NADH, NADPH Reduction Ovary, endometrium, breast, brain, prostate, placenta Strongly restricted Breast cancer, prostate cancer, endometriosis 2 HSD17B2 387 16q23.3 Estrogens, androgens, progestogens NAD+ Oxidation Liver, intestine, endometrium, placenta, pancreas, prostate, colon, bone Selectively distributed Breast cancer, prostate cancer, endometriosis, osteoporosis 3 HSD17B3 310 9q22.32 Androgens NADPH Reduction Testis, ovary, blood, saliva, skin, adipose tissue, brain, bone Strongly restricted deficiency, prostate cancer 4 HSD17B4 , 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 HSD17B6 317 12q13.3 Endosomes Retinoids, androgens, estrogens NAD+ Oxidation Liver, testis, lung, spleen, brain, ovary, kidney, adrenal, prostate Selectively distributed ? 7 HSD17B7 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 HSD17B8 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 HSD17B10 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 HSD17B11 300 4q22.1 , Estrogens, androgens NAD+ Oxidation Liver, pancreas, intestine, kidney, adrenal gland, heart, lung, testis, ovary, placenta, sebaceous gland Nearly ubiquitous ? 12 HSD17B12 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 HSD17B13 300 4q22.1 , ? NAD+? Oxidation? Liver, bone marrow, lung, ovary, testis, kidney, skeletal muscle, brain, bladder, nasal epithelia Strongly restricted ? 14 HSD17B14 270 19q13.33 Cytosol Estrogens, androgens, fatty acids NAD+ Oxidation Liver, kidney, brain, gallbladder, breast, adrenal, placenta Widely distributed Breast cancer (prognostic) 15 , HSD17B15 318 14q23-24.3 Retinoids, androgens NADPH Reduction Retina, prostate, brain, testis ? Retinitis pigmentosa

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.

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

See also Steroidogenic enzyme 3α-Hydroxysteroid dehydrogenase

References

External links