The Catalytic Mechanism of Decarboxylation of L‐DOPA to Dopamine by <i>Papaver somniferum</i> Aromatic Amino Acid Decarboxylase – A Computational Study

Abstract Morphine and codeine are essential medicines isolated from the opium poppy, whose biosynthesis is limited by the plant's L‐DOPA decarboxylase activity. In the present study, we use molecular dynamics and hybrid quantum mechanics/ molecular mechanics calculations to clarify the L‐DOPA decarboxylase chemical mechanism of decarboxylation and quinonoid intermediate protonation. In addition, the contribution of residues in the periphery of the active site to the rate‐limiting decarboxylation barrier was determined to guide future experimental mutagenesis aimed at increasing the catalytic activity of the aromatic amino acid decarboxylase enzyme, a fundamental step for the opiumpoppy‐free production of BIAs. Our calculations indicate that the decarboxylation barrier is higher in conformations in which the interaction between Tyr350B and the carboxylate leaving group is formed. Furthermore, the barrier for the protonation of the quinonoid intermediate by Tyr350B is predicted to be lower than the decarboxylation and dependent on His205A protonation by the bulk solvent. Residues Glu171, Asp270, Asp313 and Arg482 were identified as possible candidates for rate‐enhancing mutations of P. somniferum aromatic amino acid decarboxylase.