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Peri active site catalysis of proline isomerisation is the molecular basis of allomorphy in β-phosphoglucomutase
Cruz-Navarrete, F. A. Baxter, N. J. Flinders, Adam J Buzoianu, A. Cliff, M. J. Baker, P. J. Waltho, J. P.
Cruz-Navarrete, F. A.
Baxter, N. J.
Flinders, Adam J
Buzoianu, A.
Cliff, M. J.
Baker, P. J.
Waltho, J. P.
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Abstract
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. beta-Phosphoglucomutase (beta PGM) uses allomorphy in the catalysis of isomerisation of beta-glucose 1-phosphate to glucose 6-phosphate via beta-glucose 1,6-bisphosphate. Herein, we describe structural and biophysical approaches to reveal its allomorphic regulatory mechanism. Binding of the full allomorphic activator beta-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 beta PGM. In contrast, binding of the partial allomorphic activator fructose 1,6-bisphosphate arrests beta PGM at a NAC I conformation and phosphoryl transfer to both cis-P beta PGM and trans-P beta PGM occurs slowly. Thus, allomorphy allows a rapid response to changes in food supply while not otherwise impacting substantially on levels of important metabolites. A structural study shows that the enzyme beta PGM uses an allomorphically controlled switch that accelerates proline isomerisation to alleviate the wastage of valuable metabolites while allowing the organism to react quickly to changes in food supply.
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2024
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Cruz-Navarrete FA, Baxter NJ, Flinders AJ, Buzoianu A, Cliff MJ, Baker PJ, et al. Peri active site catalysis of proline isomerisation is the molecular basis of allomorphy in β-phosphoglucomutase. Communications biology. 2024 JUL 27;7(1). PubMed PMID: WOS:001282808800002. English.