Molecular Cloning of Mouse 17β‐Hydroxysteroid Dehydrogenase Type 1 and Characterization of Enzyme Activity

Nokelainen, Pasi; Puranen, Terhi; Peltoketo, Hellevi; Orava, Mauri; Vihko, Pirkko; Vihko, R.

doi:10.1111/j.1432-1033.1996.00482.x

Cited by 92 publications

(73 citation statements)

References 48 publications

(43 reference statements)

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“…In human, 17 -HSD 5 is widely expressed , Dufort et al 1999, Qin & Rosenfield 2000 and accepts similar substrates as 17 -HSD 3. In mouse, 17 -HSD 5 is predominantly present in liver ) but murine 17 -HSD 1 has been demonstrated to convert androstenedione to testosterone with similar efficiency to 17 -HSD 3 (Nokelainen et al 1996) and is expressed in many different organs (Sha et al 1997). The ability to form testosterone by reduction of androstenedione might be present almost ubiquitously in the vertebrate organism, as was also suggested by measurements of androgenic activity in several tissues of rat (Martel et al 1992) and monkey (Labrie et al 1997).…”

Section: -Hsd 3 In An Evolutionary Contextmentioning

confidence: 75%

“…In human, mouse and rat, the reduction of androstenedione to testosterone is catalyzed by 17 -HSD type 3 (Geissler et al 1994, Tsai-Morris et al 1999 and type 5 (Dufort et al 1999, Luu-The et al 2001. In rodents, additionally 17 -HSD type 1 catalyzes this reaction very efficiently (Akinola et al 1996, Nokelainen et al 1996. In mammals, testicular formation of testosterone seems to be mainly governed by 17 -HSD type 3, which has been shown to be highly and almost exclusively expressed in the testis of human (Geissler et al 1994), mouse (Mustonen et al 1997, Sha et al 1997) and rat (Tsai-Morris et al 1999).…”

Section: Introductionmentioning

confidence: 99%

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Androgen metabolism via 17β-hydroxysteroid dehydrogenase type 3 in mammalian and non-mammalian vertebrates: comparison of the human and the zebrafish enzyme

Mindnich¹,

Haller²,

Halbach³

et al. 2005

Journal of Molecular Endocrinology

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Formation and inactivation of testosterone is performed by various members of the 17 -hydroxysteroid dehydrogenase (17 -HSD) family. The main player in testosterone formation is considered to be 17 -HSD type 3, which catalyzes the reduction of androstenedione to testosterone with high efficiency and is almost exclusively expressed in testis. So far, only the mammalian homologs have been characterized but nothing is known about the role of 17 -HSD type 3 in other vertebrates. In this study, we describe the identification and characterization of the zebrafish homolog. We found zebrafish 17 -HSD type 3 to be expressed in embryogenesis from sphere to 84 h post-fertilization. Expression was also detected in various tissues of both male and female adults, but displayed sexual dimorphism. Interestingly, expression was not highest in male testis but in male liver. In female adults, strongest expression was observed in ovaries. At the subcellular level, both human and zebrafish 17 -HSD type 3 localize to the endoplasmic reticulum. The zebrafish enzyme in vitro effectively catalyzed the conversion of androstenedione to testosterone by use of NADPH as cofactor. Among further tested androgens epiandrosterone and dehydroepiandrosterone were accepted as substrates and reduced at C-17 by the human and the zebrafish enzyme. Androsterone and androstanedione though, were only substrates of human 17 -HSD type 3, not the zebrafish enzyme. Furthermore, we found that both enzymes can reduce 11-ketoandrostenedione as well as 11 -hydroxyandrostenedione at C-17 to the respective testosterone forms. Our results suggest that 17 -HSD type 3 might play slightly different roles in zebrafish compared with human although testosterone itself is likely to have similar functions in both organisms.

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Section: -Hsd 3 In An Evolutionary Contextmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Androgen metabolism via 17β-hydroxysteroid dehydrogenase type 3 in mammalian and non-mammalian vertebrates: comparison of the human and the zebrafish enzyme

Mindnich¹,

Haller²,

Halbach³

et al. 2005

Journal of Molecular Endocrinology

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“…Mouse 17b-HSD1 is only 63% homologous to human 17b-HSD1 at the amino acid level, and this is reflected in its different substrate affinity, as, in addition to E 1 to E 2 activity, it also converts Adione to testosterone (Nokelainen et al 1996). The rat enzyme has 93% homology to that of the mouse, but only 68% to human 17b-HSD1 (Ghersevich et al 1994).…”

Section: Inhibitors Of 17b-hsd1mentioning

confidence: 99%

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

Day¹,

Tutill²,

Purohit³

et al. 2008

Endocrine Related Cancer

114

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Abstract17b-Hydroxysteroid dehydrogenases (17b-HSDs) are enzymes that are responsible for reduction or oxidation of hormones, fatty acids and bile acids in vivo, regulating the amount of the active form that is available to bind to its cognate receptor. All require NAD(P)(H) for activity. Fifteen 17b-HSDs have been identified to date, and with one exception, 17b-HSD type 5 (17b-HSD5), an aldo-keto reductase, they are all short-chain dehydrogenases/reductases, although overall homology between the enzymes is low. Although named as 17b-HSDs, reflecting the major redox activity at the 17b-position of the steroid, the activities of these 15 enzymes vary, with several of the 17b-HSDs able to reduce and/or oxidise multiple substrates at various positions. These activities are involved in the progression of a number of diseases, including those related to steroid metabolism. Despite the success of inhibitors of steroidogenic enzymes in the clinic, such as those of aromatase and steroid sulphatase, the development of inhibitors of 17b-HSDs is at a relatively early stage, as at present none have yet reached clinical trials. However, many groups are now working on inhibitors specific for several of these enzymes for the treatment of steroid-dependent diseases, including breast and prostate cancer, and endometriosis, with demonstrable efficacy in in vivo disease models. In this review, the recent advances in the validation of these enzymes as targets for the treatment of these diseases, with emphasis on 17b-HSD1, 3 and 5, the development of specific inhibitors, the models used for their evaluation, and their progress towards the clinic will be discussed.

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“…According to bootstrap analyses, using the programs PHYLIP and PaupSearch, of the sequences analyzed, mouse Psdrl and human PSDRl cluster together, suggesting that human PSDRl and the described mouse Psdrl are orthologs. Human and mouse PSDRl clustered most closely with mouse 17|3-HSD 7 (data not shown) an enzyme involved in ovarian estradiol biosynthesis in luteinized cells (Nokelainen et al, 1996). Also clustering closely with PSDRl were enzymes involved in retinoid metabolism, including mouse cis-retinol/androgen dehydrogenase type 2 (CRAD2).…”

Section: Phylogenetic Analysismentioning

confidence: 91%

The Prostate Expression Database (PEDB)

Nelson¹

2003

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Molecular Cloning of Mouse 17β‐Hydroxysteroid Dehydrogenase Type 1 and Characterization of Enzyme Activity

Cited by 92 publications

References 48 publications

Androgen metabolism via 17β-hydroxysteroid dehydrogenase type 3 in mammalian and non-mammalian vertebrates: comparison of the human and the zebrafish enzyme

Androgen metabolism via 17β-hydroxysteroid dehydrogenase type 3 in mammalian and non-mammalian vertebrates: comparison of the human and the zebrafish enzyme

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

The Prostate Expression Database (PEDB)

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