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.

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

MANDRILE, Giorgia;DE MARCHI, Mario;AMOROSO, Antonio
2010-01-01

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.
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http://www.jnephrol.com/
AGXT; molecular genetics; molecular modelling; primary hyperoxaluria
Robbiano A; Frecer V; Miertus J; Zadro C; Ulivi S; Bevilacqua E; Mandrile G; De Marchi M; Miertus S; Amoroso A
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/76969
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