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

Autor: Hellemann E; Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America., Walker JL; Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America., Lesko MA; Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America., Chandrashekarappa DG; University of Pittsburgh School of Medicine, Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America., Schmidt MC; University of Pittsburgh School of Medicine, Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America., O'Donnell AF; Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America., Durrant JD; Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Jazyk: angličtina
Zdroj: PLoS computational biology [PLoS Comput Biol] 2022 Mar 02; Vol. 18 (3), pp. e1009929. Date of Electronic Publication: 2022 Mar 02 (Print Publication: 2022).
DOI: 10.1371/journal.pcbi.1009929
Abstrakt: 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, hxk2G238V, 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 hxk2G238V 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 Hxk2G238V 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.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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