{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:12:34Z","timestamp":1790727154833,"version":"4.1.0"},"reference-count":44,"publisher":"National Academy of Sciences","issue":"12","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2007,3,20]]},"abstract":"<jats:p>\n                    Porphyria cutanea tarda (PCT), the most common form of porphyria in humans, is due to reduced activity of uroporphyrinogen decarboxylase (URO-D) in the liver. Previous studies have demonstrated that protein levels of URO-D do not change when catalytic activity is reduced, suggesting that an inhibitor of URO-D is generated in hepatocytes. Here, we describe the identification and characterization of an inhibitor of URO-D in liver cytosolic extracts from two murine models of PCT: wild-type mice treated with iron, \u03b4-aminolevulinic acid, and polychlorinated biphenyls; and mice with one null allele of\n                    <jats:italic>Uro-d<\/jats:italic>\n                    and two null alleles of the hemochromatosis gene (\n                    <jats:italic>Uro-d<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    ,\n                    <jats:italic>Hfe<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ) that develop PCT with no treatments. In both models, we identified an inhibitor of recombinant human URO-D (rhURO-D). The inhibitor was characterized by solid-phase extraction, chromatography, UV-visible spectroscopy, and mass spectroscopy and proved to be uroporphomethene, a compound in which one bridge carbon in the uroporphyrinogen macrocycle is oxidized. We synthesized uroporphomethene by photooxidation of enzymatically generated uroporphyrinogen I or III. Both uroporphomethenes inhibited rhURO-D, but the III isomer porphomethene was a more potent inhibitor. Finally, we detected an inhibitor of rhURO-D in cytosolic extracts of liver biopsy samples of patients with PCT. These studies define the mechanism underlying clinical expression of the PCT phenotype, namely oxidation of uroporphyrinogen to uroporphomethene, a competitive inhibitor of URO-D. The oxidation reaction is iron-dependent.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0700547104","type":"journal-article","created":{"date-parts":[[2007,3,9]],"date-time":"2007-03-09T20:52:21Z","timestamp":1173473541000},"page":"5079-5084","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":135,"title":["A porphomethene inhibitor of uroporphyrinogen decarboxylase causes porphyria cutanea tarda"],"prefix":"10.1073","volume":"104","author":[{"given":"John D.","family":"Phillips","sequence":"first","affiliation":[{"name":"Departments of *Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hector A.","family":"Bergonia","sequence":"additional","affiliation":[{"name":"Departments of *Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher A.","family":"Reilly","sequence":"additional","affiliation":[{"name":"Pharmacology and Toxicology, University of Utah School of 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