{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMTARC2 is one of two human mitochondrial amidoxime reducing components that belongs to a novel family of molybdenum-containing enzymes. Unlike classical dimeric molybdenum enzymes, MTARC2 is active as a monomer and functions in concert with electron transport proteins—namely, cytochrome b5 and NADH-cytochrome b5 reductase—to mediate redox reactions within the mitochondria. This arrangement places MTARC2 at a critical intersection between mitochondrial metabolism and cellular detoxification processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nA pivotal function of MTARC2 is its role in nitrogen‐oxygen redox chemistry. It catalyzes the reduction of nitrite to nitric oxide (NO), a process that is enhanced under more acidic (hypoxic) conditions. In addition, MTARC2 (together with its isoform MTARC1) markedly increases the conversion of N(ω)-hydroxy-L-arginine (NOHA)—an intermediate in nitric oxide synthesis—thereby contributing to the steady generation of NO. This activity suggests that MTARC2 may serve as an alternative or supportive pathway for NO production under conditions where conventional nitric oxide synthases are compromised."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in NO metabolism, MTARC2 is integral to the reductive activation of N-hydroxylated prodrugs and the inactivation of toxic, mutagenic N-hydroxylated compounds. Through its N-reductive enzymatic activity, MTARC2 converts these potentially harmful intermediates—including modified nucleobases and nucleosides—into their canonical forms, thereby reducing cellular stress and mitigating apoptotic signals. This detoxification mechanism underscores the enzyme’s importance in maintaining the fidelity of DNA precursor pools and safeguarding cellular health."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nInvestigations into the structural and mechanistic attributes of MTARC2 have revealed that its catalytic center is defined by a unique coordination of its molybdenum cofactor. Studies employing electron paramagnetic resonance spectroscopy and density functional theory have demonstrated that the active site incorporates an exchangeable hydroxyl ligand along with a nonexchangeable, protein-derived equatorial ligand. These insights not only differentiate MTARC2 from other molybdenum enzymes but also clarify how its specialized architecture imparts distinct reactivity and substrate specificity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nEmerging evidence further extends the functional repertoire of MTARC2 beyond enzymatic catalysis. A recent study has characterized a circular RNA derived from the MTARC2 gene (circ‐MARC2), which acts as a molecular sponge for miR‐335-5p. By modulating the miR‐335-5p/TRPM7 regulatory axis, circ‐MARC2 appears to influence cellular responses during myocardial ischemia-reperfusion injury, thereby linking MTARC2 to cardioprotective signaling pathways."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Bettina Wahl, Debora Reichmann, Dimitri Niks, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Biochemical and spectroscopic characterization of the human mitochondrial amidoxime reducing components hmARC-1 and hmARC-2 suggests the existence of a new molybdenum enzyme family in eukaryotes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110.169532"}], "href": "https://doi.org/10.1074/jbc.M110.169532"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20861021"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20861021"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Courtney E Sparacino-Watkins, Jesús Tejero, Bin Sun, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nitrite reductase and nitric-oxide synthase activity of the mitochondrial molybdopterin enzymes mARC1 and mARC2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M114.555177"}], "href": "https://doi.org/10.1074/jbc.M114.555177"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24500710"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24500710"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Jürke Kotthaus, Bettina Wahl, Antje Havemeyer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Reduction of N(ω)-hydroxy-L-arginine by the mitochondrial amidoxime reducing component (mARC)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BJ20100960"}], "href": "https://doi.org/10.1042/BJ20100960"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21029045"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21029045"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Birte Plitzko, Gudrun Ott, Debora Reichmann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The involvement of mitochondrial amidoxime reducing components 1 and 2 and mitochondrial cytochrome b5 in N-reductive metabolism in human cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M113.474916"}], "href": "https://doi.org/10.1074/jbc.M113.474916"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23703616"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23703616"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Birte Plitzko, Antje Havemeyer, Thomas Kunze, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The pivotal role of the mitochondrial amidoxime reducing component 2 in protecting human cells against apoptotic effects of the base analog N6-hydroxylaminopurine."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M115.640052"}], "href": "https://doi.org/10.1074/jbc.M115.640052"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25713076"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25713076"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Gudrun Ott, Debora Reichmann, Cornelia Boerger, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Functional characterization of protein variants encoded by nonsynonymous single nucleotide polymorphisms in MARC1 and MARC2 in healthy Caucasians."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Drug Metab Dispos (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1124/dmd.113.055202"}], "href": "https://doi.org/10.1124/dmd.113.055202"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24423752"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24423752"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Alejandro Chamizo-Ampudia, Aurora Galvan, Emilio Fernandez, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Chlamydomonas reinhardtii molybdenum cofactor enzyme crARC has a Zn-dependent activity and protein partners similar to those of its human homologue."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eukaryot Cell (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/EC.05096-11"}], "href": "https://doi.org/10.1128/EC.05096-11"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21803866"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21803866"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Asha Rajapakshe, Andrei V Astashkin, Eric L Klein, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "CIRC-MARC2 SILENCING PROTECTS HUMAN CARDIOMYOCYTES FROM HYPOXIA/REOXYGENATION-INDUCED INJURY BY MODULATING MIR-335-5P/TRPM7 AXIS."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Shock (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/SHK.0000000000002244"}], "href": "https://doi.org/10.1097/SHK.0000000000002244"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38010085"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38010085"}]}]}]}