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Journal of Biochemistry Advance Access originally published online on November 14, 2008
Journal of Biochemistry 2009 145(2):161-168; doi:10.1093/jb/mvn152
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© The Authors 2008. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved

Prostaglandin F2{alpha} Synthase Activities of Aldo–Keto Reductase 1B1, 1B3 and 1B7

Zakayi Kabututu1, Michèle Manin2, Jean-Christophe Pointud2, Toshihiko Maruyama1, Nanae Nagata1, Sarah Lambert2, Anne-Marie Lefrançois-Martinez2, Antoine Martinez2 and Yoshihiro Urade1,*

1Department of Molecular Behavioral Biology, Osaka Bioscience Institute, 6-2-4 Furuedai, Suita, Osaka 565-0874, Japan; and 2CNRS, UMR6247—Genetic, Reproduction and Development (GReD), Clermont University, 63177 Aubière, France

*To whom correspondence should be addressed. Tel: +81-6-6872-4851, Fax: +81-6-6872-2841, E-mail: uradey{at}obi.or.jp

Received September 4, 2008; Accepted October 30, 2008


  Abstract

Here, we show that three enzymes belonging to the 1B group of the aldo–keto reductase (AKR) superfamily, i.e., human placental aldose reductase (AKR1B1), mouse kidney aldose reductase (AKR1B3) and mouse vas deferens protein (AKR1B7), catalyse the reduction of prostaglandin (PG) H2, a common intermediate of various prostanoids, to form PGF2{alpha} in the presence of NADPH. AKR1B1, AKR1B3 and AKR1B7 displayed higher affinities for PGH2 (Km = 1.9, 9.3 and 3.8 µM, respectively) and Vmax values (26, 53 and 44 nmol/min/mg protein, respectively) than did the human lung PGF2{alpha} synthase (AKR1C3; 18 µM and 4 nmol/min/mg protein, respectively). The PGF2{alpha} synthase activity of AKR1B1 and AKR1B3 was efficiently inhibited by two AKR inhibitors, tolrestat (Ki = 3.6 and 0.26 µM, respectively) and sorbinil (Ki = 21.7 and 0.89 µM, respectively), in a non-competitive or mixed-type manner, whereas that of AKR1B7 was not sensitive to these inhibitors (Ki = 9.2 and 18 mM, respectively). These data provide a molecular basis for investigating novel functional roles for AKR1B members and PGF2{alpha} as mediators of physiological and pathological processes in mammalian organisms.

Key Words: prostaglandin F2{alpha}, prostaglandin H2, prostaglandin H2 F2{alpha}-reductase, tolrestat, sorbinil

Abbreviations: AKR, aldo–keto reductase; ARI, aldose reductase inhibitors; ARLP, aldose reductase-like proteins; LC–MS, liquid chromatography–mass spectrometry; PG, prostaglandin; PGFS, prostaglandin F2{alpha} synthase


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