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The mammalian molybdenum enzymes of mARC

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Abstract

The “mitochondrial amidoxime reducing component” (mARC) is the most recently discovered molybdenum-containing enzyme in mammals. All mammalian genomes studied to date contain two mARC genes: MARC1 and MARC2. The proteins encoded by these genes are mARC-1 and mARC-2 and represent the simplest form of eukaryotic molybdenum enzymes, only binding the molybdenum cofactor. In the presence of NADH, mARC proteins exert N-reductive activity together with the two electron transport proteins cytochrome b5 type B and NADH cytochrome b5 reductase. This enzyme system is capable of reducing a great variety of N-hydroxylated substrates. It plays a decisive role in the activation of prodrugs containing an amidoxime structure, and in detoxification pathways, e.g., of N-hydroxylated purine and pyrimidine bases. It belongs to a group of drug metabolism enzymes, in particular as a counterpart of P450 formed N-oxygenated metabolites. Its physiological relevance, on the other hand, is largely unknown. The aim of this article is to summarize our current knowledge of these proteins with a special focus on the mammalian enzymes and their N-reductive activity.

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Abbreviations

Cyt b5 :

Cytochrome b5 type B

Cyt b5 R:

NADH cytochrome b5 reductase

mARC:

Mitochondrial amidoxime reducing component

Moco:

Molybdenum cofactor

MOSC:

Moco-sulfurase C-terminal domain

mPTS:

Peroxisomal membrane targeting signal

NO:

Nitric oxide

NOHA:

N ω-hydroxy-l-arginine

SO:

Sulfite oxidase

SNP:

Single-nucleotide polymorphism

XO:

Xanthine oxidase

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Acknowledgments

We are very grateful to Dr. Florian Bittner for critical reviewing of this article and thank Dr. Markus Islinger for discussing peroxisomal localization of mARC. Financial support by the Deutsche Forschungsgemeinschaft [DFG, Cl 56/9-1, DFG, ME 1266/24-1] is greatly appreciated.

Conflict of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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  1. Institute of Pharmacy, Christian-Albrechts-University of Kiel, Gutenbergstraße 76, 24118, Kiel, Germany

    Gudrun Ott, Antje Havemeyer & Bernd Clement

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  1. Gudrun Ott
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Correspondence to Bernd Clement.

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Ott, G., Havemeyer, A. & Clement, B. The mammalian molybdenum enzymes of mARC. J Biol Inorg Chem 20, 265–275 (2015). https://doi.org/10.1007/s00775-014-1216-4

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