Surface Plasmon Resonance Identifies High-Affinity Binding of l -DOPA to Siderocalin/Lipocalin-2 through Iron–Siderophore Action: Implications for Parkinson’s Disease Treatment

l -3,4-Dihydroxyphenylalanine ( l -DOPA), the dopamine precursor, remains the frontline treatment for Parkinson’s disease (PD). With the treatment progress, l -DOPA efficacy decreases, necessitating higher and more frequent doses, with higher risks of dyskinesia. l -DOPA chelates iron through its catechol group, forming the l -DOPA:Fe complex; however, the fate of this complex is unknown. Catechol siderophore-like compounds are known to bind siderocalin (Scn)/lipocalin-2 to form stable siderophore:Fe:Scn complexes. Scn is upregulated in PD patients’ substantia nigra and may play a role in PD pathophysiology. Therefore, in this study, we used the surface plasmon resonance (SPR) technique to examine the binding properties of l -DOPA to Scn. We found that l -DOPA formed a stable complex with Scn in the presence of Fe 3+ . Our analysis of the binding properties of l -DOPA precursors and metabolites indicates that the catechol group is necessary but not sufficient to form a stable complex with Scn. Finally, the affinity constant ( K d ) of DOPA:Fe 3+ binding with Scn (0.8 μM) was lower than l -DOPA plasma peak concentrations in l -DOPA preparations in the past six decades. Our results speculate a significant role for the l -DOPA–Scn complex in the decreased bioavailability of l -DOPA with the progress of PD.