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Novel mutation in hexokinase 2 confers resistance to 2-deoxyglucose by altering protein dynamics

Glucose is central to many biological processes, serving as an energy source and a building block for biosynthesis. After glucose enters the cell, hexokinases convert it to glucose-6-phosphate (Glc-6P) for use in anaerobic fermentation, aerobic oxidative phosphorylation, and the pentose-phosphate pa...

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Autores principales: Hellemann, Erich, Walker, Jennifer L., Lesko, Mitchell A., Chandrashekarappa, Dakshayini G., Schmidt, Martin C., O’Donnell, Allyson F., Durrant, Jacob D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8920189/
https://www.ncbi.nlm.nih.gov/pubmed/35235554
http://dx.doi.org/10.1371/journal.pcbi.1009929
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author Hellemann, Erich
Walker, Jennifer L.
Lesko, Mitchell A.
Chandrashekarappa, Dakshayini G.
Schmidt, Martin C.
O’Donnell, Allyson F.
Durrant, Jacob D.
author_facet Hellemann, Erich
Walker, Jennifer L.
Lesko, Mitchell A.
Chandrashekarappa, Dakshayini G.
Schmidt, Martin C.
O’Donnell, Allyson F.
Durrant, Jacob D.
author_sort Hellemann, Erich
collection PubMed
description Glucose is central to many biological processes, serving as an energy source and a building block for biosynthesis. After glucose enters the cell, hexokinases convert it to glucose-6-phosphate (Glc-6P) for use in anaerobic fermentation, aerobic oxidative phosphorylation, and the pentose-phosphate pathway. We here describe a genetic screen in Saccharomyces cerevisiae that generated a novel spontaneous mutation in hexokinase-2, hxk2(G238V), that confers resistance to the toxic glucose analog 2-deoxyglucose (2DG). Wild-type hexokinases convert 2DG to 2-deoxyglucose-6-phosphate (2DG-6P), but 2DG-6P cannot support downstream glycolysis, resulting in a cellular starvation-like response. Curiously, though the hxk2(G238V) mutation encodes a loss-of-function allele, the affected amino acid does not interact directly with bound glucose, 2DG, or ATP. Molecular dynamics simulations suggest that Hxk2(G238V) impedes sugar binding by altering the protein dynamics of the glucose-binding cleft, as well as the large-scale domain-closure motions required for catalysis. These findings shed new light on Hxk2 dynamics and highlight how allosteric changes can influence catalysis, providing new structural insights into this critical regulator of carbohydrate metabolism. Given that hexokinases are upregulated in some cancers and that 2DG and its derivatives have been studied in anti-cancer trials, the present work also provides insights that may apply to cancer biology and drug resistance.
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spelling pubmed-89201892022-03-15 Novel mutation in hexokinase 2 confers resistance to 2-deoxyglucose by altering protein dynamics Hellemann, Erich Walker, Jennifer L. Lesko, Mitchell A. Chandrashekarappa, Dakshayini G. Schmidt, Martin C. O’Donnell, Allyson F. Durrant, Jacob D. PLoS Comput Biol Research Article Glucose is central to many biological processes, serving as an energy source and a building block for biosynthesis. After glucose enters the cell, hexokinases convert it to glucose-6-phosphate (Glc-6P) for use in anaerobic fermentation, aerobic oxidative phosphorylation, and the pentose-phosphate pathway. We here describe a genetic screen in Saccharomyces cerevisiae that generated a novel spontaneous mutation in hexokinase-2, hxk2(G238V), that confers resistance to the toxic glucose analog 2-deoxyglucose (2DG). Wild-type hexokinases convert 2DG to 2-deoxyglucose-6-phosphate (2DG-6P), but 2DG-6P cannot support downstream glycolysis, resulting in a cellular starvation-like response. Curiously, though the hxk2(G238V) mutation encodes a loss-of-function allele, the affected amino acid does not interact directly with bound glucose, 2DG, or ATP. Molecular dynamics simulations suggest that Hxk2(G238V) impedes sugar binding by altering the protein dynamics of the glucose-binding cleft, as well as the large-scale domain-closure motions required for catalysis. These findings shed new light on Hxk2 dynamics and highlight how allosteric changes can influence catalysis, providing new structural insights into this critical regulator of carbohydrate metabolism. Given that hexokinases are upregulated in some cancers and that 2DG and its derivatives have been studied in anti-cancer trials, the present work also provides insights that may apply to cancer biology and drug resistance. Public Library of Science 2022-03-02 /pmc/articles/PMC8920189/ /pubmed/35235554 http://dx.doi.org/10.1371/journal.pcbi.1009929 Text en © 2022 Hellemann et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Hellemann, Erich
Walker, Jennifer L.
Lesko, Mitchell A.
Chandrashekarappa, Dakshayini G.
Schmidt, Martin C.
O’Donnell, Allyson F.
Durrant, Jacob D.
Novel mutation in hexokinase 2 confers resistance to 2-deoxyglucose by altering protein dynamics
title Novel mutation in hexokinase 2 confers resistance to 2-deoxyglucose by altering protein dynamics
title_full Novel mutation in hexokinase 2 confers resistance to 2-deoxyglucose by altering protein dynamics
title_fullStr Novel mutation in hexokinase 2 confers resistance to 2-deoxyglucose by altering protein dynamics
title_full_unstemmed Novel mutation in hexokinase 2 confers resistance to 2-deoxyglucose by altering protein dynamics
title_short Novel mutation in hexokinase 2 confers resistance to 2-deoxyglucose by altering protein dynamics
title_sort novel mutation in hexokinase 2 confers resistance to 2-deoxyglucose by altering protein dynamics
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8920189/
https://www.ncbi.nlm.nih.gov/pubmed/35235554
http://dx.doi.org/10.1371/journal.pcbi.1009929
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