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Journal of Biochemistry 2006 139(6):1053-1063; doi:10.1093/jb/mvj109
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© 2006 The Japanese Biochemical Society.

Regular Paper

Molecular Cloning of a Novel Type of Rat Cytoplasmic 17ß-Hydroxysteroid Dehydrogenase Distinct from the Type 5 Isozyme

Shuhei Ishikura1,*, Kengo Matsumoto1, Masaharu Sanai1, Kenji Horie1, Toshiyuki Matsunaga1, Kazuo Tajima2, Ossama El-Kabbani3 and Akira Hara1,{dagger}

1 Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 502-8585; 2 Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa 920-1181; and 3 Department of Medicinal Chemistry, Victorian College of Pharmacy, Monash University, Parkville, Victoria 3052, Australia

{dagger} To whom correspondence should be addressed. Phone/Fax: +81-58-237-8586, E-mail: hara{at}gifu-pu.ac.jp

Rat liver contains two cytosolic enzymes (TBER1 and TBER2) that reduce 6-tert-butyl-2,3-epoxy-5-cyclohexene-1,4-dione into its 4R- and 4S-hydroxy metabolites. In this study, we cloned the cDNA for TBER1 and examined endogenous substrates using the homogenous recombinant enzyme. The cDNA encoded a protein composed of 323 amino acids belonging to the aldo-keto reductase family. The recombinant TBER1 efficiently oxidized 17ß-hydroxysteroids and xenobiotic alicyclic alcohols using NAD+ as the preferred coenzyme at pH 7.4, and showed low activity towards 20{alpha}- and 3{alpha}-hydroxysteroids, and 9-hydroxyprostaglandins. The enzyme was potently inhibited by diethylstilbestrol, hexestrol and zearalenone. The coenzyme specificity, broad substrate specificity and inhibitor sensitivity of the enzyme differed from those of rat NADPH-dependent 17ß-hydroxysteroid dehydrogenase type 5, which was cloned from the liver and characterized using the recombinant enzyme. The mRNA for TBER1 was highly expressed in rat liver, gastrointestinal tract and ovary, in contrast to specific expression of 17ß-hydroxysteroid dehydrogenase type 5 mRNA in the liver and kidney. Thus, TBER1 represents a novel type of 17ß-hydroxysteroid dehydrogenase with unique catalytic properties and tissue distribution. In addition, TBER2 was identified as 3{alpha}-hydroxysteroid dehydrogenase on chromatographic analysis of the enzyme activities in rat liver cytosol and characterization of the recombinant 3{alpha}-hydroxysteroid dehydrogenase.

* Present address: The Hospital for Sick Children, 555 University Ave, Toronto, Ontario M5G 1X8, Canada.


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