Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.1.1.3 (HSD)
 3,464 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The enzyme 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) catalyzes the 17 beta-oxidation/reduction of C18- and C19-steroids in a variety of tissues. Three human genes encoding isozymes of 17 beta-HSD, designated 17 beta-HSD types 1, 2 and 3 have been cloned. 17 beta-HSD type 1 (also referred to as estradiol 17 beta-dehydrogenase) catalyzes the conversion of estrone to estradiol, primarily in the ovary and placenta. The 17 beta-HSD type 2 is expressed to high levels in the liver, secretory endometrium and placenta. The type 2 isozyme catalyzes the oxidation of androgens and estrogens equally efficiently. Also, the enzyme possesses 20 alpha-HSD activity demonstrated by its ability to convert 20 alpha-dihydroprogesterone to progesterone. Testicular 17 beta-HSD type 3 catalyzes the conversion of androstenedione to testosterone, dehydroepiandrosterone to 5-androstenediol and estrone to estradiol. The 17 beta-HSD3 gene is mutated in male pseudohermaphrodites with the genetic disease 17 beta-HSD deficiency.
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PMID:The molecular biology of androgenic 17 beta-hydroxysteroid dehydrogenases. 762 83

Defects in the conversion of androstenedione to testosterone in the fetal testes by the enzyme 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) give rise to genetic males with female external genitalia. We have used expression cloning to isolate cDNAs encoding a microsomal 17 beta-HSD type 3 isozyme that shares 23% sequence identity with other 17 beta-HSD enzymes, uses NADPh as a cofactor, and is expressed predominantly in the testes. The 17 beta HSD3 gene on chromosome 9q22 contains 11 exons. Four substitution and two splice junction mutations were identified in the 17 beta HSD3 genes of five unrelated male pseudohermaphrodites. The substitution mutations severely compromised the activity of the 17 beta-HSD type 3 isozyme.
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PMID:Male pseudohermaphroditism caused by mutations of testicular 17 beta-hydroxysteroid dehydrogenase 3. 807 45

17 beta-Hydroxysteroid dehydrogenase (17 beta-HSD) type 2 catalyzes the NAD(+)-dependent oxidation of androgens, estrogens and progestins, predominantly in the secretory endometrium, placenta, liver and small intestine. 17 beta-HSD type 3 catalyzes the NADPH-dependent conversion of androstenedione to testosterone in the testis, and the genetic disease 17 beta-HSD deficiency is caused by mutations in the 17 beta-HSD3 gene.
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PMID:Molecular genetics of androgenic 17 beta-hydroxysteroid dehydrogenases. 854 78

Four isozymes of steroid 17 beta-hydroxysteroid dehydrogenase (17 beta HSD) encoded by different loci catalyze the reversible conversion of androstenedione to testosterone and that of estrone to estradiol. The 17 beta HSD type 3 (17 beta HSD3) isozyme is encoded by the 17 beta HSD3 gene on chromosome 9q22 and expressed only in testes. Inherited defects in the 17 beta HSD3 isozyme cause a form of male pseudohermaphroditism that is rare within the general population, but frequent among a highly inbred Arab population in the Gaza strip. A point mutation in exon 3, codon 80 of the 17 beta HSD3 gene, R80Q, caused by a single base substitution from CGG to CAG was identified in both alleles of 24 individuals from 9 extended Arab families from Gaza, Jerusalem, and Lod-Ramle. Twenty-one homozygotes were male pseudohermaphrodites (46,XY) with testicular 17 beta HSD3 deficiency, born with either female-looking external genitalia or various degrees of genital ambiguity. If not reassigned in infancy, they were reared as females until puberty, when marked virilization occurred, often leading to the spontaneous adoption of a male gender role. In contrast, the 3 homozygote females (46,XX) were asymptomatic, had normal internal and external genitalia and normal sexual development, and revealed no biochemical evidence of 17 beta HSD3 deficiency. The molecular pattern in these families is compatible with an autosomal recessive mode of inheritance that is sex dependent.
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PMID:A (R80Q) mutation in 17 beta-hydroxysteroid dehydrogenase type 3 gene among Arabs of Israel is associated with pseudohermaphroditism in males and normal asymptomatic females. 862 42

Three isozymes of 17 beta-hydroxysteroid dehydrogenase (17 beta HSD) have been cloned and characterized as distinct gene products (17 beta HSD1, 17 beta HSD2, and 17 beta HSD3). The presence and location of these isozymes in the human ovary have not been defined. In this study, we utilized Northern analysis and RT-PCR to examine transcripts for the three isozymes of 17 beta HSD. RNA was isolated from ovarian cortex, stroma (pre- and postmenopausal), hilum, follicles, and corpora lutea obtained from adult women, as well as whole fetal ovaries. By Northern analysis, high levels of 17 beta HSD1 messenger RNA were found in follicles, corpora lutea, and cortex, whereas low levels were detected in the postmenopausal stroma and in fetal ovaries by RT-PCR. 17 beta HSD1 messenger RNA was not detected in hilar tissue by either Northern analysis or RT-PCR. Utilizing RT-PCR, transcripts for 17 beta HSD2 were not detectable in cortex, stroma, (pre-or postmenopausal), hilum, or follicles, but were present in RNA derived from the corpora lutea and fetal ovary. The androgenic isozyme 17 beta HSD3 was not detectable in any of the ovarian compartments examined by either Northern analysis or RT-PCR. These data provide additional insight into the mechanism of testosterone and estradiol synthesis within the ovary. Specifically, the high level of 17 beta HSD1 is clearly localized to follicles and corpora lutea indicating involvement in the synthesis of estradiol. Secondly, androgenic 17 beta HSD3 is not expressed in the human ovary. Thus testosterone production within the human ovary, occurring under physiological conditions, arises from either the 17 beta HSD1 or an uncharacterized isozyme.
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PMID:Human ovarian expression of 17 beta-hydroxysteroid dehydrogenase types 1, 2, and 3. 885 7

We have isolated, by screening a lambda gt11 human prostatic cDNA library, a cDNA clone that shows after transfection into transformed human embryonal kidney (293) cells high 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) activity that catalyzes efficiently the transformation of dihydrotestosterone to 5 alpha-androstane-3 alpha, 17 beta-diol. Chronologically, we name this enzyme type 3 3 alpha-HSD (3 alpha-HSD3). Surprisingly, human 3 alpha-HSD3 shares much higher amino acids sequence identity with human 20 alpha-HSD (97.8%) than with human type 1 and type 2 3 alpha-HSD (81.1 and 85.7% identity, respectively). DNA analysis predicts a protein of 323 amino acids with a molecular mass of 36,844. Alignment of the amino acid sequence of 3 alpha-HSD3 with other related 3 alpha- and 20 alpha-HSDs indicates that 3 alpha-HSD3 shares 68.1, 78.3, and 67.4% identity with rat 3 alpha-HSD and rabbit and rat 20 alpha-HSD, respectively. 3 alpha-HSD3 belongs to the aldo-keto reductase family and like almost all the members of this family preferred NADPH as cofactor.
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PMID:Molecular cloning of human type 3 3 alpha-hydroxysteroid dehydrogenase that differs from 20 alpha-hydroxysteroid dehydrogenase by seven amino acids. 892 Sep 37

17 beta-Hydroxysteroid dehydrogenases (17 beta-HSDs) are enzymes involved in both the activation and inactivation of androgens and estrogens. 17 beta-HSD type 1 shows a high specificity for C18 steroids and is the major isozyme in the granulosa cells of the ovary. Its role is to convert the inactive C18 steroid estrone to the active estrogen estradiol, which in turn locally promotes maturation of the follicle. In contrast, attenuation of estradiol action in the glandular epithelium of the secretory endometrium is achieved by expression of the oxidative type 2 isozyme that inactivates estradiol to estrone. An interesting feature of 17 beta-HSD type 2 is that the enzyme also possesses 20 alpha-HSD activity, i.e., it catalyzes the 20 alpha-oxidation of the inactive C21 steroid 20 alpha-dihydroprogesterone to the active progestin progesterone. As the type 2 enzyme is also active on androgens, it may play a general role in the peripheral inactivation of androgens and estrogens, thus determining their steady-state levels in target tissues. The reductive 17 beta-HSD type 3 is predominantly expressed in the testis and converts the inactive C19 steroid androstenedione to the active androgen testosterone. The importance of the type 3 enzyme in male steroid hormone physiology is underscored by the genetic disease 17 beta-HSD deficiency. Mutations in the 17 beta-HSD3 gene impair the formation of testosterone in the fetal testis and give rise to genetic males with normal male Wolffian duct structures but female external genitalia. To date, 15 mutations have been identified in 18 subjects with the disease.
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PMID:Physiology and molecular genetics of 17 beta-hydroxysteroid dehydrogenases. 902 29

In the present study we have inspected estrogen metabolism in cultured human prostate cancer cells (LNCaP, DU145, PC3), in relation to the expression of mRNAs for different 17 beta hydroxysteroid dehydrogenase (17 beta HSD) enzymes (from 1 to 4). Using an intact cell analysis, we have compared precursor degradation and product formation after incubation of cells with physiological amounts of radioactive E2 or estrone (E1) for 24-72 h and subsequent reverse-phase high performance liquid chromatography analysis. The LNCaP and DU145 cells only partly converted E2 to E1 (26 and 13% at 72 h, respectively), giving rise to an appreciable production of E2 from E1 (nearly 20% in all cases). Conversely, PC3 cells revealed a massive E2 oxidation to E1 (up to 90% by 72 h) and a scant formation of E2 (<2%) from E1. In addition, an appreciable formation of 16 alpha OHE1 was seen in either PC3 (11%) or DU145 (5%) cells. respectively using E2 or E1 as precursor. All three cell lines exhibited marked amounts of 17 beta HSD4 mRNA species, whilst even greater amounts of 17 beta HSD2 transcript were found in PC3 cells only. No mRNA for either 17 beta HSD1 or 17 beta HSD3 could be detected in any cell line. The present evidence indicates that pathways of estrogen metabolism are distinctly governed in prostate cancer cells depending on their endocrine status, being associated with a differential expression of mRNA for different 17 beta HSD enzymes.
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PMID:Molecular expression of 17 beta hydroxysteroid dehydrogenase types in relation to their activity in intact human prostate cancer cells. 925 63

In the endometrium two enzymes are known to convert estradiol to its inactive metabolite estrone: microsomal 17beta-hydroxysteroid dehydrogenase type 2 (17beta-HSD2) and peroxisomal 17beta-HSD4. In order to elucidate the particular function of each of these two different enzymes, the human endometrial epithelial cell lines HEC-1-A and RL95-2 were examined with respect to the expression of 17betaHSD isozymes. They were compared with human endometrium in vivo. Non-radioactive in situ hybridization revealed both enzymes in glandular epithelial cells of human endometrium. The two cell lines were screened for mRNA expression of 17beta-HSD 1-4 by RT-PCR and Northern blot. 17beta-HSD2 and 4 could be detected by either method, 17beta-HSD1 only by RT-PCR, 17beta-HSD3 not at all. Both cell lines were proven to have no receptor for progesterone which is known as a physiological inducer of several 17beta-HSD isozymes. To study the regulation of 17beta-HSD2 and 17betaHSD4, the concentration of fetal calf serum in the cell culture media was reduced stepwise to 0.3% by dilution with a defined serum replacement. This treatment led to an inhibition of 17beta-HSD2 mRNA expression and an increase in the mRNA expression of 17beta-HSD4. Concomitantly, distinct morphological changes were observed, such as a decrease in the number and length of microvilli and a decrease in the formation of domes on top of the monolayers. The endometrial epithelial cell lines HEC-1-A and RL95-2 represent a suitable in vitro model for further studies of the differential expression of the major endometrial HSD isozymes, independent of the effect of progesterone.
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PMID:Differential expression of 17beta-hydroxysteroid dehydrogenases types 2 and 4 in human endometrial epithelial cell lines. 1065 5

Human 20alpha-hydroxysteroid dehydrogenase (h20alpha-HSD; AKR1C1) catalyzes the transformation of progesterone (Prog) into 20alpha-hydroxy-progesterone (20alpha-OHProg). Although h20alpha-HSD shares 98% sequence identity with human type 3 3alpha-HSD (h3alpha-HSD3, AKR1C2), these two enzymes differ greatly in their activities. In order to explain these differences, we have solved the crystal structure of h20alpha-HSD in a ternary complex with NADP(+) and 20alpha-OHProg at 1.59A resolution. The steroid is stabilized by numerous hydrophobic interactions and a hydrogen bond between its O20 and the N(epsilon ) atom of His222. This new interaction prevents the formation of a hydrogen bond with the cofactor, as seen in h3alpha-HSD3 ternary complexes. By combining structural, direct mutagenesis and kinetic studies, we found that the H(222)I substitution decreases the K(m) value for the cofactor 95-fold. With these results, we hypothesize that the rotation of the lateral chain of His222 could be a mediating step between the transformation of Prog and the release of the cofactor. Moreover, crystal structure analysis and direct mutagenesis experiments lead us to identify a new residue involved in the binding of Prog. Indeed, the R(304)L substitution leads to a 65-fold decrease in the K(m) value for Prog reduction. We thus propose that Prog is maintained in a new steroid-binding site composed mainly of residues found in the carboxy-terminal region of the protein.
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PMID:Human 20alpha-hydroxysteroid dehydrogenase: crystallographic and site-directed mutagenesis studies lead to the identification of an alternative binding site for C21-steroids. 1289 31


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