Carbonyl reductase catalyses the reduction of steroids, prostaglandins and a variety of xenobiotics. An unusual property of human and rat carbonyl reductases is that they undergo modification at lysine-239 by an autocatalytic process involving 2-oxocarboxylic acids, such as pyruvate and 2-oxoglutarate. Comparison of human carbonyl reductase with the pig enzyme, which does not undergo autocatalytic modification, identified three sites, alanine-236, threonine-241 and glutamic acid-246, on human carbonyl reductase that could be important in the reaction of lysine-239 with 2-oxocarboxylic acids. Mutagenesis experiments show that replacement of threonine-241 with proline (T241P) in human carbonyl reductase eliminates the formation of carboxyethyl-lysine-239. In contrast, the T241A mutant has autocatalytic activity similar to wild-type carbonyl reductase. The T241P mutant retains catalytic activity towards menadione, although with one-fifth the catalytic efficiency of wild-type carbonyl reductase. Replacement of threonine-241 with proline is likely to disrupt the local structure near lysine-239. We propose that integrity of this local environment is essential for chemical modification of lysine-239, but not absolutely required for carbonyl reductase activity.
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Research Article|
August 09 2000
Mutation of threonine-241 to proline eliminates autocatalytic modification of human carbonyl reductase
Michel A. SCIOTTI;
Michel A. SCIOTTI
*Chemisches Zentrallabor, Inselspital, 3010 Berne, Switzerland
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Shizuo NAKAJIN;
Shizuo NAKAJIN
†Department of Biochemistry, Faculty of Pharmaceutical Sciences, Hoshi University, 2-4-41, Ebara, Shinagawa-ku, Tokyo 142, Japan
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Bendicht WERMUTH;
Bendicht WERMUTH
1
*Chemisches Zentrallabor, Inselspital, 3010 Berne, Switzerland
1Correspondence may be addressed to either of these two authors (e-mail Wermuth@insel.ch or mbaker@ucsd.edu).
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Michael E. BAKER
Michael E. BAKER
1
‡Department of Medicine, 0823, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0823, U.S.A.
1Correspondence may be addressed to either of these two authors (e-mail Wermuth@insel.ch or mbaker@ucsd.edu).
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Publisher: Portland Press Ltd
Received:
May 08 2000
Accepted:
June 01 2000
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 2000
2000
Biochem J (2000) 350 (1): 89–92.
Article history
Received:
May 08 2000
Accepted:
June 01 2000
Citation
Michel A. SCIOTTI, Shizuo NAKAJIN, Bendicht WERMUTH, Michael E. BAKER; Mutation of threonine-241 to proline eliminates autocatalytic modification of human carbonyl reductase. Biochem J 15 August 2000; 350 (1): 89–92. doi: https://doi.org/10.1042/bj3500089
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