{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nUroporphyrinogen III synthase (UROS) is a key enzyme in heme biosynthesis that catalyzes the cyclization and D‐ring isomerization of hydroxymethylbilane into uroporphyrinogen III, the first cyclic tetrapyrrole required for the production of heme, chlorophyll, and corrin. Structural studies including high‐resolution NMR analyses and in silico docking have defined the active site residues and provided mechanistic insight into substrate binding and catalysis, thus clarifying how UROS avoids the formation of nonphysiologic porphyrin isomers."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nA wide spectrum of pathogenic UROS mutations underlies congenital erythropoietic porphyria (CEP). Numerous missense changes—some directly affecting residues implicated in substrate binding while others perturb the protein’s folding—lead to partial catalytic impairment, thermolability, and enhanced proteasome‐mediated degradation. A recurrent mutation, C73R, for example, accelerates irreversible unfolding and aggregation, resulting in markedly reduced intracellular levels despite its retained intrinsic activity. These findings, supported by computational and cell‐based studies as well as by clinical analyses in diverse populations, not only attest to the molecular heterogeneity of CEP but also suggest that stabilization of the mutant enzyme (via proteasome inhibitors or chemical chaperones) may offer a promising therapeutic approach."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to mutational defects, UROS expression and functional transcript processing contribute to disease severity. Studies in hepatic cells reveal that hypoxia can down‐regulate UROS mRNA—possibly through hypoxia‐inducible factor 1α—highlighting a coordinated regulatory mechanism among heme biosynthetic enzymes. Furthermore, aberrations in pre–mRNA splicing, such as mutations affecting branchpoint sequences that cause intron retention and generation of dysfunctional transcripts, further reduce the level of active enzyme in CEP patients."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Luis Cunha, Miklos Kuti, David F Bishop, et al. 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