{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMTARC1 is a mitochondrial molybdenum‐dependent enzyme that functions as the catalytic unit in an electron transfer system. In multiple studies, it has been shown to reduce a variety of N‑hydroxylated substrates – including amidoximes used as prodrugs – and to catalyze the reduction of nitrite and nitric oxide intermediates such as NOHA. This capacity depends on its molybdenum cofactor and proper coordination at critical active‐site residues, with reaction rates that can be modulated by factors like pH. These biochemical activities highlight MTARC1’s role in both drug bioactivation and nitric oxide signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nStructurally, MTARC1 is anchored in the outer mitochondrial membrane with its catalytic domain exposed to the cytosol. Its activity is tightly linked to partner proteins such as cytochrome b5 (particularly the mitochondrial isoform) and NADH‐cytochrome b5 reductase that supply reducing equivalents. Although MTARC1 shares homology with other molybdenum enzymes, it behaves as a monomer and is assembled into large protein complexes. Detailed kinetic studies have further characterized how subtle changes—in particular in regions surrounding the catalytic site—can impact cofactor binding and electron transfer, thereby modulating overall enzyme performance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic studies have now established that common variants in the MTARC1 gene—most notably the p.Ala165Thr substitution—are associated with a reduced risk of liver diseases such as cirrhosis, non‐alcoholic fatty liver disease, and metabolic dysfunction–associated steatotic liver disease. Population‐based investigations and functional analyses in both human cells and preclinical models indicate that this variant decreases MTARC1 protein stability, leads to aberrant subcellular localization, and diminishes N‑reductive enzyme activity. In addition, outcomes related to circulating lipid profiles and liver inflammation have been favorably modulated by this variant in pediatric, adult, and bariatric populations, with further investigations in autoimmune and alcohol‐related liver disease underscoring the broader clinical impact. Collectively, these findings suggest that reduced MTARC1 function is protective, and that its modulation represents a promising target for therapeutic intervention."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Sanja Gruenewald, Bettina Wahl, Florian Bittner, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The fourth molybdenum containing enzyme mARC: cloning and involvement in the activation of N-hydroxylated prodrugs."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Med Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/jm8010417"}], "href": "https://doi.org/10.1021/jm8010417"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19053771"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19053771"}]}, {"type": "r", "ref": 2, "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": 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": "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": 5, "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": 6, "children": [{"type": "t", "text": "Julian M Klein, Jakob D Busch, Christoph Potting, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The mitochondrial amidoxime-reducing component (mARC1) is a novel signal-anchored protein of the outer mitochondrial membrane."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M112.419424"}], "href": "https://doi.org/10.1074/jbc.M112.419424"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23086957"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23086957"}]}, {"type": "r", "ref": 7, "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": 8, "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": 9, "children": [{"type": "t", "text": "Connor A Emdin, Mary E Haas, Amit V Khera, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Genet (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pgen.1008629"}], "href": "https://doi.org/10.1371/journal.pgen.1008629"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32282858"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32282858"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Hamish Innes, Stephan Buch, Sharon Hutchinson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genome-Wide Association Study for Alcohol-Related Cirrhosis Identifies Risk Loci in MARC1 and HNRNPUL1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gastroenterology (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1053/j.gastro.2020.06.014"}], "href": "https://doi.org/10.1053/j.gastro.2020.06.014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32561361"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32561361"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Carolin V Schneider, Kai Markus Schneider, Donna M Conlon, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A genome-first approach to mortality and metabolic phenotypes in "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "MTARC1"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " p.Ala165Thr (rs2642438) heterozygotes and homozygotes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Med (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.medj.2021.04.011"}], "href": "https://doi.org/10.1016/j.medj.2021.04.011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34258604"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34258604"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Maciej K Janik, Wiktor Smyk, Beata Kruk, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MARC1 p.A165T variant is associated with decreased markers of liver injury and enhanced antioxidant capacity in autoimmune hepatitis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-021-03521-3"}], "href": "https://doi.org/10.1038/s41598-021-03521-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34949757"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34949757"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Christian A Hudert, Leon A Adams, Anna Alisi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Variants in mitochondrial amidoxime reducing component 1 and hydroxysteroid 17-beta dehydrogenase 13 reduce severity of nonalcoholic fatty liver disease in children and suppress fibrotic pathways through distinct mechanisms."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hepatol Commun (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/hep4.1955"}], "href": "https://doi.org/10.1002/hep4.1955"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35411667"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35411667"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Berenice Rivera-Paredez, Diana I Aparicio-Bautista, Anna D Argoty-Pantoja, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association of "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "MARC1"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": ", "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "ADCY5,"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " and "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "BCO1"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " Variants with the Lipid Profile, Suggests an Additive Effect for Hypertriglyceridemia in Mexican Adult Men."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms231911815"}], "href": "https://doi.org/10.3390/ijms231911815"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36233117"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36233117"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Piotr Kalinowski, Wiktor Smyk, Małgorzata Nowosad, et al. "}, {"type": "b", "children": [{"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "MTARC1"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " and "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "HSD17B13"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " Variants Have Protective Effects on Non-Alcoholic Fatty Liver Disease in Patients Undergoing Bariatric Surgery."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms232415825"}], "href": "https://doi.org/10.3390/ijms232415825"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36555467"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36555467"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Mengyue Wu, Meng Tie, Liwei Hu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Fatty liver disease protective MTARC1 p.A165T variant reduces the protein stability of MTARC1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2024.149655"}], "href": "https://doi.org/10.1016/j.bbrc.2024.149655"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38340654"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38340654"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Tanmoy Dutta, Kavitha Sasidharan, Ester Ciociola, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mitochondrial amidoxime-reducing component 1 p.Ala165Thr increases protein degradation mediated by the proteasome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Liver Int (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/liv.15857"}], "href": "https://doi.org/10.1111/liv.15857"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38375985"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38375985"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Eriks Smagris, Lisa M Shihanian, Ivory J Mintah, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Divergent role of Mitochondrial Amidoxime Reducing Component 1 (MARC1) in human and mouse."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Genet (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pgen.1011179"}], "href": "https://doi.org/10.1371/journal.pgen.1011179"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38437227"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38437227"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Amanda K Jones, Besnik Bajrami, Morgan K Campbell, et al. "}, {"type": "b", "children": [{"type": "t", "text": "mARC1 in MASLD: Modulation of lipid accumulation in human hepatocytes and adipocytes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hepatol Commun (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/HC9.0000000000000365"}], "href": "https://doi.org/10.1097/HC9.0000000000000365"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38619429"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38619429"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Wangfang Hou, Christian Watson, Ted Cecconie, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Biochemical and functional characterization of the p.A165T missense variant of mitochondrial amidoxime-reducing component 1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jbc.2024.107353"}], "href": "https://doi.org/10.1016/j.jbc.2024.107353"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38723751"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38723751"}]}]}]}