The fourth mammalian molybdenum enzyme mARC: current state of research

Abstract

The mitochondrial amidoxime-reducing component (mARC) is a recently discovered molybdenum-containing enzyme in mammalians. Upon reconstitution with the electron transport proteins, cytochrome b(5) and its reductase, this molybdenum enzyme is capable of reducing N-hydroxylated compounds. It was named mARC because the N-reduction of amidoxime structures was initially studied using this isolated mitochondrial enzyme. All hitherto analyzed mammalian genomes harbor two mARC genes: molybdenum cofactor (Moco) sulferase C-terminal domain MOSC1 and MOSC2. Proteins encoded by these genes represent the simplest eukaryotic molybdenum enzymes, in that they bind only the Moco. It is also suggested that they are members of a new family of molybdenum enzymes. mARC and its N-reductive enzyme system plays a major role in drug metabolism, especially in the activation of so-called "amidoxime-prodrugs" and in the detoxification of N-hydroxylated xenobiotics, though its physiological relevance is largely unknown.

Nitrite Reductase and Nitric-oxide Synthase Activity of the Mitochondrial Molybdopterin Enzymes mARC1 and mARC2

“…Therefore, we conclude that mARC-1 reduces nitrite to NO in the molybdenum active site, and Cys-273 is an integral amino acid of this site, presumably required for direct coordination to the molybdenum. Assuming the mARC active site is the same as sulfite oxidase, as predicted (27), removing the molybdenum coordinating cysteine ligand probably produce an oxygen-coordinated ligand (from water) (28). This mutation of the active site cysteine to alanine in sulfite oxidase family enzymes abolishes catalytic activity and has been demonstrated with sulfite oxidase (28), Chlamydomonas reinhardtii ARC (29), and similar molybdopterin enzymes.…”

The Pivotal Role of the Mitochondrial Amidoxime Reducing Component 2 in Protecting Human Cells against Apoptotic Effects of the Base Analog N6-Hydroxylaminopurine

“…Therefore, it is well accepted that it plays a major role in N-reductive metabolism (46). However, its endogenous substrates are as yet unknown.…”

Functional Characterization of Protein Variants Encoded by Nonsynonymous Single Nucleotide Polymorphisms inMARC1andMARC2in Healthy Caucasians

“…Previous studies in tissues of different species showed that at least one isoform of mARC was detectable in mitochondria (Da Cruz et al, 2003;Havemeyer et al, 2006;Wahl et al, 2010;Havemeyer et al, 2011;Krompholz et al, 2012;Neve et al, 2012). mARC-2 is also localized in peroxisomes (Islinger et al, 2007;Wiese et al, 2007).…”

“…Eukaryotic molybdenum enzymes are classified by the coordination chemistry of the molybdenum atom of Moco in two groups: the xanthine oxidoreductase family and the sulfite oxidase family. mARC proteins are regarded as members of the sulfite oxidase family (ChamizoAmpudia et al, 2011;Havemeyer et al, 2011;Rajapakshe et al, 2011;Mendel and Kruse, 2012).…”