DFT investigation on the reaction mechanism catalyzed by α-phosphomannomutase1 in protonated/deprotonated states.

Congenital disorder of glycosylation type 1a (CDG-1a) which is a congenital disease, is caused by mutations in α-Phosphomannomutase1. The reaction mechanism of the α-phosphomannomutase1 enzyme has been investigated by means of density functional theory using the hybrid functional B3LYP. The α-phosphomannomutase1 catalyzes the interconversion of the α-D-mannose 1-phosphate to D-mannose 6-phosphate via a mannose-1,6-(bis) phosphate intermediate. The quantum chemical models, which were chosen in protonated/deprotonated states models, were built on the basis of the docking result. The process of the phosphoryl group transferred from Asp19 to the mannose 6-phosphate is in different steps in the two states, but are both coupled with the protons transfer. Our computational results support the hypothesis that the Asp19 as a nucleophile plays an important role in the α-phosphomannomutase1 biology function, and indicate Gln62 could help to stabilize the phosphoryl group and the structure of the substrate. In addition, we can conjecture that the deprotonated state is more suitable for product release.