Induced Structural Disorder as a Molecular Mechanism for Enzyme Dysfunction in Phosphoglucomutase 1 Deficiency

Area of Science:

• Biochemistry
• Structural Biology
• Metabolic Disorders

Background:

• Human phosphoglucomutase 1 (PGM1) is crucial for glucose homeostasis, linking glycolysis and gluconeogenesis.
• PGM1 deficiency, a glycogen storage disease and congenital disorder of glycosylation, results from mutations in the PGM1 enzyme.

Purpose of the Study:

• To determine the first crystal structures of wild-type and two disease-related missense variants (G121R and G291R) of human PGM1.
• To elucidate the structural basis of PGM1 enzyme dysfunction in PGM1 deficiency.

Main Methods:

• X-ray crystallography was used to obtain high-resolution structures of wild-type and mutant PGM1.
• Analysis of structural changes, including disordered regions and conformational alterations, in response to disease-associated mutations.

Main Results:

• Disease-related glycine-to-arginine substitutions (G121R, G291R) induce significant structural disorder in PGM1, affecting active site loops.
• Mutations lead to widespread structural rearrangements, including changes in loop and side-chain conformations distant from the mutation site.
• Induced structural disorder correlates with increased proteolysis and reduced diffraction quality, particularly for the G291R variant.

Conclusions:

• The study provides the first structural insights into the molecular mechanisms underlying PGM1 deficiency.
• A correlation between interdomain interfaces and disease-associated PGM1 variants is established.
• Biophysical characterization of proteins is highlighted as essential for understanding and treating metabolic diseases in the era of precision medicine.