Abstract
Recent studies have identified phosphoglucomutase 1 (PGM1) deficiency as an inherited metabolic disorder in humans. PGM1 deficiency is classified as both a muscle glycogenosis (type XIV) and a congenital disorder of glycosylation of types I and II. Affected patients show multiple disease phenotypes, reflecting the central role of the enzyme in glucose homeostasis, where it catalyzes the interconversion of glucose 1-phosphate and glucose 6-phosphate. The influence of PGM1 deficiency on protein glycosylation patterns is also widespread, affecting both biosynthesis and processing of glycans and their precursors. To date, 21 different mutations involved in PGM1 deficiency have been identified, including 13 missense mutations resulting in single amino acid changes. Growing clinical interest in PGM1 deficiency prompts a review of the molecular context of these mutations in the three-dimensional structure of the protein. Here the known crystal structure of PGM from rabbit (97 % sequence identity to human) is used to analyze the mutations associated with disease and find that many map to regions with clear significance to enzyme function. In particular, amino acids in and around the active site cleft are frequently involved, including regions responsible for catalysis, binding of the metal ion required for activity, and interactions with the phosphosugar substrate. Several of the known mutations, however, are distant from the active site and appear to manifest their effects indirectly. An understanding of how the different mutations that cause PGM1 deficiency affect enzyme structure and function is foundational to providing clinical prognosis and the development of effective treatment strategies.
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Acknowledgments
I thank Charlotte Phillips and several helpful reviewers for comments on the manuscript. This work was supported by a grant from the National Science Foundation (MCB-0918389).
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Communicated by: Eva Morava
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Table S1
Summary of PGM1 deficiency mutants and their clinical phenotypes. (GIF 856 kb)
Fig. S1
Superposition of the 3D structure of rabbit PGM (light orange; PDB ID:3pmg), parafusin from P. tetraurelia (pink; PDB ID:1kfi), S. typhimurium PGM (light blue; PDB ID:3na5), and P. aeruginosa PMM/PGM (light green; PDB ID:1 k35). Note the high structural similarity, especially around the central active site cleft. Domain 4 (on right) shows more variability due to its mobility relative to the rest of the enzyme. (GIF 3503 kb)
Fig. S2
Amino acid sequence alignments of the proteins used in our structural analyses, all members of the α-D-phosphexomutase superfamily: rabbit PGM (UniProtKB P00949), parafusin from P. tetraurelia (UniProtKB P47244), S. typhimurium PGM (UniProtKB Q8ZQW9), and P. aeruginosa PMM/PGM (UniProtKB P26276). Residues involved in key regions (i-iv) of the active site (see text) are highlighted by orange shading. Overall amino acid sequence identities between rabbit PGM and the other proteins are: parafusin – 54 %; S. typhimurium PGM – 25 %; and P. aeruginosa PMM/PGM – 22 %. Residues involved in missense mutations associated with human PGM1 deficiency are indicated below brown triangles; residues that are known functional polymorphic variants of human PGM1 are indicated below green triangles. See also Fig. 2. (GIF 2094 kb)
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Beamer, L.J. Mutations in hereditary phosphoglucomutase 1 deficiency map to key regions of enzyme structure and function. J Inherit Metab Dis 38, 243–256 (2015). https://doi.org/10.1007/s10545-014-9757-9
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DOI: https://doi.org/10.1007/s10545-014-9757-9