Amidoxime Reductase System Containing Cytochrome b5 Type B (CYB5B) and MOSC2 Is of Importance for Lipid Synthesis in Adipocyte Mitochondria

Neve, Etienne P.A.; Nordling, Åsa; Andersson, Tommy; Hellman, Ulf; Diczfalusy, Ulf; Johansson, Inger; Ingelman‐Sundberg, Magnus

doi:10.1074/jbc.m111.328237

Cited by 55 publications

(90 citation statements)

References 40 publications

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“…Assuming a similar localization of mARC1 and mARC2, our results are in line with the previous studies detecting mARC2 in purified outer membrane fractions (5,9). In addition, for the first time we were also able to clarify the orientation of one of both mARC proteins in the outer membrane, demonstrating the exposure of the C-terminal catalytic domain toward the cytosol.…”

Section: Discussionsupporting

confidence: 91%

“…Different views on the subcellular localization of mARC1 have been reported, localizing mARC1 to the outer or inner membrane of mitochondria (9,10).…”

Section: Discussionmentioning

confidence: 99%

“…Initially, mARC2 was isolated from outer mitochondrial membranes, and consistently, its localization was later confirmed within mitochondria (8,9). However, the exact localization to one of the four mitochondrial subcompartments has not been unambiguously addressed so far, as the evidence in the literature is contradictory in respect to the submitochondrial localization (5,9,10).…”

mentioning

confidence: 99%

“…However, the exact localization to one of the four mitochondrial subcompartments has not been unambiguously addressed so far, as the evidence in the literature is contradictory in respect to the submitochondrial localization (5,9,10). In addition, the subcellular localization of mARC1 has remained completely unexplored.…”

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confidence: 99%

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The Mitochondrial Amidoxime-reducing Component (mARC1) Is a Novel Signal-anchored Protein of the Outer Mitochondrial Membrane

Klein

Busch

Potting

et al. 2012

Journal of Biological Chemistry

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Background: mARC1 is a novel molybdenum enzyme functioning in pro-drug metabolism with unknown subcellular localization. Results: mARC1 localizes to the outer mitochondrial membrane with its catalytic domain facing the cytosol. Import is dependent on two N-terminal motifs (mitochondrial targeting signal, transmembrane domain) resulting in high oligomeric complexes. Conclusion: mARC1 is a novel signal-anchored protein of the outer mitochondrial membrane. Significance: We identify mARC protein maturation.

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Section: Discussionsupporting

confidence: 91%

“…Different views on the subcellular localization of mARC1 have been reported, localizing mARC1 to the outer or inner membrane of mitochondria (9,10).…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The Mitochondrial Amidoxime-reducing Component (mARC1) Is a Novel Signal-anchored Protein of the Outer Mitochondrial Membrane

Klein

Busch

Potting

et al. 2012

Journal of Biological Chemistry

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“…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).…”

Section: Introductionmentioning

confidence: 98%

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

et al. 2014

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Human molybdenum-containing enzyme mitochondrial amidoxime reducing component (mARC), cytochrome b 5 type B, and NADH cytochrome b 5 reductase form an N-reductive enzyme system that is capable of reducing N-hydroxylated compounds. Genetic variations are known, but their functional relevance is unclear. Our study aimed to investigate the incidence of nonsynonymous single nucleotide polymorphisms (SNPs) in the mARC genes in healthy Caucasian volunteers, to determine saturation of the protein variants with molybdenum cofactor (Moco), and to characterize the kinetic behavior of the protein variants by in vitro biotransformation studies. Genotype frequencies of six SNPs in the mARC genes (c.493A>G, c.560T>A, c.736T>A, and c.739G>C in MARC1; c.730G>A and c.735T>G in MARC2) were determined by pyrosequencing in a cohort of 340 healthy Caucasians. Protein variants were expressed in Escherichia coli. Saturation with Moco was determined by measurement of molybdenum by inductively coupled mass spectrometry. Steady state assays were performed with benzamidoxime. The six variants were of low frequency in this Caucasian population. Only one homozygous variant (c.493A; MARC1) was detected. All protein variants were able to bind Moco. Steady state assays showed statistically significant decreases of catalytic efficiency values for the mARC-2 wild type compared with the mARC-1 wild type (P < 0.05) and for two mARC-2 variants compared with the mARC-2 wild type (G244S, P < 0.05; C245W, P < 0.05). After simultaneous substitution of more than two amino acids in the mARC-1 protein, N-reductive activity was decreased 5-fold. One homozygous variant of MARC1 was detected in our sample. The encoded protein variant (A165T) showed no different kinetic parameters in the N-reduction of benzamidoxime.

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The molybdenum cofactor enzyme mARC: Moonlighting or promiscuous enzyme?

et al. 2017

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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.

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Amidoxime Reductase System Containing Cytochrome b5 Type B (CYB5B) and MOSC2 Is of Importance for Lipid Synthesis in Adipocyte Mitochondria

Cited by 55 publications

References 40 publications

The Mitochondrial Amidoxime-reducing Component (mARC1) Is a Novel Signal-anchored Protein of the Outer Mitochondrial Membrane

The Mitochondrial Amidoxime-reducing Component (mARC1) Is a Novel Signal-anchored Protein of the Outer Mitochondrial Membrane

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

The molybdenum cofactor enzyme mARC: Moonlighting or promiscuous enzyme?

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