Cancer‐associated mutations in human pyruvate kinase M2 impair enzyme activity
| Autor: | William J. Israelsen, Aaron M. Hosios, Vivian M. Liu, Matthew G. Vander Heiden, Zhaoqi Li, Andrea J. Howell |
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| Rok vydání: | 2019 |
| Předmět: |
Thyroid Hormones
Allosteric regulation Mutant Biophysics PKM2 medicine.disease_cause Biochemistry Article 03 medical and health sciences Structural Biology Neoplasms Genetics medicine Humans Glycolysis Protein Structure Quaternary Molecular Biology 030304 developmental biology chemistry.chemical_classification 0303 health sciences Mutation biology Chemistry 030302 biochemistry & molecular biology Membrane Proteins Cell Biology Enzyme assay Kinetics Enzyme biology.protein Protein Multimerization Carrier Proteins Pyruvate kinase |
| Zdroj: | FEBS Lett |
| ISSN: | 1873-3468 0014-5793 |
| DOI: | 10.1002/1873-3468.13648 |
| Popis: | Mammalian pyruvate kinase catalyzes the final step of glycolysis, and its M2 isoform (PKM2) is widely expressed in proliferative tissues. Mutations in PKM2 are found in some human cancers; however, the effects of these mutations on enzyme activity and regulation are unknown. Here, we characterized five cancer-associated PKM2 mutations, occurring at various locations on the enzyme, with respect to substrate kinetics and activation by the allosteric activator fructose-1,6-bisphosphate (FBP). The mutants exhibit reduced maximal velocity, reduced substrate affinity, and/or altered activation by FBP. The kinetic parameters of five additional PKM2 mutants that have been used to study enzyme function or regulation also demonstrate the deleterious effects of mutations on PKM2 function. Our findings indicate that PKM2 is sensitive to many amino acid changes and support the hypothesis that decreased PKM2 activity is selected for in rapidly proliferating cells. |
| Databáze: | OpenAIRE |
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