{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n DNPEP is an aspartyl aminopeptidase with a strict preference for N‐terminal acidic amino acids that plays multiple roles in peptide and protein metabolism across diverse tissues. Structural studies have revealed that DNPEP assembles into a dodecameric complex harboring a binuclear zinc active site whose metal‐binding plasticity (including exchange with manganese) dictates both substrate access and specificity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Additional mutational analyses further emphasize the importance of key histidine residues in maintaining its catalytic efficiency and quaternary structure."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Functionally, DNPEP contributes to the regulation of the renin–angiotensin system by processing angiotensin peptides, thereby influencing blood pressure homeostasis. In addition to this classic role, DNPEP is emerging as a multifunctional player in disease pathophysiology. In breast cancer, for example, reduced DNPEP expression has been associated with enhanced cellular proliferation, migration, invasion, and stemness, while restoration of DNPEP levels suppresses these oncogenic properties; indeed, a PAK5–DNPEP–USP4 signaling axis has been implicated in promoting breast cancer progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the context of skeletal repair, DNPEP expression is modulated during bone healing; elevated levels of specific microRNAs targeting Dnpep are correlated with nonunion formation, suggesting that DNPEP may be required for proper callus development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, DNPEP interacts with the chloride/proton exchanger ClC‐5 in renal proximal tubule cells where it contributes to actin cytoskeletal stabilization and albumin endocytosis. Urinary DNPEP levels correlate with the severity of proteinuria, indicating its potential as a biomarker for renal dysfunction."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Expression studies in pancreatic islet cells have localized DNPEP primarily to α‐cells, with its association to lysosomal‐like structures and secretory granules indicating a role in post‐translational processing and hormone secretion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, a high‐throughput screening approach has identified several small‐molecule inhibitors of DNPEP, providing useful chemical tools to further delineate its enzymatic functions and potentially to modulate its activity in disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings underscore the multifunctional nature of DNPEP in regulating peptide processing, modulating cell signaling pathways, and maintaining tissue homeostasis in both physiological and pathological contexts.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Apirat Chaikuad, Ewa S Pilka, Antonio De Riso, et al. 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