An efficient and stable ascorbate/O 2 ‑driven route for L‑DOPA synthesis by heme‑dependent tyrosine hydroxylase
An efficient and stable ascorbate/O 2 ‑driven route for L‑DOPA synthesis by heme‑dependent tyrosine hydroxylase
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Original abstract
L-DOPA is a key therapeutic agent for Parkinson’s disease, with growing demand due to global population aging. Here we report that heme-dependent tyrosine hydroxylase (TyrH) can utilize an ascorbate/O 2 system—as an alternative to H 2 O 2 —to synthesize L-DOPA with markedly enhanced operational stability. While exogenous H 2 O 2 rapidly inactivates TyrH within minutes, sodium ascorbate (NaAsc) enables sustained catalysis for up to 24 h, surpassing the H 2 O 2 -driven yield after only 30 min. UV-vis spectroscopy confirms that H 2 O 2 readily degrades the heme center, whereas the heme remains intact in the presence of NaAsc. QM/MM simulations reveal that in situ generated H 2 O 2 leads to the active species of Compound I for tyrosine hydroxylation. Through systematic optimization, we establish efficient reaction conditions (40 µM TyrH, 1 mM L-Tyr, 100 mM NaAsc, pH 8.5, 40 °C), achieving >95% conversion of L-Tyr to L-DOPA within 2 h. This work not only provides a robust and sustainable biocatalytic route for L-DOPA production but also highlights the broader applicability of the ascorbate/O 2 pathway in heme-enzyme catalysis.