ReviewTopics in current chemistry2013
Multiple intermediates, diverse conformations, and cooperative conformational changes underlie the catalytic hydride transfer reaction of dihydrofolate reductase.
Review in Topics in current chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 23 citations in OpenAlex.
- Modeling Ensembles of Enzyme Reaction Pathways with Hi-MSM Reveals the Importance of Accounting for Pathway Diversity.The journal of physical chemistry. B · 2022Article
- Comparison of the Role of Protein Dynamics in Catalysis by Dihydrofolate Reductase fromThe journal of physical chemistry. B · 2022Article
- Biliverdin Reductase B Dynamics Are Coupled to Coenzyme Binding.Journal of molecular biology · 2018Article
- The unassembled flavoprotein subunits of human and bacterial complex II have impaired catalytic activity and generate only minor amounts of ROS.The Journal of biological chemistry · 2018Article
- The role of the MetThe Journal of biological chemistry · 2017Article
- Resolution of Submillisecond Kinetics of Multiple Reaction Pathways for Lactate Dehydrogenase.Biophysical journal · 2017Article
- Ligand-Dependent Conformational Dynamics of Dihydrofolate Reductase.Biochemistry · 2016Article
- Hydride Transfer in DHFR by Transition Path Sampling, Kinetic Isotope Effects, and Heavy Enzyme Studies.Biochemistry · 2016Article
- Isotope-specific and amino acid-specific heavy atom substitutions alter barrier crossing in human purine nucleoside phosphorylase.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Protein Conformational Changes Are Detected and Resolved Site Specifically by Second-Harmonic Generation.Biophysical journal · 2015Article
- Direct evidence of catalytic heterogeneity in lactate dehydrogenase by temperature jump infrared spectroscopy.The journal of physical chemistry. B · 2014Article
- Protein mass-modulated effects in the catalytic mechanism of dihydrofolate reductase: beyond promoting vibrations.Journal of the American Chemical Society · 2014Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
It has become increasingly clear that protein motions play an essential role in enzyme catalysis. However, exactly how these motions are related to an enzyme's chemical step is still intensely debated. This chapter examines the possible role of protein motions that display a hierarchy of timescales in enzyme catalysis. The linkage between protein motions and catalysis is investigated in the context of a model enzyme, E. coli dihydrofolate reductase (DHFR), that catalyzes the hydride transfer reaction in the conversion of dihydrofolate to tetrahydrofolate. The results of extensive computer simulations probing the protein motions that are manifest during different steps along the turnover cycle of DHFR are summarized. Evidence is presented that the protein motions modulate the catalytic efficacy of DHFR by generating a conformational ensemble conducive to the hydride transfer. The alteration of the equilibrium conformational ensemble rather than any protein dynamical effects is found to be sufficient to explain the rate-diminishing effects of mutation on the kinetics of the enzyme. These data support the view that the protein motions facilitate catalysis by establishing reaction competent conformations of the enzyme, but they do not directly couple to the chemical reaction itself. These findings have broad implications for our understanding of enzyme mechanisms and the design of novel protein catalysts.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.