The molybdenum cofactor enzyme mARC: Moonlighting or promiscuous enzyme?

Abstract

Molybdenum (Mo) is present in the active center of eukaryotic enzymes as a tricyclic pyranopterin chelate compound forming the Mo Cofactor (Moco). Four Moco containing enzymes are known in eukaryotes, nitrate reductase (NR), sulfite oxidase (SO), xanthine oxidoreductase (XOR), and aldehyde oxidase (AO). A fifth Moco enzyme has been recently identified. Because of the ability of this enzyme to convert by reduction several amidoximes prodrugs into their active amino forms, it was named mARC (mitochondrial Amidoxime Reducing Component). This enzyme is also able to catalyze the reduction of a broad range of N-hydroxylated compounds (NHC) as the base analogue 6-hydroxylaminopurine (HAP), as well as nitrite to nitric oxide (NO). All the mARC proteins need reducing power that is supplied by other proteins. The human and plants mARC proteins require a Cytochrome b5 (Cytb5) and a Cytochrome b5 reductase (Cytb5-R) to form an electron transfer chain from NADH to the NHC. Recently, plant mARC proteins were shown to be implicated in the reduction of nitrite to NO, and it was proposed that the electrons required for the reaction were supplied by NR instead of Cytochrome b5 components. This newly characterized mARC activity was termed NO Forming Nitrite Reductase (NOFNiR). Moonlighting proteins form a special class of multifunctional enzymes that can perform more than one function; if the extra function is not physiologically relevant, they are called promiscuous enzymes. In this review, we summarize the current knowledge on the mARC protein, and we propose that mARC is a new moonlighting enzyme. © 2017 BioFactors, 43(4):486-494, 2017.

Propionyl-CoA carboxylase – A review

“…Several enzymes are thought to moonlight often by impacting transcription. These include the molybdenum co-factor enzyme mARC [83], holocarboxylase synthase [84], pyruvate kinase, lactate dehydrogenase, and succinate dehydrogenase [85]. PCCB mRNA accounts for 0.02% total hepatic mRNA [86] and this may reflect moonlighting roles.…”

Iron Sulfur and Molybdenum Cofactor Enzymes Regulate the Drosophila Life Cycle by Controlling Cell Metabolism

“…The enzyme from humans has been proposed to reduce a broad range of N-hydroxylated compounds receiving electrons from cytochrome b5 (Gruenewald et al, 2008 ) and to reduce nitrite to nitric oxide (Sparacino-Watkins et al, 2014 ). A number of controversies over the function, subcellular localization and whether the newly discovered enzyme binds to sulfurated or oxo Moco, have been reviewed (Llamas et al, 2017 ).…”

Crystal structure of human mARC1 reveals its exceptional position among eukaryotic molybdenum enzymes

“…Furthermore, recent studies suggest that mARC is important for organisms to ensure reductive detoxification strategies, for example of toxic hydroxylamines (4) or mutagenic N-hydroxylated nucleobases (5,12). After its discovery, subsequent studies have shown that the enzyme is able to reduce the full range of Noxygenated compounds, including the capacity to reduce inorganic nitrite to nitric oxide (13) and N ω -hydroxy-L-arginine to arginine (14). All annotated genomes of mammals appear to possess two copies of mARC genes, with both copies showing strong similarities on nucleotide and amino acid levels, thus making a discrimination difficult, but defining them as paralogous proteins.…”