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Title: Caenorhabditis elegans AGXT-1 is a mitochondrial and temperature-adapted ortholog of peroxisomal human AGT1: New insights into between-species divergence in glyoxylate metabolism.
Authors: Mesa-Torres, Noel
Calvo, Ana C
Oppici, Elisa
Titelbaum, Nicholas
Montioli, Riccardo
Miranda-Vizuete, Antonio
Cellini, Barbara
Salido, Eduardo
Pey, Angel L
Keywords: Conformational disease;Enzyme kinetics;Primary hyperoxaluria;Protein stability;Substrate specificity
metadata.dc.subject.mesh: Adaptation, Biological
Amino Acid Sequence
Biological Evolution
Caenorhabditis elegans
Caenorhabditis elegans Proteins
Cloning, Molecular
Energy Metabolism
Enzyme Stability
Escherichia coli
Gene Expression
Protein Structure, Secondary
Pyridoxal Phosphate
Recombinant Proteins
Sequence Alignment
Species Specificity
Structural Homology, Protein
Issue Date: 11-May-2016
Abstract: In humans, glyoxylate is an intermediary product of metabolism, whose concentration is finely balanced. Mutations in peroxisomal alanine:glyoxylate aminotransferase (hAGT1) cause primary hyperoxaluria type 1 (PH1), which results in glyoxylate accumulation that is converted to toxic oxalate. In contrast, glyoxylate is used by the nematode Caenorhabditis elegans through a glyoxylate cycle to by-pass the decarboxylation steps of the tricarboxylic acid cycle and thus contributing to energy production and gluconeogenesis from stored lipids. To investigate the differences in glyoxylate metabolism between humans and C. elegans and to determine whether the nematode might be a suitable model for PH1, we have characterized here the predicted nematode ortholog of hAGT1 (AGXT-1) and compared its molecular properties with those of the human enzyme. Both enzymes form active PLP-dependent dimers with high specificity towards alanine and glyoxylate, and display similar three-dimensional structures. Interestingly, AGXT-1 shows 5-fold higher activity towards the alanine/glyoxylate pair than hAGT1. Thermal and chemical stability of AGXT-1 is lower than that of hAGT1, suggesting temperature-adaptation of the nematode enzyme linked to the lower optimal growth temperature of C. elegans. Remarkably, in vivo experiments demonstrate the mitochondrial localization of AGXT-1 in contrast to the peroxisomal compartmentalization of hAGT1. Our results support the view that the different glyoxylate metabolism in the nematode is associated with the divergent molecular properties and subcellular localization of the alanine:glyoxylate aminotransferase activity.
metadata.dc.identifier.doi: 10.1016/j.bbapap.2016.05.004
ISSN: 0006-3002
Appears in Collections:Producción 2020

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