The Mitochondrial Amidoxime Reducing Component (mARC) Is Involved in Detoxification of N-Hydroxylated Base Analogues

Krompholz, N., Krischkowski, C., Reichmann, D., Garbe-Schönberg, Dieter, Mendel, R. R., Bittner, F., Clement, B. and Havemeyer, A. (2012) The Mitochondrial Amidoxime Reducing Component (mARC) Is Involved in Detoxification of N-Hydroxylated Base Analogues Chemical Research in Toxicology, 25 (11). pp. 2443-2450.

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Abstract

The "mitochondrial Amidoxime Reducing Component" (mARC) is the newly discovered fourth molybdenum enzyme in mammals. All hitherto analyzed mammals express two mARC proteins, referred to as mARC1 and mARC2. Together with their electron transport proteins cytochrome b(5) and NADH cytochrome b(5) reductase, they form a three-component enzyme system and catalyze the reduction of N-hydroxylated prodrugs. Here, we demonstrate the reductive detoxification of toxic and mutagenic N-hydroxylated nucleobases and their corresponding nucleosides by the mammalian mARC-containing enzyme system. The N-reductive activity was found in all tested tissues with the highest detectable conversion rates in liver, kidney, thyroid, and pancreas. According to the presumed localization, the N-reductive activity is most pronounced in enriched mitochondrial fractions. In vitro assays with the respective recombinant three-component enzyme system show that both mARC isoforms are able to reduce N-hydroxylated base analogues, with mARC1 representing the more efficient isoform. On the basis of the high specific activities with N-hydroxylated base analogues relative to other N-hydroxylated substrates, our data suggest that mARC proteins might be involved in protecting cellular DNA from misincorporation of toxic N-hydroxylated base analogues during replication by converting them to the correct purine or pyrimidine bases, respectively.

Document Type: Article
Additional Information: Clement, B Univ Kiel, Inst Pharmaceut, Olshaussenstr 40, D-24118 Kiel, Germany Univ Kiel, Inst Pharmaceut, Olshaussenstr 40, D-24118 Kiel, Germany Univ Kiel, Inst Pharmaceut, D-24118 Kiel, Germany Tech Univ Carolo Wilhelmina Braunschweig, Dept Plant Biol, D-38106 Braunschweig, Germany Univ Kiel, Inst Geosci, D-24118 Kiel, Germany
Keywords: cofactor-dependent resistance containing enzyme marc escherichia-coli molybdenum enzyme outer-membrane 6-n-hydroxylaminopurine reduction proteins adenine system
Research affiliation: Kiel University > Kiel Marine Science
OceanRep > The Future Ocean - Cluster of Excellence
Kiel University
Refereed: Yes
ISSN: 0893-228X
Projects: Future Ocean
Date Deposited: 14 May 2014 09:53
Last Modified: 11 Apr 2018 11:59
URI: http://eprints.uni-kiel.de/id/eprint/24077

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