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Computational modeling of tyrosine hydroxylase pathway for dopamine synthesis in nerve cells: effect of tetrahydrobiopterin deficiency and oxidative stress
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DOI：10.1007/s11571-026-10486-4.png)
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Abstract
En 中文
In neuronal dysfunction, there is a disruption of synthesis and release of neurotransmitters including dopamine. Oxidative stress is a major contributor to neuronal dysfunction. Oxidative stress affects tetrahydrobiopterin (BH4), an essential cofactor in the synthesis of several neurotransmitters such as dopamine and nitric oxide. BH4 supports the activity of enzyme tyrosine hydroxylase (TH) and initiates dopamine synthesis. Studies have reported contradictory results on neuronal dysfunction and disease progression following treatments to reduce oxidative stress and BH4 supplementation. In this study, we developed a computational model of TH biochemical pathway in dopaminergic nerve cells. Using this model, we quantitatively analyzed the impact of reduced BH4 synthesis and oxidative stress on L-dopa and dopamine synthesis. The base case concentration of L-dopa was 382.5 nM and cytosolic dopamine was 12.4 nM. The results showed a significant decrease in the concentrations of L-dopa and dopamine with reduction in BH4 synthesis. The presence of oxidative stress further exacerbated these decreases in concentration. The mechanistic analysis suggests that this computational model provides an initial framework for evaluating how BH4-related perturbations influence species concentrations in the TH biochemical pathway in dopaminergic nerve cells. Our findings indicate that under the simulated conditions, BH4 supplementation produced short-term changes in species concentrations and that sustained improvement in nerve cell dysfunction likely requires a multi-target approach that simultaneously enhances de novo BH4 synthesis and reduces cellular oxidative stress.
Keywords:
Tetrahydrobiopterin
Dopaminergic nerve cell
Computational biochemical pathway model
Mass-action kinetics model
Dopamine synthesis
Tyrosine hydroxylase
Oxidative stress
Superoxide
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