| Modeling the effect of 3 missense AGXT mutations on dimerization of the AGT enzyme in primary hyperoxaluria type 1. | |
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MedLine Citation:
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PMID: 20564000 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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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Authors:
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Angela Robbiano; Vladimir Frecer; Jan Miertus; Cristina Zadro; Sheila Ulivi; Elena Bevilacqua; Giorgia Mandrile; Mario De Marchi; Stanislav Miertus; Antonio Amoroso |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of nephrology Volume: 23 ISSN: 1121-8428 ISO Abbreviation: J. Nephrol. Publication Date: 2010 Nov-Dec |
Date Detail:
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Created Date: 2010-11-01 Completed Date: 2011-01-20 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9012268 Medline TA: J Nephrol Country: Italy |
Other Details:
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Languages: eng Pagination: 667-76 Citation Subset: IM |
Affiliation:
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Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole, Orbassano, Italy. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Sequence Female Humans Male Models, Molecular Molecular Sequence Data Mutation, Missense* Protein Multimerization* Transaminases / chemistry, genetics* |
| Chemical | |
Reg. No./Substance:
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EC 2.6.1.-/Transaminases; EC 2.6.1.44/Alanine-glyoxylate transaminase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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