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

Angela Robbiano, Vladimir Frecer, Jan Miertus, Cristina Zadro, Sheila Ulivi, Elena Bevilacqua, Giorgia Mandrile, Mario De Marchi, Stanislav Miertus, Antonio Amoroso

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)667-676
Number of pages10
JournalJournal of Nephrology
Volume23
Issue number6
Publication statusPublished - Nov 2010

Fingerprint

Dimerization
Missense Mutation
Enzymes
Pyridoxine
Mutation
Computer Simulation
Virulence
Primary hyperoxaluria type 1
Liver
Genes
Proteins

Keywords

  • AGT enzyme
  • AGXT gene
  • Molecular modeling
  • Primary hyperoxaluria type 1

ASJC Scopus subject areas

  • Nephrology

Cite this

Robbiano, A., Frecer, V., Miertus, J., Zadro, C., Ulivi, S., Bevilacqua, E., ... Amoroso, A. (2010). Modeling the effect of 3 missense AGXT mutations on dimerization of the AGT enzyme in primary hyperoxaluria type 1. Journal of Nephrology, 23(6), 667-676.

Modeling the effect of 3 missense AGXT mutations on dimerization of the AGT enzyme in primary hyperoxaluria type 1. / Robbiano, Angela; Frecer, Vladimir; Miertus, Jan; Zadro, Cristina; Ulivi, Sheila; Bevilacqua, Elena; Mandrile, Giorgia; De Marchi, Mario; Miertus, Stanislav; Amoroso, Antonio.

In: Journal of Nephrology, Vol. 23, No. 6, 11.2010, p. 667-676.

Research output: Contribution to journalArticle

Robbiano, A, Frecer, V, Miertus, J, Zadro, C, Ulivi, S, Bevilacqua, E, Mandrile, G, De Marchi, M, Miertus, S & Amoroso, A 2010, 'Modeling the effect of 3 missense AGXT mutations on dimerization of the AGT enzyme in primary hyperoxaluria type 1', Journal of Nephrology, vol. 23, no. 6, pp. 667-676.
Robbiano, Angela ; Frecer, Vladimir ; Miertus, Jan ; Zadro, Cristina ; Ulivi, Sheila ; Bevilacqua, Elena ; Mandrile, Giorgia ; De Marchi, Mario ; Miertus, Stanislav ; Amoroso, Antonio. / Modeling the effect of 3 missense AGXT mutations on dimerization of the AGT enzyme in primary hyperoxaluria type 1. In: Journal of Nephrology. 2010 ; Vol. 23, No. 6. pp. 667-676.
@article{85eca143a7ee4849a28675ceb79dccb2,
title = "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.",
keywords = "AGT enzyme, AGXT gene, Molecular modeling, 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 {De Marchi}, Mario and Stanislav Miertus and Antonio Amoroso",
year = "2010",
month = "11",
language = "English",
volume = "23",
pages = "667--676",
journal = "Journal of Nephrology",
issn = "1121-8428",
publisher = "Springer International Publishing",
number = "6",

}

TY - JOUR

T1 - Modeling the effect of 3 missense AGXT mutations on dimerization of the AGT enzyme in primary hyperoxaluria type 1

AU - Robbiano, Angela

AU - Frecer, Vladimir

AU - Miertus, Jan

AU - Zadro, Cristina

AU - Ulivi, Sheila

AU - Bevilacqua, Elena

AU - Mandrile, Giorgia

AU - De Marchi, Mario

AU - Miertus, Stanislav

AU - Amoroso, Antonio

PY - 2010/11

Y1 - 2010/11

N2 - 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.

AB - 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.

KW - AGT enzyme

KW - AGXT gene

KW - Molecular modeling

KW - Primary hyperoxaluria type 1

UR - http://www.scopus.com/inward/record.url?scp=78549279499&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78549279499&partnerID=8YFLogxK

M3 - Article

VL - 23

SP - 667

EP - 676

JO - Journal of Nephrology

JF - Journal of Nephrology

SN - 1121-8428

IS - 6

ER -