{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSulfite oxidase (SUOX) is a critical molybdohemoprotein that catalyzes the oxidation of the toxic metabolite sulfite to sulfate, thereby detoxifying sulfite and enabling proper sulfur‐amino acid metabolism. Structural and kinetic studies show that SUOX contains a molybdenum cofactor in one domain and a cytochrome b₅ domain in another, with efficient intramolecular electron transfer between these domains being essential for rapid catalysis. Specific conserved residues (for example, Tyr343 and Arg160) and a flexible polypeptide tether facilitate substrate binding and electron shuttling, while spectroscopic and crystallographic analyses have elucidated distinct coordination modes and even secondary nitrite reductase activity under low oxygen conditions. These mechanistic insights also underscore the importance of proper metal (molybdate/tungstate) insertion into the molybdopterin site for enzyme activity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDeficiencies in SUOX arising from pathogenic mutations lead to dramatic impairments in enzyme maturation, substrate binding, and intramolecular electron transfer. Such mutations—including novel frameshift and missense alterations that disrupt key residues or destabilize the dimeric structure—severely attenuate catalytic turnover, resulting in the accumulation of toxic sulfite and its derivatives. Clinically, these molecular defects manifest in isolated sulfite oxidase deficiency as early-onset seizures, profound developmental delays, and distinctive neuroimaging findings. Detailed genetic and kinetic analyses have established that these molecular perturbations are directly responsible for the devastating neurometabolic phenotype observed in affected patients."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its fundamental catalytic role, SUOX expression has been explored as a biomarker in various clinical contexts. Altered levels of SUOX have been correlated with tumor progression and aggressiveness in hepatocellular carcinoma, oral squamous cell carcinoma, prostate cancer, and pancreatic adenocarcinoma, suggesting that diminished SUOX expression may be linked to aberrant cellular differentiation and proliferation. Complementary studies of tissue‐specific expression further support a role for SUOX not only in metabolic detoxification but also as a potential diagnostic and prognostic indicator in cancer, offering avenues for enzyme‐substitution therapy in cases of inherent SUOX deficiency."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "22", "end_ref": "26"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Wen-Hann Tan, Florian S Eichler, Sadaf Hoda, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Sulfite Oxidase Catalyzes Single-Electron Transfer at Molybdenum Domain to Reduce Nitrite to Nitric Oxide."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Antioxid Redox Signal (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1089/ars.2013.5397"}], "href": "https://doi.org/10.1089/ars.2013.5397"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25314640"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25314640"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Heather L Wilson, K V Rajagopalan "}, {"type": "b", "children": [{"type": "t", "text": "The role of tyrosine 343 in substrate binding and catalysis by human sulfite oxidase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M314288200"}], "href": "https://doi.org/10.1074/jbc.M314288200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14729666"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14729666"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Changjian Feng, Heather L Wilson, John K Hurley, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Essential role of conserved arginine 160 in intramolecular electron transfer in human sulfite oxidase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochemistry (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/bi0350194"}], "href": "https://doi.org/10.1021/bi0350194"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14567685"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14567685"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Meina Neumann, Silke Leimkühler "}, {"type": "b", "children": [{"type": "t", "text": "Heavy metal ions inhibit molybdoenzyme activity by binding to the dithiolene moiety of molybdopterin in Escherichia coli."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS J (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1742-4658.2008.06694.x"}], "href": "https://doi.org/10.1111/j.1742-4658.2008.06694.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18959753"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18959753"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Andrei V Astashkin, Kayunta Johnson-Winters, Eric L Klein, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural studies of the molybdenum center of the pathogenic R160Q mutant of human sulfite oxidase by pulsed EPR spectroscopy and 17O and 33S labeling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Am Chem Soc (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/ja801406f"}], "href": "https://doi.org/10.1021/ja801406f"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18529001"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18529001"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Kayunta Johnson-Winters, Anna R Nordstrom, Safia Emesh, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Effects of interdomain tether length and flexibility on the kinetics of intramolecular electron transfer in human sulfite oxidase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochemistry (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/bi9020296"}], "href": "https://doi.org/10.1021/bi9020296"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20063894"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20063894"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Changjian Feng, Heather L Wilson, John K Hurley, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of conserved tyrosine 343 in intramolecular electron transfer in human sulfite oxidase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M210374200"}], "href": "https://doi.org/10.1074/jbc.M210374200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12424234"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12424234"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Abdel A Belaidi, Juliane Röper, Sita Arjune, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Oxygen reactivity of mammalian sulfite oxidase provides a concept for the treatment of sulfite oxidase deficiency."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BJ20140768"}], "href": "https://doi.org/10.1042/BJ20140768"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26171830"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26171830"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Asha Rajapakshe, Kayunta Johnson-Winters, Anna R Nordstrom, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Characterization of chloride-depleted human sulfite oxidase by electron paramagnetic resonance spectroscopy: experimental evidence for the role of anions in product release."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochemistry (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/bi902172n"}], "href": "https://doi.org/10.1021/bi902172n"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20491442"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20491442"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Michael J Rudolph, Jean L Johnson, K V Rajagopalan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The 1.2 A structure of the human sulfite oxidase cytochrome b(5) domain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Crystallogr D Biol Crystallogr (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1107/s0907444903009934"}], "href": "https://doi.org/10.1107/s0907444903009934"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12832761"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12832761"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Changjian Feng, Heather L Wilson, Gordon Tollin, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Impaired mitochondrial maturation of sulfite oxidase in a patient with severe sulfite oxidase deficiency."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddz109"}], "href": "https://doi.org/10.1093/hmg/ddz109"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31127934"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31127934"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Amanda C Davis, Matthew J Cornelison, Kimberly T Meyers, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Effects of mutating aromatic surface residues of the heme domain of human sulfite oxidase on its heme midpoint potential, intramolecular electron transfer, and steady-state kinetics."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dalton Trans (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1039/c2dt31508d"}], "href": "https://doi.org/10.1039/c2dt31508d"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22975842"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22975842"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "John H Enemark "}, {"type": "b", "children": [{"type": "t", "text": "Mechanistic complexities of sulfite oxidase: An enzyme with multiple domains, subunits, and cofactors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Inorg Biochem (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jinorgbio.2023.112312"}], "href": "https://doi.org/10.1016/j.jinorgbio.2023.112312"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37441922"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37441922"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Chen Hoffmann, Bruria Ben-Zeev, Yair Anikster, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Molybdenum cofactor and isolated sulphite oxidase deficiencies: Clinical and molecular spectrum among Egyptian patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Paediatr Neurol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ejpn.2016.05.011"}], "href": "https://doi.org/10.1016/j.ejpn.2016.05.011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27289259"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27289259"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Heather L Wilson, Sara R Wilkinson, K V Rajagopalan "}, {"type": "b", "children": [{"type": "t", "text": "The G473D mutation impairs dimerization and catalysis in human sulfite oxidase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochemistry (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/bi051609l"}], "href": "https://doi.org/10.1021/bi051609l"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16475804"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16475804"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Syuan-Yu Hong, Chien-Heng Lin "}, {"type": "b", "children": [{"type": "t", "text": "Epilepsy in sulfite oxidase deficiency and related disorders: insights from neuroimaging and genetics."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Epilepsy Behav (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.yebeh.2023.109246"}], "href": "https://doi.org/10.1016/j.yebeh.2023.109246"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37187015"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37187015"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Amanda C Davis, Kayunta Johnson-Winters, Anna R Arnold, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Kinetic results for mutations of conserved residues H304 and R309 of human sulfite oxidase point to mechanistic complexities."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Metallomics (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1039/c4mt00099d"}], "href": "https://doi.org/10.1039/c4mt00099d"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24968320"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24968320"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Mallory J Owen, Jerica Lenberg, Annette Feigenbaum, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Postmortem whole-genome sequencing on a dried blood spot identifies a novel homozygous SUOX variant causing isolated sulfite oxidase deficiency."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cold Spring Harb Mol Case Stud (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1101/mcs.a006091"}], "href": "https://doi.org/10.1101/mcs.a006091"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34117075"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34117075"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Guang-Zhi Jin, Wen-Long Yu, Hui Dong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SUOX is a promising diagnostic and prognostic biomarker for hepatocellular carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Hepatol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jhep.2013.04.028"}], "href": "https://doi.org/10.1016/j.jhep.2013.04.028"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23665285"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23665285"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Wee Hong Woo, Hongyuan Yang, Kim Ping Wong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sulphite oxidase gene expression in human brain and in other human and rat tissues."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0006-291x(03)00833-7"}], "href": "https://doi.org/10.1016/s0006-291x(03"}, {"type": "t", "text": "00833-7) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12763039"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12763039"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Yoshiki Naito, Jun Akiba, Yoshinao Kinjo, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "SUOX is negatively associated with multistep carcinogenesis and proliferation in oral squamous cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Med Mol Morphol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00795-017-0177-4"}], "href": "https://doi.org/10.1007/s00795-017-0177-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29280012"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29280012"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Hirofumi Kurose, Yoshiki Naito, Jun Akiba, et al. 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