Modeling the effect of 3 missense AGXT mutations on dimerization of the AGT enzyme in primary hyperoxaluria type 1.
J Nephrol
; 23(6): 667-76, 2010.
Article
em En
| MEDLINE
| ID: mdl-20564000
ABSTRACT
INTRODUCTION:
Mutations of the AGXT gene encoding the alanineglyoxylate aminotransferase liver enzyme (AGT) cause primary hyperoxaluria type 1 (PH1). Here we report a molecular modeling study of selected missense AGXT mutations the common Gly170Arg and the recently described Gly47Arg and Ser81Leu variants, predicted to be pathogenic using standard criteria.METHODS:
Taking advantage of the refined 3D structure of AGT, we computed the dimerization energy of the wild-type and mutated proteins.RESULTS:
Molecular modeling predicted that Gly47Arg affects dimerization with a similar effect to that shown previously for Gly170Arg through classical biochemical approaches. In contrast, no effect on dimerization was predicted for Ser81Leu. Therefore, this probably demonstrates pathogenic properties via a different mechanism, similar to that described for the adjacent Gly82Glu mutation that affects pyridoxine binding.CONCLUSION:
This study shows that the molecular modeling approach can contribute to evaluating the pathogenicity of some missense variants that affect dimerization. However, in silico studies--aimed to assess the relationship between structural change and biological effects--require the integrated use of more than 1 tool.
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Base de dados:
MEDLINE
Assunto principal:
Mutação de Sentido Incorreto
/
Multimerização Proteica
/
Transaminases
Tipo de estudo:
Prognostic_studies
Limite:
Female
/
Humans
/
Male
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article