RRC ID 53527
著者 Mesa-Torres N, Calvo AC, Oppici E, Titelbaum N, Montioli R, Miranda-Vizuete A, Cellini B, Salido E, Pey AL.
タイトル Caenorhabditis elegans AGXT-1 is a mitochondrial and temperature-adapted ortholog of peroxisomal human AGT1: New insights into between-species divergence in glyoxylate metabolism.
ジャーナル Biochim Biophys Acta
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.
巻・号 1864(9)
ページ 1195-1205
公開日 2016-9-1
DOI 10.1016/j.bbapap.2016.05.004
PII S1570-9639(16)30092-9
PMID 27179589
MeSH Adaptation, Biological Alanine / chemistry Alanine / metabolism Amino Acid Sequence Animals Biological Evolution Caenorhabditis elegans / genetics Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / chemistry* Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism Cloning, Molecular Dimerization Energy Metabolism Enzyme Stability Escherichia coli / genetics Escherichia coli / metabolism Gene Expression Glyoxylates / chemistry Glyoxylates / metabolism* Humans Mitochondria / metabolism* Mutation Peroxisomes / metabolism* Protein Structure, Secondary Pyridoxal Phosphate / chemistry Pyridoxal Phosphate / metabolism Recombinant Proteins / chemistry Recombinant Proteins / genetics Recombinant Proteins / metabolism Sequence Alignment Species Specificity Structural Homology, Protein Temperature Transaminases / chemistry* Transaminases / genetics Transaminases / metabolism
IF 3.411
引用数 2
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