research communications
Phosphoglucomutase 1 (PGM1) plays a central role in glucose homeostasis in human cells. Missense variants of this enzyme cause an inborn error of metabolism, which is categorized as a congenital disorder of glycosylation. Here, two disease-related variants of PGM1, T337M and G391V, which are both located in domain 3 of the four-domain protein, were characterized via X-ray crystallography and biochemical assays. The studies show multiple impacts resulting from these dysfunctional variants, including both short- and long-range structural perturbations. In the T337M variant these are limited to a small shift in an active-site loop, consistent with reduced enzyme activity. In contrast, the G391V variant produces a cascade of structural perturbations, including displacement of both the catalytic phosphoserine and metal-binding loops. This work reinforces several themes that were found in prior studies of dysfunctional PGM1 variants, including increased structural flexibility and the outsized impacts of mutations affecting interdomain interfaces. The molecular mechanisms of PGM1 variants have implications for newly described inherited disorders of related enzymes.
Keywords: missense variants; enzymes; inherited diseases; X-ray crystallography; congenital disorders of glycosylation; structural perturbation; human phosphoglucomutase 1.
Supporting information
Portable Document Format (PDF) file https://doi.org/10.1107/S2053230X22004174/us5143sup1.pdf |
PDB references: phosphoglucomutase 1, G391V variant, 7s77; T337M variant, 7s0w