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...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2022-03-01
|
| Series: | PLoS Computational Biology |
| Online Access: | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1009929&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849707910346571776 |
|---|---|
| author | Erich Hellemann Jennifer L Walker Mitchell A Lesko Dakshayini G Chandrashekarappa Martin C Schmidt Allyson F O'Donnell Jacob D Durrant |
| author_facet | Erich Hellemann Jennifer L Walker Mitchell A Lesko Dakshayini G Chandrashekarappa Martin C Schmidt Allyson F O'Donnell Jacob D Durrant |
| author_sort | Erich Hellemann |
| collection | DOAJ |
| 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, 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. |
| format | Article |
| id | doaj-art-15f4c4e3c2344d9089e14c5d30a5d4e8 |
| institution | DOAJ |
| issn | 1553-734X 1553-7358 |
| language | English |
| publishDate | 2022-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj-art-15f4c4e3c2344d9089e14c5d30a5d4e82025-08-20T03:15:48ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582022-03-01183e100992910.1371/journal.pcbi.1009929Novel mutation in hexokinase 2 confers resistance to 2-deoxyglucose by altering protein dynamics.Erich HellemannJennifer L WalkerMitchell A LeskoDakshayini G ChandrashekarappaMartin C SchmidtAllyson F O'DonnellJacob D DurrantGlucose 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.https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1009929&type=printable |
| spellingShingle | Erich Hellemann Jennifer L Walker Mitchell A Lesko Dakshayini G Chandrashekarappa Martin C Schmidt Allyson F O'Donnell Jacob D Durrant Novel mutation in hexokinase 2 confers resistance to 2-deoxyglucose by altering protein dynamics. PLoS Computational Biology |
| 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 |
| url | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1009929&type=printable |
| work_keys_str_mv | AT erichhellemann novelmutationinhexokinase2confersresistanceto2deoxyglucosebyalteringproteindynamics AT jenniferlwalker novelmutationinhexokinase2confersresistanceto2deoxyglucosebyalteringproteindynamics AT mitchellalesko novelmutationinhexokinase2confersresistanceto2deoxyglucosebyalteringproteindynamics AT dakshayinigchandrashekarappa novelmutationinhexokinase2confersresistanceto2deoxyglucosebyalteringproteindynamics AT martincschmidt novelmutationinhexokinase2confersresistanceto2deoxyglucosebyalteringproteindynamics AT allysonfodonnell novelmutationinhexokinase2confersresistanceto2deoxyglucosebyalteringproteindynamics AT jacobddurrant novelmutationinhexokinase2confersresistanceto2deoxyglucosebyalteringproteindynamics |