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Near attack conformers dominate β-phosphoglucomutase complexes where geometry and charge distribution reflect those of substrate.

Griffin JL, Bowler MW, Baxter NJ, Leigh KN, Dannatt HR, Hounslow AM, Blackburn GM, Webster CE, Cliff MJ, Waltho JP
Proc Natl Acad Sci U S A 109 6910-5 (2012)
Related entries: 2wf8, 2wf9

Cited: 27 times
EuropePMC logo PMID: 22505741

Abstract

Experimental observations of fluoromagnesate and fluoroaluminate complexes of β-phosphoglucomutase (β-PGM) have demonstrated the importance of charge balance in transition-state stabilization for phosphoryl transfer enzymes. Here, direct observations of ground-state analog complexes of β-PGM involving trifluoroberyllate establish that when the geometry and charge distribution closely match those of the substrate, the distribution of conformers in solution and in the crystal predominantly places the reacting centers in van der Waals proximity. Importantly, two variants are found, both of which satisfy the criteria for near attack conformers. In one variant, the aspartate general base for the reaction is remote from the nucleophile. The nucleophile remains protonated and forms a nonproductive hydrogen bond to the phosphate surrogate. In the other variant, the general base forms a hydrogen bond to the nucleophile that is now correctly orientated for the chemical transfer step. By contrast, in the absence of substrate, the solvent surrounding the phosphate surrogate is arranged to disfavor nucleophilic attack by water. Taken together, the trifluoroberyllate complexes of β-PGM provide a picture of how the enzyme is able to organize itself for the chemical step in catalysis through the population of intermediates that respond to increasing proximity of the nucleophile. These experimental observations show how the enzyme is capable of stabilizing the reaction pathway toward the transition state and also of minimizing unproductive catalysis of aspartyl phosphate hydrolysis.

Articles - 2wfa mentioned but not cited (5)

  1. Near attack conformers dominate β-phosphoglucomutase complexes where geometry and charge distribution reflect those of substrate. Griffin JL, Bowler MW, Baxter NJ, Leigh KN, Dannatt HR, Hounslow AM, Blackburn GM, Webster CE, Cliff MJ, Waltho JP. Proc. Natl. Acad. Sci. U.S.A. 109 6910-6915 (2012)
  2. New Molecular-Mechanics Model for Simulations of Hydrogen Fluoride in Chemistry and Biology. Orabi EA, Faraldo-Gómez JD. J Chem Theory Comput 16 5105-5126 (2020)
  3. An Enzyme with High Catalytic Proficiency Utilizes Distal Site Substrate Binding Energy to Stabilize the Closed State but at the Expense of Substrate Inhibition. Robertson AJ, Cruz-Navarrete FA, Wood HP, Vekaria N, Hounslow AM, Bisson C, Cliff MJ, Baxter NJ, Waltho JP. ACS Catal 12 3149-3164 (2022)
  4. 1H, 15N and 13C backbone resonance assignments of the P146A variant of β-phosphoglucomutase from Lactococcus lactis in its substrate-free form. Cruz-Navarrete FA, Baxter NJ, Wood HP, Hounslow AM, Waltho JP. Biomol NMR Assign 13 349-356 (2019)
  5. Allomorphy as a mechanism of post-translational control of enzyme activity. Wood HP, Cruz-Navarrete FA, Baxter NJ, Trevitt CR, Robertson AJ, Dix SR, Hounslow AM, Cliff MJ, Waltho JP. Nat Commun 11 5538 (2020)


Reviews citing this publication (4)

  1. Metal Fluorides as Analogues for Studies on Phosphoryl Transfer Enzymes. Jin Y, Richards NG, Waltho JP, Blackburn GM. Angew. Chem. Int. Ed. Engl. 56 4110-4128 (2017)
  2. Reflections on biocatalysis involving phosphorus. Blackburn GM, Bowler MW, Jin Y, Waltho JP. Biochemistry (Mosc) 77 1083-1096 (2012)
  3. Conformational dynamics in phosphoglycerate kinase, an open and shut case? Bowler MW. FEBS Lett. 587 1878-1883 (2013)
  4. Metal Fluorides: Tools for Structural and Computational Analysis of Phosphoryl Transfer Enzymes. Jin Y, Molt RW, Blackburn GM. Top Curr Chem (Cham) 375 36 (2017)

Articles citing this publication (18)

  1. α-Fluorophosphonates reveal how a phosphomutase conserves transition state conformation over hexose recognition in its two-step reaction. Jin Y, Bhattasali D, Pellegrini E, Forget SM, Baxter NJ, Cliff MJ, Bowler MW, Jakeman DL, Blackburn GM, Waltho JP. Proc. Natl. Acad. Sci. U.S.A. 111 12384-12389 (2014)
  2. Challenges in computational studies of enzyme structure, function and dynamics. Carvalho AT, Barrozo A, Doron D, Kilshtain AV, Major DT, Kamerlin SC. J. Mol. Graph. Model. 54 62-79 (2014)
  3. Modeling of solvent flow effects in enzyme catalysis under physiological conditions. Schofield J, Inder P, Kapral R. J Chem Phys 136 205101 (2012)
  4. (19)F NMR and DFT Analysis Reveal Structural and Electronic Transition State Features for RhoA-Catalyzed GTP Hydrolysis. Jin Y, Molt RW, Waltho JP, Richards NG, Blackburn GM. Angew. Chem. Int. Ed. Engl. 55 3318-3322 (2016)
  5. Charge-balanced metal fluoride complexes for protein kinase A with adenosine diphosphate and substrate peptide SP20. Jin Y, Cliff MJ, Baxter NJ, Dannatt HR, Hounslow AM, Bowler MW, Blackburn GM, Waltho JP. Angew. Chem. Int. Ed. Engl. 51 12242-12245 (2012)
  6. Understanding a substrate's product regioselectivity in a family of enzymes: a case study of acetaminophen binding in cytochrome P450s. Yang Y, Wong SE, Lightstone FC. PLoS ONE 9 e87058 (2014)
  7. Induced fit of the peptidyl-transferase center of the ribosome and conformational freedom of the esterified amino acids. Lehmann J. RNA 23 229-239 (2017)
  8. Engineering enzyme activity using an expanded amino acid alphabet. Birch-Price Z, Taylor CJ, Ortmayer M, Green AP. Protein Eng Des Sel 36 gzac013 (2023)
  9. Extein residues regulate the catalytic function of Spl DnaX intein enzyme by restricting the near-attack conformations of the active-site residues. Boral S, Sen S, Kushwaha T, Inampudi KK, De S. Protein Sci 32 e4699 (2023)
  10. J-UNIO protocol used for NMR structure determination of the 206-residue protein NP_346487.1 from Streptococcus pneumoniae TIGR4. Jaudzems K, Pedrini B, Geralt M, Serrano P, Wüthrich K. J. Biomol. NMR 61 65-72 (2015)
  11. A transition state "trapped"? QM-cluster models of engineered threonyl-tRNA synthetase. Summers TJ, Cheng Q, DeYonker NJ. Org. Biomol. Chem. 16 4090-4100 (2018)
  12. Assessing the Influence of Mutation on GTPase Transition States by Using X-ray Crystallography, 19 F NMR, and DFT Approaches. Jin Y, Molt RW, Pellegrini E, Cliff MJ, Bowler MW, Richards NGJ, Blackburn GM, Waltho JP. Angew. Chem. Int. Ed. Engl. 56 9732-9735 (2017)
  13. Computer simulations of the catalytic mechanism of wild-type and mutant β-phosphoglucomutase. Barrozo A, Liao Q, Esguerra M, Marloie G, Florián J, Williams NH, Kamerlin SCL. Org. Biomol. Chem. 16 2060-2073 (2018)
  14. Essential Functional Interplay of the Catalytic Groups in Acid Phosphatase. Pfeiffer M, Crean RM, Moreira C, Parracino A, Oberdorfer G, Brecker L, Hammerschmidt F, Kamerlin SCL, Nidetzky B. ACS Catal 12 3357-3370 (2022)
  15. Evidence for substrate-assisted catalysis in N-acetylphosphoglucosamine mutase. Raimi OG, Hurtado-Guerrero R, van Aalten DMF. Biochem. J. 475 2547-2557 (2018)
  16. MgF3- and AlF4- transition state analogue complexes of yeast phosphoglycerate kinase. McCormick NE, Forget SM, Syvitski RT, Jakeman DL. Biochem. Cell Biol. 95 295-303 (2017)
  17. Observing enzyme ternary transition state analogue complexes by 19F NMR spectroscopy. Ampaw A, Carroll M, von Velsen J, Bhattasali D, Cohen A, Bowler MW, Jakeman DL. Chem Sci 8 8427-8434 (2017)
  18. Synthesis and Evaluation of Fluoroalkyl Phosphonyl Analogues of 2- C-Methylerythritol Phosphate as Substrates and Inhibitors of IspD from Human Pathogens. Bartee D, Wheadon MJ, Freel Meyers CL. J. Org. Chem. 83 9580-9591 (2018)


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