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Structural and functional insights into aromatic amino acid decarboxylase deficiency variants producing an α-synuclein-targeting L-Dopa–pyridoxal 5′-phosphate cyclic adduct
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DOI：10.1016/j.ijbiomac.2026.153968.png)
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Abstract
En 中文
The inherent reactivity of free- or enzyme-linked pyridoxal 5′-phosphate (PLP) in the presence of catechol compounds with an aminic group is known and leads, after the formation of a Schiff base, to an irreversible cyclic adduct, called the Pictet-Spengler condensation product. In PLP-dependent aromatic amino acid decarboxylase (AADC), the protein scaffold protects PLP, preventing its leakage as a cyclic adduct complexed with the L-Dopa substrate. Here, we demonstrate that a group of AADC deficiency enzyme variants can undergo this unproductive reaction at a high rate. By using computational modeling, spectroscopic and functional studies with twelve pathogenic variants, we uncovered the basis of the variants' ability to synthesize this adduct. Since the metabolic conditions present in patients (high PLP amount as medical treatment and high L-Dopa concentrations as a consequence of enzyme impairment) may trigger Pictet-Spengler adduct synthesis, we modeled the possible oxidative effects played by this compound on α-synuclein (Syn) in solution and in neuroblastoma SH-SY5Y cells, given the known sensitivity of this protein to dopamine or dopa-related compounds. By multiple experimental approaches including chromatographic analysis, colorimetric assays, native mass spectrometry, dynamic light scattering and isothermal titration calorimetry, transmission electron microscopy, as well as cytotoxicity assays, we determined that the Pictet-Spengler adduct is not toxic to cells, exhibits a dose dependent inhibition of Syn fibrillation, and promotes Syn oxidation. These observations suggest that the AADC pathogenic variants undergoing Pictet-Spengler condensation could synthesize the biologically active adduct enhancing oxidative stress in neuronal cells, thereby contributing to the worsening of the phenotype.
Keywords:
Aromatic amino acid decarboxylase deficiency
Pictet-Spengler adduct
Α-Synuclein
Pyridoxal 5′-phosphate
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