Peri active site catalysis of proline isomerisation is the molecular basis of allomorphy in β-phosphoglucomutase.

Cruz-Navarrete, F Aaron; Baxter, Nicola J; Flinders, Adam J; Buzoianu, Anamaria; Cliff, Matthew J; Baker, Patrick J; Waltho, Jonathan P (2024). Peri active site catalysis of proline isomerisation is the molecular basis of allomorphy in β-phosphoglucomutase. Communications biology, 7(1), p. 909. Springer Nature 10.1038/s42003-024-06577-9

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Metabolic regulation occurs through precise control of enzyme activity. Allomorphy is a post-translational fine control mechanism where the catalytic rate is governed by a conformational switch that shifts the enzyme population between forms with different activities. β-Phosphoglucomutase (βPGM) uses allomorphy in the catalysis of isomerisation of β-glucose 1-phosphate to glucose 6-phosphate via β-glucose 1,6-bisphosphate. Herein, we describe structural and biophysical approaches to reveal its allomorphic regulatory mechanism. Binding of the full allomorphic activator β-glucose 1,6-bisphosphate stimulates enzyme closure, progressing through NAC I and NAC III conformers. Prior to phosphoryl transfer, loops positioned on the cap and core domains are brought into close proximity, modulating the environment of a key proline residue. Hence accelerated isomerisation, likely via a twisted anti/C4-endo transition state, leads to the rapid predominance of active cis-P βPGM. In contrast, binding of the partial allomorphic activator fructose 1,6-bisphosphate arrests βPGM at a NAC I conformation and phosphoryl transfer to both cis-P βPGM and trans-P βPGM occurs slowly. Thus, allomorphy allows a rapid response to changes in food supply while not otherwise impacting substantially on levels of important metabolites.

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