Remolding laccase for whole-cell and in vivo modulation of dopamine signal
- Xiaoti Yang
- Shilong Fan
- Jing Liu
- Shuli Chen
- Wenjie Wu
- Xiling Chen
- Wenliang Ji
- Shuxin Li
- Yifei Xue
- Xinjie Sun
- Ming Wang
- Ji Liu
- Fei Wu
- Ping Yu
- Lanqun Mao
2025-10-22
Biocatalytic regulation of dopamine signals paves an effective and biocompatible way to modulate dopaminergic functions and disorders. Here, we report the remolding of bacterial laccase, catalyzing conversions of dopamine and O 2 to o -quinone and H 2 O, into a biocatalytic neuromodulator by reactive oxygen species–free dopamine catabolism. Given the poor activity of native laccase in the physiological context because of OH − inhibition of its geometrically constrained O 2 -reducing center, we designed a highly dynamic Ru-Cu binuclear center to counteract the inhibition effect. Structural and computational investigations unravel a self-adaptive catalytic mechanism by reversive Ru-Cu active site reconfiguration that lowers the kinetic barriers for O 2 -to-H 2 O conversion in neutral solution. The remolded laccase exhibits substantial enhancement of physiological activity (up to one order of magnitude) and improved catecholamine substrate specificity, enabling whole-cell down-regulation of vesicular dopamine and extracellular erasure of evoked dopamine signals in intact brains. Our work elucidates a picture of artificial metalloenzymes for neuromodulation through a rationalized neurotransmitter metabolism pathway.