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Toward a quantum-mechanical description of metal-assisted phosphoryl transfer in pyrophosphatase
Abstract
The wealth of kinetic and structural information makes inorganic pyrophosphatases (PPases) a good model system to study the details of enzymatic phosphoryl transfer. The enzyme accelerates metal-complexed phosphoryl transfer 10 10 -fold: but how? Our structures of the yeast PPase product complex at 1.15 Å and fluoride-inhibited complex at 1.9 Å visualize the active site in three different states: substrate-bound, immediate product bound, and relaxed product bound. These span the steps around chemical catalysis and provide strong evidence that a water molecule (O nu ) directly attacks PPi with a p K a vastly lowered by coordination to two metal ions and D117. They also suggest that a low-barrier hydrogen bond (LBHB) forms between D117 and O nu , in part because of steric crowding by W100 and N116. Direct visualization of the double bonds on the phosphates appears possible. The flexible side chains at the top of the active site absorb the motion involved in the reaction, which may help accelerate catalysis. Relaxation of the product allows a new nucleophile to be generated and creates symmetry in the elementary catalytic steps on the enzyme. We are thus moving closer to understanding phosphoryl transfer in PPases at the quantum mechanical level. Ultra-high resolution structures can thus tease out overlapping complexes and so are as relevant to discussion of enzyme mechanism as structures produced by time-resolved crystallography.
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“For example, in pyrophosphatase, F− displaces the hydrolytic water in the coordination sphere of the enzyme-bound Mg2+, acting as a transition state analogue of the activated water molecule(17, 18) (Figure 2a).”
From Membrane exporters of fluoride ion (2021) · cites this paper as [18]
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Membrane exporters of fluoride ion
McIlwain, B. C., Ruprecht, M. T., & Stockbridge, R. B. (2021) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-071520-112507 · Cited by 69
Destruction Of C7, C9 Perfluorocarboxylic Acids By The Strain Ensifer Adhaerens M1
Hkudaigulov, G., Sharipov, D., Starikov, S., & Chetverikov, S. (2024) · Malaysian Journal of Fundamental and Applied Sciences · doi:10.11113/mjfas.v20n6.3655
Metadata
- Authors
- Heikinheimo, P., Tuominen, V., Ahonen, A.-K., Teplyakov, A., Cooperman, B. S., Baykov, A. A., Lahti, R., & Goldman, A.
- Affiliations
- Center for Biotechnology, PL 123, FIN-20521 Turku, Finland; Department of Biochemistry, University of Turku, FIN-20014 Turku, Finland; Institute of Biotechnology, University of Helsinki, PL 56, FIN-00014 Helsinki, Finland; European Molecular Biology Laboratory, Deutsches Elektronen Synchrotron, D-22603 Hamburg, Germany; Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104; and AN Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow 119899, ...
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2001-03-06
- Volume
- 98
- Issue
- 6
- Pages
- 3121-3126
- ISSN
- 0027-8424
- 1091-6490
- Cited by
- 90
- References
- 0
- Language
- en
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