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Triosephosphate isomerase I170V alters catalytic site, enhances stability and induces pathology in a Drosophila model of TPI deficiency.
- Source :
-
Biochimica et biophysica acta [Biochim Biophys Acta] 2015 Jan; Vol. 1852 (1), pp. 61-9. Date of Electronic Publication: 2014 Oct 16. - Publication Year :
- 2015
-
Abstract
- Triosephosphate isomerase (TPI) is a glycolytic enzyme which homodimerizes for full catalytic activity. Mutations of the TPI gene elicit a disease known as TPI Deficiency, a glycolytic enzymopathy noted for its unique severity of neurological symptoms. Evidence suggests that TPI Deficiency pathogenesis may be due to conformational changes of the protein, likely affecting dimerization and protein stability. In this report, we genetically and physically characterize a human disease-associated TPI mutation caused by an I170V substitution. Human TPI(I170V) elicits behavioral abnormalities in Drosophila. An examination of hTPI(I170V) enzyme kinetics revealed this substitution reduced catalytic turnover, while assessments of thermal stability demonstrated an increase in enzyme stability. The crystal structure of the homodimeric I170V mutant reveals changes in the geometry of critical residues within the catalytic pocket. Collectively these data reveal new observations of the structural and kinetic determinants of TPI Deficiency pathology, providing new insights into disease pathogenesis.<br /> (Copyright © 2014 Elsevier B.V. All rights reserved.)
- Subjects :
- Anemia, Hemolytic, Congenital Nonspherocytic enzymology
Animals
Behavior, Animal
Carbohydrate Metabolism, Inborn Errors enzymology
Disease Models, Animal
Drosophila
Enzyme Stability
Humans
Mutation
Triose-Phosphate Isomerase chemistry
Triose-Phosphate Isomerase genetics
Anemia, Hemolytic, Congenital Nonspherocytic pathology
Carbohydrate Metabolism, Inborn Errors pathology
Catalytic Domain
Triose-Phosphate Isomerase deficiency
Triose-Phosphate Isomerase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0006-3002
- Volume :
- 1852
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Biochimica et biophysica acta
- Publication Type :
- Academic Journal
- Accession number :
- 25463631
- Full Text :
- https://doi.org/10.1016/j.bbadis.2014.10.010