{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMethylmalonyl‐CoA mutase (MMUT), the mitochondrial enzyme encoded by the MUT gene, is central to propionate metabolism through its catalytic conversion of methylmalonyl‐CoA to succinyl‐CoA. This reaction requires the cofactor adenosylcobalamin (AdoCbl), which is synthesized and delivered through a complex intracellular pathway. Defects in MMUT or impairments in cofactor assembly result in methylmalonic acidurias, in which accumulation of methylmalonic acid disturbs multiple organ systems and metabolic homeostasis."}, {"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": "\nMMUT’s proper function is maintained not only by its catalytic machinery but also via a network of protein–protein interactions and structural elements that ensure cofactor binding, enzyme stability, and resistance to inactivation during turnover. Accessory GTPases such as MMAA (the human homologue of bacterial MeaB) play a protective and reparative role, promoting the assembly of AdoCbl into MMUT and reactivating enzyme function when the cofactor becomes oxidized or damaged. Structural studies have pinpointed conserved residues—such as a key glutamate that modulates cofactor labilization—and have provided insight into how missense, frameshift, splice‐site, and truncation mutations disrupt MMUT’s conformation and activity. These findings underscore that the enzyme’s catalytic efficiency and protein stability are tightly linked to its three‐dimensional structure and the fidelity of cofactor incorporation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurthermore, detailed genotype–phenotype analyses have linked specific MMUT mutations to variations in disease severity, treatment response, and clinical outcome. Both chemical chaperone strategies and gene/mRNA‐replacement approaches are under investigation as potential treatments that aim to restore MMUT activity in affected patients. In parallel, cell‐ and animal‐based models have provided evidence that targeting MMUT dysfunction—either by stabilizing its structure with accessory proteins such as MMAA or by bypassing the metabolic block through advanced therapeutic modalities—may ameliorate the multisystem manifestations of methylmalonic acidemia. These insights are critical for developing tailored intervention strategies and for improving the long‐term prognosis of patients with MMUT deficiency."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "38"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Friederike Hörster, Matthias R Baumgartner, Caroline Viardot, et al. 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