ArticleProceedings of the National Academy of Sciences of the United States of America2015
Isotope-specific and amino acid-specific heavy atom substitutions alter barrier crossing in human purine nucleoside phosphorylase.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 26 citations in OpenAlex.
- Coapplication of Adenine with Inosine or Guanosine Supports Rapid ATP Restoration by ATP-deprived Cultured Primary Astrocytes.Neurochemical research · 2025Article
- Phosphate Binding in PNP Alters Transition-State Analogue Affinity and Subunit Cooperativity.Biochemistry · 2023Article
- Decreased Transition-State Analogue Affinity in Isotopically Heavy MTAN with Increased Catalysis.Biochemistry · 2023Article
- Atomistic description of the relationship between protein dynamics and catalysis with transition path sampling.Methods in enzymology · 2023Review
- Protein Mass-Modulated Effects in Alkaline Phosphatase.Biochemistry · 2021Article
- Effect of Protein Isotope Labeling on the Catalytic Mechanism of Lactate Dehydrogenase.The journal of physical chemistry. B · 2019Article
- Heavy Enzymes and the Rational Redesign of Protein Catalysts.Chembiochem : a European journal of chemical biology · 2019Article
- Article
- Inverse enzyme isotope effects in human purine nucleoside phosphorylase with heavy asparagine labels.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Promoting Vibrations and the Function of Enzymes. Emerging Theoretical and Experimental Convergence.Biochemistry · 2018Review
- Engineered control of enzyme structural dynamics and function.Protein science : a publication of the Protein Society · 2018Review
- Protein Mass Effects on Formate Dehydrogenase.Journal of the American Chemical Society · 2017Article
- Catalytic-site design for inverse heavy-enzyme isotope effects in human purine nucleoside phosphorylase.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Minimization of dynamic effects in the evolution of dihydrofolate reductase.Chemical science · 2016Article
- Modulating Enzyme Catalysis through Mutations Designed to Alter Rapid Protein Dynamics.Journal of the American Chemical Society · 2016Article
- Pinpointing dynamic coupling in enzymes for efficient drug design.Future science OA · 2016Article
Corrections and comments
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
Abstract
Computational chemistry predicts that atomic motions on the femtosecond timescale are coupled to transition-state formation (barrier-crossing) in human purine nucleoside phosphorylase (PNP). The prediction is experimentally supported by slowed catalytic site chemistry in isotopically labeled PNP (13C, 15N, and 2H). However, other explanations are possible, including altered volume or bond polarization from carbon-deuterium bonds or propagation of the femtosecond bond motions into slower (nanoseconds to milliseconds) motions of the larger protein architecture to alter catalytic site chemistry. We address these possibilities by analysis of chemistry rates in isotope-specific labeled PNPs. Catalytic site chemistry was slowed for both [2H]PNP and [13C, 15N]PNP in proportion to their altered protein masses. Secondary effects emanating from carbon-deuterium bond properties can therefore be eliminated. Heavy-enzyme mass effects were probed for local or global contributions to catalytic site chemistry by generating [15N, 2H]His8-PNP. Of the eight His per subunit, three participate in contacts to the bound reactants and five are remote from the catalytic sites. [15N, 2H]His8-PNP had reduced catalytic site chemistry larger than proportional to the enzymatic mass difference. Altered barrier crossing when only His are heavy supports local catalytic site femtosecond perturbations coupled to transition-state formation. Isotope-specific and amino acid specific labels extend the use of heavy enzyme methods to distinguish global from local isotope effects.
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