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First published on November 10, 2004; DOI: 10.1124/dmd.104.002006

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Sukhwinder S Lakhman
Debashis Ghosh
Javier G Blanco
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Received for publication September 20, 2004.
Revised November 3, 2004.
Accepted for publication November 9, 2004.

Functional Significance of a Natural Allelic Variant of Human Carbonyl Reductase 3 (CBR3)

Sukhwinder S Lakhman 1, Debashis Ghosh 2, Javier G Blanco 1*

1 Department of Pharmaceutical Sciences, State University of New York at Buffalo 2 Department of Structural Biology, Hauptman-Woodward Medical Research Institute

* Address correspondence to: E-mail: jgblanco{at}buffalo.edu

Abstract

Human carbonyl reductase activity accounts for a significant fraction of the metabolism of endogenous and xenobiotic carbonyl compounds. It is possible that genetic polymorphisms in CBR1 and CBR3 may be key for the wide interindividual variability in the disposition of CBR drug substrates. We pinpointed a single nucleotide polymorphism in CBR3 (CBR3 V244M) that encodes for a V244 to M244 change. Blacks showed a higher frequency of the M244 allele (q = 0.51, n = 49) than whites (q = 0.31, n = 70; p = 0.003). In addition, DNA variation panels from 10 ethnic groups presented a wide range of CBR3 V244M genotype distributions. Kinetic experiments with the recombinant CBR3 protein variants and menadione revealed that CBR3 M244 has significantly higher VMax than CBR3 V244 (VMax CBR3 M244 = 40.6 ± 1.3 µmol/min·mg vs. VMax CBR3 V244 = 19.6 ± 2.0 µmol/min·mg, p = 0.002). In contrast, both isoforms presented similar Km values (Km CBR3 M244 = 22.9 ± 2.9 µM vs. Km CBR3 V244 = 24.6 ± 3.2 µM, p = 0.43). Assays with NADP(H) demonstrated a higher VMaxNADP(H) (1.6-fold) and increased catalytic efficiency (VMaxNADP(H) /Km NADP(H)) for CBR3 M244 compared to CBR3 V244 (p = 0.013). Comparative three dimensional analyses based on the structure of the homologous porcine carbonyl reductase suggested that the V244M substitution is positioned in a region critical for interactions with the NADP(H) cofactor. These studies demonstrate that the common CBR3 V244M polymorphism encodes for CBR3 isoforms with distinctive enzymatic properties.


Key words: enzyme kinetics, enzyme mechanism, ethnic differences, genetic polymorphism, genotype, human genetics, pharmacogenetics, polymorphisms, recombinant proteins, reductases


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