Triosephosphate isomerase I170V alters catalytic site, enhances stability and induces pathology in a Drosophila model of TPI deficiency.
Biochim Biophys Acta
; 1852(1): 61-9, 2015 Jan.
Article
em En
| MEDLINE
| ID: mdl-25463631
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.
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Base de dados:
MEDLINE
Assunto principal:
Triose-Fosfato Isomerase
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Erros Inatos do Metabolismo dos Carboidratos
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Domínio Catalítico
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Anemia Hemolítica Congênita não Esferocítica
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article