Role of human aldo-keto-reductase AKR1B10 in the protection against toxic aldehydes.

Martin, H. J. and Maser, Edmund (2009) Role of human aldo-keto-reductase AKR1B10 in the protection against toxic aldehydes. Chemico-Biological Interactions, 178 (1-3). pp. 145-150. DOI 10.1016/j.cbi.2008.10.021.

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Supplementary data:

Abstract

Damage of cell membranes by reactive oxygen species results in the formation of toxic lipid peroxides which may ultimately lead to cell death. Among the best characterized intermediates of oxidative stress are the unsaturated aldehydes 4-hydroxynon-2-enal (4-HNE) and its oxidized counterpart 4-oxonon-2-enal (4-ONE). 4-HNE has been linked to various pathological conditions including atherosclerosis, Parkinson's and Alzheimer's disease. 4-Methylpentanal (4-MP) is a side-chain cleavage product formed endogenously during steroidogenesis from cholesterol. Like 4-HNE and 4-ONE, 4-MP is capable of binding covalently to and cross-linking of proteins. These aldehydes are also damaging DNA by the formation of adducts. We found that AKR1B10, a cytosolic member of the aldo-keto reductase superfamily, efficiently catalyzes the reduction of 4-HNE (K-m = 0.3mM, k(cat) = 43 min(-1)), 4-ONE (K-m = 0.3 mM, k(cat) = 40 min(-1)) and 4-MP (K-m = 0.05 mM, k(cat) = 25 min(-1)). AKR1B10 catalyzed 4-MP reduction with a 30-fold increase in activity using NADPH as cofactor compared with NADH. As was observed for aldose reductase (AKR1B1) 4-ONE rapidly inactivates AKR1B10, while this inactivation is not observed when the enzyme is pre-incubated with NADPH. It was shown that cysteine 298 of aldose reductase was protected by NADPH from the alpha,beta-unsaturated carbonyls of 4-ONE thus rendering resistance towards inactivation. We generated a mutant AKR1B10, changing the respective cysteine on position 299 of AKR1B10 into a serine. This C299S mutant is still active towards 4-HNE and 4-ONE, albeit at a somewhat lower catalytic efficiency. However, it is still inactivated by 4-ONE in the absence of NADPH. While the best substrates for AKR1B10 are retinals, the high catalytic efficiency together with the protection from inactivation by NADPH suggests a role of AKR1B10 in the detoxification of biogenic aldehydes. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

Document Type: Article
Keywords: aldo-keto reductaseakr1b10 4-hne 4-one toxic aldehydes lipid peroxidation lipid-peroxidation side-chain catalyzes reduction carbonyl reductase family isocaproaldehyde determinants cholesterol glutathione products
Research affiliation: OceanRep > The Future Ocean - Cluster of Excellence
Kiel University
Refereed: Yes
Open Access Journal?: No
Publisher: Elsevier
Projects: Future Ocean
Date Deposited: 11 Feb 2011 12:14
Last Modified: 29 Jul 2019 06:26
URI: https://oceanrep.geomar.de/id/eprint/9570

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