{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nCoproporphyrinogen oxidase (CPOX) is a pivotal enzyme in heme biosynthesis that catalyzes the two‐step oxidative decarboxylation of coproporphyrinogen III into protoporphyrinogen IX. Structural studies of human CPOX have revealed an unusual tertiary fold featuring a flat seven‐stranded β‐sheet surrounded by α‐helices and a dimeric organization that appears central to its function. Key active‐site residues have been identified—such as Ser‐244, His‐258, Asn‐260, Arg‐262, Asp‐282, and Arg‐332—which appear to mediate substrate binding and decarboxylation without metal ions or additional cofactors. Studies using substrate analogues further support a model in which the enzyme’s active site is built around a central tunnel used for substrate accommodation and processing."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its biochemical function, alterations in the CPOX gene are directly linked to several porphyric disorders. Mutations that reduce the enzyme’s activity—by disturbing key residues involved in catalysis or by impairing dimer formation—lead to a partial deficiency in CPOX and can manifest clinically as hereditary coproporphyria (HCP) or its variant, harderoporphyria. Investigations have identified both novel and recurrent missense and deletion mutations that modify enzyme kinetics and substrate affinity, thereby contributing to variable disease penetrance and distinct clinical phenotypes. Some studies further suggest that differences in the expression of the wild‐type allele might modulate the clinical severity in porphyrias caused by CPOX mutations, underscoring the importance of both mutation type and genetic background in disease expression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurthermore, a specific genetic polymorphism in CPOX, designated CPOX4 (a change in exon 4), has been implicated in modifying the neurotoxic effects of mercury exposure. In both adults and children, individuals carrying the CPOX4 variant exhibit altered urinary porphyrin excretion and are more susceptible to mercury-induced neurobehavioral deficits. The interaction between mercury exposure and this polymorphism suggests that even subtle changes in CPOX function can have significant downstream effects on both heme biosynthesis and neurological outcomes, with emerging evidence of sex-specific differences in mercury sensitivity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Dong-Sun Lee, Eva Flachsová, Michaela Bodnárová, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural basis of hereditary coproporphyria."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0506557102"}], "href": "https://doi.org/10.1073/pnas.0506557102"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16176984"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16176984"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Nathalie Colloc'h, Jean-Paul Mornon, Jean-Michael Camadro "}, {"type": "b", "children": [{"type": "t", "text": "Towards a new T-fold protein?: the coproporphyrinogen III oxidase sequence matches many structural features from urate oxidase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0014-5793(02)03123-x"}], "href": "https://doi.org/10.1016/s0014-5793(02"}, {"type": "t", "text": "03123-x) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12208494"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12208494"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Timothy D Lash, Teresa R Lamm, J Andy Schaber, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Normal and abnormal heme biosynthesis. Part 7. Synthesis and metabolism of coproporphyrinogen-III analogues with acetate or butyrate side chains on rings C and D. Development of a modified model for the active site of coproporphyrinogen oxidase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Bioorg Med Chem (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bmc.2010.12.053"}], "href": "https://doi.org/10.1016/j.bmc.2010.12.053"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21277781"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21277781"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Christopher L Cooper, Timothy D Lash, Marjorie A Jones "}, {"type": "b", "children": [{"type": "t", "text": "Kinetic evaluation of human cloned coproporphyrinogen oxidase using a ring isomer of the natural substrate."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Med Sci Monit (2005)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16258391"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16258391"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Laurent Gouya, Hervé Puy, Anne-Marie Robreau, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Modulation of penetrance by the wild-type allele in dominantly inherited erythropoietic protoporphyria and acute hepatic porphyrias."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Genet (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00439-003-1059-5"}], "href": "https://doi.org/10.1007/s00439-003-1059-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14669009"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14669009"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Caroline Schmitt, Laurent Gouya, Eva Malonova, et al. 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