Mechanistic Insights on Human Phosphoglucomutase Revealed by Transition Path Sampling and Molecular Dynamics Calculations.

ABSTRACT: Human ?-phosphoglucomutase?1 (?-PGM) catalyzes the isomerization of glucose-1-phosphate into glucose-6-phosphate (G6P) through two sequential phosphoryl transfer steps with a glucose-1,6-bisphosphate (G16P) intermediate. Given that the release of G6P in the gluconeogenesis raises the glucose output levels, ?-PGM represents a tempting pharmacological target for type?2 diabetes. Here, we provide the first theoretical study of the catalytic mechanism of human ?-PGM. We performed transition-path sampling simulations to unveil the atomic details of the two catalytic chemical steps, which could be key for developing transition state (TS) analogue molecules with inhibitory properties. Our calculations revealed that both steps proceed through a concerted SN 2-like mechanism, with a loose metaphosphate-like TS. Even though experimental data suggests that the two steps are identical, we observed noticeable differences: 1)?the transition state ensemble has a well-defined TS region and a late TS for the second step, and 2)?larger coordinated protein motions are required to reach the TS of the second step. We have identified key residues (Arg23, Ser117, His118, Lys389), and the Mg2+ ion that contribute in different ways to the reaction coordinate. Accelerated molecular dynamics simulations suggest that the G16P intermediate may reorient without leaving the enzymatic binding pocket, through significant conformational rearrangements of the G16P and of specific loop regions of the human ?-PGM.

SUBMITTER: Bras NF 

PROVIDER: S-EPMC5801119 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature