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. 2018 Feb 6;24(8):1978-1987.
doi: 10.1002/chem.201705090. Epub 2018 Jan 4.

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

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Free PMC article

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

Natércia F Brás et al. Chemistry. .
Free PMC article

Abstract

Human α-phosphoglucomutase 1 (α-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, α-PGM represents a tempting pharmacological target for type 2 diabetes. Here, we provide the first theoretical study of the catalytic mechanism of human α-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 α-PGM.

Keywords: biosynthesis; enzymes; molecular dynamics; molecular modeling; phosphorylation.

Conflict of interest statement

Conflict of interest: The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Representation of the four domains of the human α-PGM enzyme. Domains I, II, III, and IV are colored in blue, red, yellow, and green, respectively. The catalytic Ser117 residue is shown in purple. A close-up of the quantum mechanical region and the Mg2+ ion is shown on the right-hand side.
Figure 2
Figure 2
Commitment probability for the first (black) and the second (gray) mechanistic step of human α-PGM. The first time point at the x axis corresponds to frame number 235 (for step 1) and frame number 200 (for step 2), therefore, a comparison can be made.
Figure 3
Figure 3
Twelve reactive trajectories projected on the plane of the bond-breaking and bond-forming distances for the first (left) and the second (right) mechanistic step.
Figure 4
Figure 4
Different committor distributions for the first (top) and second (bottom) mechanistic steps of human α-PGM.
Figure 5
Figure 5
Representation of the reactant, transition-state, and product structures of one representative reactive trajectory, considering the first mechanistic step. The QM region is depicted in ball-and-stick, whereas the neighboring residues and the Mg2+ ion are shown as lines and sphere, respectively.
Scheme 1
Scheme 1
Schematic representation of the reversible reaction catalyzed by α-PGM. The two steps studied in the present work are also indicated.

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