Dopamine Metabolism as a Chemically Constrained Network: Structural Regulation, Redox Liability and Dopaminergic Vulnerability in Parkinson's Disease.

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Dopamine metabolism lies at the intersection of enzymatic catalysis, redox chemistry and cellular compartmentalisation, forming a tightly regulated network that sustains neurotransmission while limiting intrinsic chemical reactivity. In catecholaminergic neurons, dopamine is both an essential signalling molecule and a redox-active substrate prone to oxidation, aldehyde formation and quinone chemistry, requiring coordinated synthesis, storage, degradation and detoxification. Recent advances in structural biology and chemical enzymology have revealed detailed conformational regulation and specific protein interactions among key components of this system-including tyrosine hydroxylase, aromatic L-amino acid decarboxylase, monoamine oxidase and catechol-O-methyltransferase-while suggesting that their spatial organisation may contribute to the control of metabolic flux and exposure to reactive intermediates. Building on previous work on dopamine dyshomeostasis, oxidative stress and reactive metabolites, this Review addresses a less explored integrative question: how structural organisation, catalytic chemistry, intracellular compartmentalisation and redox control collectively influence neuronal resilience. Dopamine metabolism is therefore conceptualised as a chemically constrained and structurally integrated network in which cofactor dynamics, vesicular sequestration, enzyme interactions and redox buffering regulate metabolic flux while limiting reactive intermediates. Disruption of this network-through impaired compartmentalisation, cofactor imbalance, oxidative and nitrosative stress, or neuroinflammatory signalling-can shift dopamine toward electrophilic and oxidative toxicity, contributing to nigrostriatal vulnerability. Neuromelanin formation, reactive nitrogen species signalling and aldehyde accumulation further link dopamine metabolism to mitochondrial dysfunction and immune activation. This framework highlights limitations of therapies centred predominantly on dopamine replacement and supports mechanism-driven approaches aimed at restoring metabolic and redox homeostasis in Parkinson's disease.

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