Modeling the effect of 3 missense AGXT mutations on dimerization of the AGT enzyme in primary hyperoxaluria type 1.

Abstract

INTRODUCTION Mutations of the AGXT gene encoding the alanine:glyoxylate 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.

Cite this paper

@article{Robbiano2010ModelingTE, title={Modeling the effect of 3 missense AGXT mutations on dimerization of the AGT enzyme in primary hyperoxaluria type 1.}, author={Angela Robbiano and Vladimir Frecer and Jan Miertus and Cristina Zadro and Sheila Ulivi and Elena Bevilacqua and Giorgia Mandrile and Mario De Marchi and Stanislav Miertus and Antonio Amoroso}, journal={Journal of nephrology}, year={2010}, volume={23 6}, pages={667-76} }