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

[primary hyperoxaluria type 1]

Mutations of the AGXT gene encoding the alanine :glyoxylate aminotransferase liver enzyme (AGT ) cause primary hyperoxaluria type 1 (PH 1 ). Here we report a molecular modeling study of selected missense AGXT mutations : the common Gly 170 Arg and the recently described Gly 47 A rg and Ser 81 Leu variants , predicted to be pathogenic using standard criteria .Taking advantage of the refined 3 D structure of AGT , we computed the dimerization energy of the wild-type and mutated proteins .M olecular modeling predicted that Gly 47 A rg affects dimerization with a similar effect to that shown previously for Gly 170 A rg through classical biochemical approaches . In contrast , no effect on dimerization was predicted for Ser 81 Leu . Therefore , this probably demonstrates pathogenic properties via a different mechanism , similar to that described for the adjacent Gly 82 G lu mutation that affects pyridoxine binding .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 .