Neurocognitive Disorders

Binding of L-DOPA With Siderocalin Through Iron-Siderophore: Implications for Parkinson Disease

Jessica Nye, PhD
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brain-illustration-parkinson-disease
Substantia nigra. Illustration showing a healthy substantia nigra in a human brain. The substantia nigra plays an important role in reward, addiction, and movement. Degeneration of this structure is characteristic of Parkinson’s disease.
L-DOPA is the frontline therapy for patients with PD, however, as the disease progresses, patients require higher and more frequent dosing. In order to better understand the binding affinity of L-DOPA and associated metabolites, binding affinity and surface plasmon resonance experiments were performed.

The progression of Parkinson disease (PD) may be associated with the bioavailability of L-3,4-dihydroxyphenylalanine (L-DOPA) and the L-DOPA-siderocalin (Scn) complex. These findings were published in ACS Chemical Neuroscience.

L-DOPA is the frontline therapy for patients with PD, however, as the disease progresses, patients require higher and more frequent dosing. In order to better understand the binding affinity of L-DOPA and associated metabolites, binding affinity and surface plasmon resonance experiments were performed.

For the first time, L-DOPA was observed to bind Scn by acting as an Fe3+ siderophore. This occurs by chelating Fe3+ and not Fe2+.

L-DOPA has been established to have Fe-chelating properties, so it is reasonable for L-DOPA to act as a siderophore. The change in resonance unit from baseline to ion injection (ΔRU) was ~16 for Scn bound with Fe3+ and ~5 for Fe2+. In the absence of metal ions, L-DOPA-Scn DRU was ~2, but in the presence of Fe3+ was 44 (P <.0001). The L-DOPA-Scn DRU in the presence of Fe2+ did not differ from Fe2+ alone (ΔRU, 5; P >.05).

The L-DOPA-Scn complex showed the highest affinity for Fe3+ compared with other metal ions.

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In assays which used L-DOPA metabolites, there was little evidence of binding affinity with Scn, indicating that the catechol structure is necessary for the L-DOPA-Scn interaction to occur.

The dose-response of the L-DOPA:Fe3+ binding to Scn was found to be 0.86±0.43 μM. This level of L-DOPA corresponds with the plasma concentrations of pharmacokinetics of L-DOPA therapeutics. However, it is reasonable to expect that not all L-DOPA binds with Fe3+ in vitro. In addition, Scn is able to bind with other iron-siderophore complexes which do not contain L-DOPA, likewise potentially decreasing its bioavailability in vitro.

This study was limited by its ex vivo approach, additional study is needed to confirm these binding interactions in PD.

The study authors concluded, “in summary, we show for the first time that L-DOPA acts as a siderophore that forms a stable complex with Scn upon chelating the iron cation. The potential role of the L-DOPA−Scn complex in PD and the treatment with L-DOPA warrants further in vivo experiments using animal models of the disease.”

Reference

Alhassen S, Senel M, Alachkar A. Surface plasmon resonance identifies high-affinity binding of L‑DOPA to siderocalin/lipocalin‑2 through iron−siderophore action: Implications for Parkinson’s disease treatment. ACS Chem Neurosci. 2022;13(1):158-165. doi:10.1021/acschemneuro.1c00693