{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMannose phosphate isomerase (MPI) serves as a pivotal enzymatic regulator that interconverts mannose‐6‐phosphate and fructose‐6‐phosphate, a reaction central to multiple metabolic pathways. Structural and mechanistic analyses reveal that MPI functions via a zinc‐dependent hydride transfer mechanism, with key active‐site residues orchestrating ligand binding and catalysis. These insights, derived from homology modeling and molecular docking studies, establish the molecular basis for substrate conversion and potential avenues for targeted modulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n\nIn the context of glycosylation disorders, MPI deficiency is implicated in congenital disorders of glycosylation (CDG), where impaired conversion of mannose‐6‐phosphate leads to incomplete glycosylation and clinical pathology. In CDG-Ib patients, mannose supplementation effectively bypasses the deficiency, whereas in CDG-Ia, excess MPI activity catabolizes mannose‐6‐phosphate. Inhibiting MPI has therefore been proposed to divert substrate toward glycosylation in patients with residual phosphomannomutase activity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n\nMPI additionally plays an essential role in sustaining Warburg metabolism. In both zebrafish embryos and mammalian cells, loss of MPI disrupts glycolysis, leads to accumulation of fructose‐6‐phosphate, and activates the hexosamine biosynthetic pathway. This metabolic imbalance promotes p53 stabilization and cell death, underscoring MPI’s critical function in maintaining rapid glycolytic flux in proliferative settings."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n\nDown-regulation of MPI has also been linked to liver fibrosis. Transcriptomic analyses in chronic liver diseases reveal that reduced MPI expression correlates with the severity of fibrosis, with MPI loss promoting hepatic stellate cell activation. Importantly, mannose supplementation shows promise in attenuating fibrogenic responses in diverse experimental models, suggesting a therapeutic role for manipulating mannose metabolism."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n\nFurthermore, MPI’s activity influences tumor cell metabolism and the tumor microenvironment. In head and neck squamous carcinoma, lower MPI expression is associated with enhanced survival and altered immune cell infiltration. The accumulation of mannose-6-phosphate in conditions of low MPI activity not only induces tumor cell apoptosis but also modulates immune responses, highlighting MPI as a potential target in cancer therapeutics."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n\nFinally, biotechnological advancements have leveraged MPI’s properties for industrial applications. The immobilization of MPI on Ni2+ charged pyridine-derived particles has been demonstrated to enhance enzyme activity, thermostability, and reusability. This approach integrates enzyme purification with catalysis, underscoring MPI’s utility in streamlining industrial biocatalytic processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jingfa Xiao, Zongru Guo, Yanshen Guo, et al. 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