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α-Fluorophosphonates reveal how a phosphomutase conserves transition state conformation over hexose recognition in its two-step reaction

Jin, Yi, Bhattasali, Debabrata, Pellegrini, Erika, Forget, Stephanie M., Baxter, Nicola J., Cliff, Matthew J., Bowler, Matthew W., Jakeman, David L., Blackburn, G. Michael and Waltho, Jonathan P. 2014. α-Fluorophosphonates reveal how a phosphomutase conserves transition state conformation over hexose recognition in its two-step reaction. Proceedings of the National Academy of Sciences 111 (34) , pp. 12384-12389. 10.1073/pnas.1402850111

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Abstract

β-Phosphoglucomutase (βPGM) catalyzes isomerization of β-d-glucose 1-phosphate (βG1P) into d-glucose 6-phosphate (G6P) via sequential phosphoryl transfer steps using a β-d-glucose 1,6-bisphosphate (βG16BP) intermediate. Synthetic fluoromethylenephosphonate and methylenephosphonate analogs of βG1P deliver novel step 1 transition state analog (TSA) complexes for βPGM, incorporating trifluoromagnesate and tetrafluoroaluminate surrogates of the phosphoryl group. Within an invariant protein conformation, the β-d-glucopyranose ring in the βG1P TSA complexes (step 1) is flipped over and shifted relative to the G6P TSA complexes (step 2). Its equatorial hydroxyl groups are hydrogen-bonded directly to the enzyme rather than indirectly via water molecules as in step 2. The (C)O–P bond orientation for binding the phosphate in the inert phosphate site differs by ∼30° between steps 1 and 2. By contrast, the orientations for the axial O–Mg–O alignment for the TSA of the phosphoryl group in the catalytic site differ by only ∼5°, and the atoms representing the five phosphorus-bonded oxygens in the two transition states (TSs) are virtually superimposable. The conformation of βG16BP in step 1 does not fit into the same invariant active site for step 2 by simple positional interchange of the phosphates: the TS alignment is achieved by conformational change of the hexose rather than the protein.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Subjects: Q Science > QD Chemistry
Uncontrolled Keywords: phosphonate analogs; phosphoryl transfer mechanism; 19F NMR; X-ray crystallography; water-mediated substrate recognition
Publisher: National Academy of Sciences
ISSN: 0027-8424
Date of Acceptance: 15 July 2014
Last Modified: 04 Feb 2020 14:00
URI: http://orca.cf.ac.uk/id/eprint/100301

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