Cancer biomarker AKR1B10 and carbonyl metabolism

Balendiran, G. K., Martin, H. J., El-Hawari, Y. and Maser, Edmund (2009) Cancer biomarker AKR1B10 and carbonyl metabolism Chemico-Biological Interactions, 178 (1-3). pp. 134-137.

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Abstract

A member of the aldo-keto reductase (AKR) protein superfamily, AKR1B10, is overexpressed in human liver cancers as well as in many adenocarcinoma cases due to smoking. AKR1B10 is also detected in instances of cervical and endometrial cancer in uterine cancer patients. In addition, AKR1B10 has been identified as a biomarker for non-small-cell lung cancer by a combined bioinformatics and clinical analysis. Furthermore, in breast cancer cells, fatty acid biosynthesis is regulated by AKR1B10. AKR1B10 contains 316 residues, shares 70% sequence identity with aldose reductase (AKR1B1) and has the conserved Cys residue at position 299. Carbonyl groups in some anticancer drugs and DL-glyceraldehyde are converted by AKR1B10 to their corresponding alcohols. The anticancer drug daunorubicin, which is currently used in the clinical treatment of various forms of cancer, is converted by AKR1B10 to daunorubicinol with a K-m and k(cat) of 1.1+/-0.18 mM and 1.4+/-0.16 min(-1), respectively. This carbonyl reducing activity of AKR1B10 decreases the anticancer effectiveness of daunorubicin. Similarly, kinetic parameters K-m and k(cat) (NADPH, DL-glyceraldehyde) for the reduction Of DL-glyceraldehyde by wild-type AKR1B10 are 2.2+/-0.2 mM and 0.71+/-0.05 sec(-1), respectively. Mutation of residue 299 from Cys to Set in AKR1B10 reduces the protein affinity for DL-glyceraldehyde and enhances AKR1B10's catalytic activity but overall catalytic efficiency is reduced. For DL-glyceraldehyde reduction that is catalyzed by the Cys299Ser mutant AKR1B10, K-m is 15.8+/-1.0 mM and k(cat) (NADPH, DL-glyceraldehyde) is 2.8+/-0.2 sec(-1). This implies that the substrate specificity of AKR1B10 is drastically affected by mutation of residue 299 from Cys to Set. In the present paper, we use this mutation in AKR1B10 to characterize a library of compounds regarding their different inhibitory potency on the carbonyl reducing activity of wild-type and the Cys299Ser mutant AKR1B10. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

Document Type: Article
Keywords: aldo-keto reductaseakr1b10 cancer chemotherapy inhibitor human aldose reductase hepatocellular-carcinoma ischemic-heart anthracyclines inhibition family member cells cardiotoxicity daunorubicin
Research affiliation: OceanRep > The Future Ocean - Cluster of Excellence
Kiel University
Refereed: Yes
ISSN: 0009-2797
Projects: Future Ocean
Date Deposited: 11 Feb 2011 12:14
Last Modified: 07 Sep 2016 12:37
URI: http://eprints.uni-kiel.de/id/eprint/9280

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