Synthesis and enzymatic evaluation of ketose phosphonates: the interplay between mutarotation, monofluorination and acidity

Forget, Stephanie M.; Bhattasali, Debabrata; Hart, V. Catherine; Cameron, T. Stanley; Syvitski, Ray T.; Jakeman, David L.

doi:10.1039/c2sc01077a

Cited by 37 publications

(41 citation statements)

References 67 publications

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“…Their syntheses used chirally defined precursor benzyl ethers having an additional hydroxyl group in the 1α-position (19). This hydroxyl was removed by Barton-McCombie deoxygenation (20)(21)(22), followed by hydrogenolysis to remove benzyl protecting groups to give three analogs of βG1P: the ammonium salts of 1-β-phosphonomethylene-1-deoxy-D-glucopyranose (βG1CP) (19), (S)-1-β-phosphonofluoromethylene-1-deoxy-D-glucopyranose (βG1CF S P), and (R)-1-β-phosphonofluoromethylene-1-deoxy-Dglucopyranose (βG1CF R P) (Fig. 2), as described in SI Appendix.…”

Section: Resultsmentioning

confidence: 99%

“…According to 19 F NMR measurements, only analogs βG1CF S P and βG1CP formed metal fluoride TSA complexes, and these were screened in crystallization trials. Crystals of TSA complexes for step 1 were obtained in three cases, βPGM-MgF 3…”

Section: Resultsmentioning

confidence: 99%

“…The corresponding TSA complexes hitherto have proved inaccessible; attempted crystallization of the mutase using βG1P with magnesium and fluoride provides the same MgF 3 − TSA complex as is formed directly with G6P because residual enzyme activity catalyzes mutation of βG1P into G6P at a rate competitive with crystallization of the complex (17). Similarly, although 19 F NMR studies have identified a transient TSA complex for an AlF 4 − complex of βG1P, it readily isomerizes into the corresponding TSA complex of G6P (SI Appendix, Fig. S1).…”

Section: Significancementioning

confidence: 99%

“…Step 2 has been studied intensively, with analyses focused on structural studies of trifluoromagnesate (MgF 3 − ) and tetrafluoroaluminate (AlF 4 − ) transition state analogs (TSAs) and trifluoroberyllate ground state analogs for G6P complexes (4)(5)(6)15). 19 F NMR resonances for these complexes additionally have provided in situ probes for the electronic and protonic environment of the phosphate moiety in the active site (4-6, 15, 16). Such studies have confirmed a trigonal bipyramidal (tbp) TS associated with inline stereochemistry and general acid-base catalysis, following the rearrangement of near-attack conformers (6).…”

Section: Significancementioning

confidence: 99%

“…Because it has been established that α-fluorination of 6-phosphonomethyl-6-deoxy-glucose (G6CP) can enhance or impair analog binding to glucose 6-phosphate dehydrogenase, depending on the stereochemistry of the α-fluorine substituent (18), we have synthesized both diastereoisomeric α-monofluoromethylenephosphonate analogs of βG1P, its methylenephosphonate analog, and the three corresponding phosphonate 1α-hydroxyl analogs. We have identified the two best-binding analogs by 19 F NMR and measured their affinities with βPGM in TSA complexes using fluorescence titration. We have thereby obtained three high-resolution crystal structures of TSA complexes for step 1 of the mutase catalytic reaction.…”

Section: Significancementioning

confidence: 99%

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

Jin

Bhattasali

Pellegrini

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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β-Phosphoglucomutase (βPGM) catalyzes isomerization of β-Dglucose 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.phosphonate analogs | phosphoryl transfer mechanism | 19 F NMR | X-ray crystallography | water-mediated substrate recognition E fficient enzyme catalysis of the manipulation of phosphates is one of the great achievements of evolution (1). Enzymes that operate on phosphate monoesters and anhydrides transfer the phosphoryl moiety, PO 3 − , with rate accelerations approaching 10 21 for monoesters, placing them among the most proficient of all enzymes (1). Phosphomutases, including α-phosphoglucomutase (αPGM) (2, 3) and β-phosphoglucomutase (βPGM) (4-6), phosphoglycerate mutase (7), α-phosphomannomutase (αPMM/PGM) (8), and N-acetylglucosamine-phosphate mutase (9), merit special attention because these enzymes have to be effective in donating a phosphoryl group to either of two hydroxyl groups that have intrinsically different reactivity. Only when both half-reactions of a phosphomutase are accessible to mechanistic analysis can the problem of how an enzyme accommodates two distinct chemistries within a single active site be resolved. Hexose 1-phosphate mutases, including enzymes central to glycolysis and other metabolic pathways, are well characterized (10, 11). They are generally activated by phosphorylation to form a covalent phosphoenzyme, which then donates its PO 3 − group to either of its substrates to deliver a common, transient, hexose 1,6-bisphosphate intermediate species. However, structural studies on phosphomutases are complicated by the rapid and often imbalanced equilibrium position between the substrates, and kinetic studies are problematic because of competitive, parallel pathways of enzyme activation and substrate inhibition (12, ...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Section: Significancementioning

confidence: 99%

See 3 more Smart Citations

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

Jin

Bhattasali

Pellegrini

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Protecting Groups at the Secondary Positions of Carbohydrates

Vidal

Goekjian

2018

Protecting Groups

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Recent Advances in Synthesis of Difluoromethylene Phosphonates for Biological Applications

et al. 2021

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For almost 40 years, difluoromethylene phosphonates have proven to be versatile molecular tools in biochemical studies owing to their close resemblance to naturally occurring phosphates and phosphonates. As bioisosteric, non‐hydrolyzable analogs of these essential molecules, difluoromethylene phosphonates can target the critical parts of the cellular machinery and therefore exhibit a diverse spectrum of biological activity. In the past ten years, there have appeared many new methods for the synthesis of difluoromethylene phosphonates. Most notably, photoredox catalysis has firmly entered the field, while cross‐coupling and nucleophilic strategies have met considerable elaboration and refinement, entirely in accord with the current trends in synthetic organic chemistry. Herein, we introduce difluoromethylene phosphonates as a distinct, high‐tech subclass of synthetic phosphonates resulting from the research efforts on the cross‐section of organophosphorus, organofluorine, and bioorganic chemistry. We then proceed to the discussion of general methods for the preparation of difluoromethylene phosphonates, comprehensively reviewing reactions developed in the past 15 years while providing the context of earlier works where appropriate. Finally, we present selected examples of molecules with high biological activity, their biological targets, and the synthetic steps employed for their preparation.

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Synthesis and enzymatic evaluation of ketose phosphonates: the interplay between mutarotation, monofluorination and acidity

Cited by 37 publications

References 67 publications

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

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

Protecting Groups at the Secondary Positions of Carbohydrates

Recent Advances in Synthesis of Difluoromethylene Phosphonates for Biological Applications

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