Theoretical model for pyruvoyl-dependent enzymatic decarboxylation of alpha-amino acids

The active site of histidine decarboxylase (HDC) has been modeled with both ab initio (MP2/6-31G(d)) and DFT (BH&HLYP/6-311G(d,p)) calculations. The results clearly point out the role of zwitterionic transition structures and the importance of hydrogen bonding interactions in enzymatic decarboxylation. A comparison between the gas-phase decarboxylation of aminoformylacetic acid (H(C=O)CH(NH2)COOH) and the corresponding process in solution according to the supermolecule model approach with six water molecules is provided. This study analyzes the role of the proton distribution in lowering the reaction barrier in an intermediate Schiff base (H2C=NCH2COOH) and its transition structure for decarboxylation (Delta E-not subset of = -29.8 kcal mol(-1) at the MP2/6-31G(d) level of theory). Electronic features displayed by the intermediate imine are analyzed by making use of models of increased complexity. The iminium ion functionality has been established to be the dominant factor in lowering the barrier for the decarboxylation of the alpha-amino acids through Coulombic stabilization of the developing negative charge on the alpha-carbon and delocalization of the positive charge induced by proton transfer to the imine nitrogen along the reaction coordinate. Further extension of the model imine by an amide group (H2N(C=O)CH=NCH2COOH) lowers the barrier height by an additional 6.7 kcal mol(-1). A net transfer of electron density to the amide functionality in the transition state is not in evidence, The stabilizing influence on the barrier height of a hydrogen bonding network with formic acid and a model peptide residue (H(C=O)NHCH2CHO) is estimated to be 3.1 kcal mol(-1) at the BH&HLYP/6-311G(d,p) level.