Mechanistic Origins of Selective Aromatic Amino Acid Oxidation by Mn-Doped TiO2 Nanozymes

Metal oxide nanozymes are emerging as robust redox catalysts, yet the molecular basis of their substrate selectivity and reaction pathways remains poorly understood. Here, we identify 20 mol% Mn-doped TiO2 as a nanozyme platform that selectively oxidizes aromatic amino acids through a surface-confined pathway distinct from conventional diffusible radical-mediated oxidation. Using tyrosine, histidine, and phenylalanine together with 13C/15N isotopically labeled analogues, we combined high-resolution NMR spectroscopy, LC-MS/MS, X-ray photoelectron spectroscopy, and density functional theory calculations to resolve the underlying reaction mechanism. The data show that substrate oxidation proceeds through direct coordination to Mn-modified surface sites, followed by oxidative deamination, Cα–Cβ bond cleavage, and decarboxylation to yield the corresponding aldehydes: 4-hydroxybenzaldehyde, 1H-imidazole-4-carbaldehyde, and benzaldehyde. Isotopic labeling establishes that this transformation follows a Strecker-type degradation pathway localized at the nanozyme interface. XPS analysis demonstrates preservation of the Mn surface redox profile during catalysis, consistent with reversible Mn(III)/Mn(IV) cycling within the TiO2 lattice. Computational modeling further supports the thermodynamic feasibility of sequential proton-coupled electron-transfer steps leading to oxidative fragmentation. These findings establish that Mn doping programs TiO2 surfaces for selective dehydrogenase-like reactivity, through surface-directed interfacial oxidation, distinct from conventional diffusible radical-mediated pathways. The results provide a framework for rationally engineering metal oxide nanozymes with enzyme-like selectivity for targeted biomolecular transformations.