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Evolution Alters the Enzymatic Reaction Coordinate of Dihydrofolate Reductase

[Image: see text] How evolution has affected enzyme function is a topic of great interest in the field of biophysical chemistry. Evolutionary changes from Escherichia coli dihydrofolate reductase (ecDHFR) to human dihydrofolate reductase (hsDHFR) have resulted in increased catalytic efficiency and a...

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Autores principales: Masterson, Jean E., Schwartz, Steven D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4306496/
https://www.ncbi.nlm.nih.gov/pubmed/25369552
http://dx.doi.org/10.1021/jp506373q
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author Masterson, Jean E.
Schwartz, Steven D.
author_facet Masterson, Jean E.
Schwartz, Steven D.
author_sort Masterson, Jean E.
collection PubMed
description [Image: see text] How evolution has affected enzyme function is a topic of great interest in the field of biophysical chemistry. Evolutionary changes from Escherichia coli dihydrofolate reductase (ecDHFR) to human dihydrofolate reductase (hsDHFR) have resulted in increased catalytic efficiency and an altered dynamic landscape in the human enzyme. Here, we show that a subpicosecond protein motion is dynamically coupled to hydride transfer catalyzed by hsDHFR but not ecDHFR. This motion propagates through residues that correspond to mutational events along the evolutionary path from ecDHFR to hsDHFR. We observe an increase in the variability of the transition states, reactive conformations, and times of barrier crossing in the human system. In the hsDHFR active site, we detect structural changes that have enabled the coupling of fast protein dynamics to the reaction coordinate. These results indicate a shift in the DHFR family to a form of catalysis that incorporates rapid protein dynamics and a concomitant shift to a more flexible path through reactive phase space.
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spelling pubmed-43064962015-11-04 Evolution Alters the Enzymatic Reaction Coordinate of Dihydrofolate Reductase Masterson, Jean E. Schwartz, Steven D. J Phys Chem B [Image: see text] How evolution has affected enzyme function is a topic of great interest in the field of biophysical chemistry. Evolutionary changes from Escherichia coli dihydrofolate reductase (ecDHFR) to human dihydrofolate reductase (hsDHFR) have resulted in increased catalytic efficiency and an altered dynamic landscape in the human enzyme. Here, we show that a subpicosecond protein motion is dynamically coupled to hydride transfer catalyzed by hsDHFR but not ecDHFR. This motion propagates through residues that correspond to mutational events along the evolutionary path from ecDHFR to hsDHFR. We observe an increase in the variability of the transition states, reactive conformations, and times of barrier crossing in the human system. In the hsDHFR active site, we detect structural changes that have enabled the coupling of fast protein dynamics to the reaction coordinate. These results indicate a shift in the DHFR family to a form of catalysis that incorporates rapid protein dynamics and a concomitant shift to a more flexible path through reactive phase space. American Chemical Society 2014-11-04 2015-01-22 /pmc/articles/PMC4306496/ /pubmed/25369552 http://dx.doi.org/10.1021/jp506373q Text en Copyright © 2014 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
spellingShingle Masterson, Jean E.
Schwartz, Steven D.
Evolution Alters the Enzymatic Reaction Coordinate of Dihydrofolate Reductase
title Evolution Alters the Enzymatic Reaction Coordinate of Dihydrofolate Reductase
title_full Evolution Alters the Enzymatic Reaction Coordinate of Dihydrofolate Reductase
title_fullStr Evolution Alters the Enzymatic Reaction Coordinate of Dihydrofolate Reductase
title_full_unstemmed Evolution Alters the Enzymatic Reaction Coordinate of Dihydrofolate Reductase
title_short Evolution Alters the Enzymatic Reaction Coordinate of Dihydrofolate Reductase
title_sort evolution alters the enzymatic reaction coordinate of dihydrofolate reductase
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4306496/
https://www.ncbi.nlm.nih.gov/pubmed/25369552
http://dx.doi.org/10.1021/jp506373q
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