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

J Nephrol. 2010 Nov-Dec;23(6):667-76.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Female
  • Humans
  • Male
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation, Missense*
  • Protein Multimerization*
  • Transaminases / chemistry
  • Transaminases / genetics*

Substances

  • Transaminases
  • Alanine-glyoxylate transaminase