Molecular cloning of a novel widely expressed human 80 kDa 17β-hydroxysteroid dehydrogenase IV

Abstract

Reactions of oestrogens and androgens at position C-17 are catalysed by 17 beta-hydroxysteroid dehydrogenases (17 beta-HSDs). Cloning of the cDNA of a novel human 17 beta-HSD IV and expression of its mRNA are described. A probe derived from the recently discovered porcine 17 beta-oestradiol dehydrogenase (17 beta-EDH) was used to isolate a 2.6 kb human cDNA encoding a continuous protein of 736 amino acids of high (84%) similarity to the porcine 17 beta-EDH. The calculated molecular mass of the human enzyme is 79,595 Da. Other sequence similarities shared by the two enzymes are: an N-terminal sequence which is similar to that of members of the short-chain alcohol dehydrogenase family; amino acids 343-607 which are similar to the C-terminal domains of a trifunctional Candida tropicalis enzyme and the FOX2 gene product of Saccharomyces cerevisiae; amino acids 596-736 which are similar to human sterol carrier protein 2. The previously cloned human 17 beta-HSD I, II and III are less than 25% identical with 17 beta-HSD IV. mRNA for HSD IV is a single species of 3.0 kb, present in many tissues with highest concentrations in liver, heart, prostate and testes. When over-expressed in mammalian cells, the human 17 beta-HSD IV enzyme displays a specific unidirectional oxidative 17 beta-HSD activity.

In vivo and in vitro expression of steroid-converting enzymes in human breast tumours: associations with interleukin-6

“…17-HSD type II oxidizes testosterone and E2 into androstendione and E1 (Luu-The et al, 1995;Penning, 1996). The function of 17-HSD type IV is similar in that it oxidizes oestrogens and androgens (Adamski et al, 1992). Much of the E1 formed from androstendione is converted by STS to oestrone sulphate, which acts as a reservoir for the formation of E1 via STS (Reed et al, 1994).…”

“…This isoform is found principally in the testis. Type IV 17-HSD is similar to the type II isoform in that it is NAD + -dependent and is principally involved in the oxidation and therefore inactivation of oestrogens and androgens (Adamski et al, 1992). 17-HSD type V belongs to the aldoketoreductase family (Jornvall et al, 1995) while the sixth isoform is a member of the short-chain alcohol reductase family (Deyashiki et al, 1995).…”

Intracrinology: role of the family of 17 beta-hydroxysteroid dehydrogenases in human physiology and disease

“…4) which shares 84% identity with the corresponding porcine enzyme and transforms E 2 into E 1 and 5-diol into DHEA (Leenders et al 1994, Adamski et al 1995. The human type 4 17 -HSD mRNA is expressed in virtually all human tissues examined by Northern blot, including the liver, heart, prostate, testis, lung, skeletal muscle, kidney, pancreas, thymus, ovary, intestine, placenta, and several human breast cancer cell lines.…”

Design and validation of specific inhibitors of 17 -hydroxysteroid dehydrogenases for therapeutic application in breast and prostate cancer, and in endometriosis

“…It comprises an N-terminal dehydrogenase domain, and a larger C-terminal domain, of around 45 kDa, which contains both hydratase and lipid carrier moieties (Breitling et al 2001, Huyghe et al 2006. Although it can have E 2 oxidoreductase activity (Adamski et al 1995), in vivo it is involved in peroxisomal fatty acid b-oxidation (Breitling et al 2001), with defects in its expression causing D-specific MFP deficiency (Huyghe et al 2006). It is present in many tissues, with highest concentrations in the liver, heart, prostate and testis, and is up-regulated in prostate cancer (Zha et al 2005).…”