| Structural highlights
Disease
AGT1_HUMAN Primary hyperoxaluria type 1. The disease is caused by variants affecting the gene represented in this entry.
Function
AGT1_HUMAN Peroxisomal aminotransferase that catalyzes the transamination of glyoxylate to glycine and contributes to the glyoxylate detoxification (PubMed:10960483, PubMed:12777626, PubMed:23229545, PubMed:24055001, PubMed:26149463). Also catalyzes the transamination between L-serine and pyruvate and contributes to gluconeogenesis from the L-serine metabolism (PubMed:10347152).[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
Alanine-glyoxylate aminotransferase is a peroxisomal enzyme, of which various missense mutations lead to irreversible kidney damage via primary hyperoxaluria type 1, in part caused by improper peroxisomal targeting. To unravel the molecular mechanism of its recognition by the peroxisomal receptor Pex5p, we have determined the crystal structure of the respective cargo-receptor complex. It shows an extensive protein/protein interface, with contributions from residues of the peroxisomal targeting signal 1 and additional loops of the C-terminal domain of the cargo. Sequence segments that are crucial for receptor recognition and hydrophobic core interactions within alanine-glyoxylate aminotransferase are overlapping, explaining why receptor recognition highly depends on a properly folded protein. We subsequently characterized several enzyme variants in vitro and in vivo and show that even minor protein fold perturbations are sufficient to impair Pex5p receptor recognition. We discuss how the knowledge of the molecular parameters for alanine-glyoxylate aminotransferase required for peroxisomal translocation could become useful for improved hyperoxaluria type 1 treatment.
Molecular requirements for peroxisomal targeting of alanine-glyoxylate aminotransferase as an essential determinant in primary hyperoxaluria type 1.,Fodor K, Wolf J, Erdmann R, Schliebs W, Wilmanns M PLoS Biol. 2012 Apr;10(4):e1001309. Epub 2012 Apr 17. PMID:22529745[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Xue HH, Sakaguchi T, Fujie M, Ogawa H, Ichiyama A. Flux of the L-serine metabolism in rabbit, human, and dog livers. Substantial contributions of both mitochondrial and peroxisomal serine:pyruvate/alanine:glyoxylate aminotransferase. J Biol Chem. 1999 Jun 4;274(23):16028-33. doi: 10.1074/jbc.274.23.16028. PMID:10347152 doi:http://dx.doi.org/10.1074/jbc.274.23.16028
- ↑ Lumb MJ, Danpure CJ. Functional synergism between the most common polymorphism in human alanine:glyoxylate aminotransferase and four of the most common disease-causing mutations. J Biol Chem. 2000 Nov 17;275(46):36415-22. PMID:10960483 doi:10.1074/jbc.M006693200
- ↑ Santana A, Salido E, Torres A, Shapiro LJ. Primary hyperoxaluria type 1 in the Canary Islands: a conformational disease due to I244T mutation in the P11L-containing alanine:glyoxylate aminotransferase. Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7277-82. Epub 2003 May 30. PMID:12777626 doi:10.1073/pnas.1131968100
- ↑ Fargue S, Lewin J, Rumsby G, Danpure CJ. Four of the most common mutations in primary hyperoxaluria type 1 unmask the cryptic mitochondrial targeting sequence of alanine:glyoxylate aminotransferase encoded by the polymorphic minor allele. J Biol Chem. 2013 Jan 25;288(4):2475-84. doi: 10.1074/jbc.M112.432617. Epub 2012 , Dec 10. PMID:23229545 doi:http://dx.doi.org/10.1074/jbc.M112.432617
- ↑ Oppici E, Roncador A, Montioli R, Bianconi S, Cellini B. Gly161 mutations associated with Primary Hyperoxaluria Type I induce the cytosolic aggregation and the intracellular degradation of the apo-form of alanine:glyoxylate aminotransferase. Biochim Biophys Acta. 2013 Dec;1832(12):2277-88. doi:, 10.1016/j.bbadis.2013.09.002. Epub 2013 Sep 17. PMID:24055001 doi:http://dx.doi.org/10.1016/j.bbadis.2013.09.002
- ↑ Montioli R, Oppici E, Dindo M, Roncador A, Gotte G, Cellini B, Borri Voltattorni C. Misfolding caused by the pathogenic mutation G47R on the minor allele of alanine:glyoxylate aminotransferase and chaperoning activity of pyridoxine. Biochim Biophys Acta. 2015 Oct;1854(10 Pt A):1280-9. doi:, 10.1016/j.bbapap.2015.07.002. Epub 2015 Jul 3. PMID:26149463 doi:http://dx.doi.org/10.1016/j.bbapap.2015.07.002
- ↑ Fodor K, Wolf J, Erdmann R, Schliebs W, Wilmanns M. Molecular requirements for peroxisomal targeting of alanine-glyoxylate aminotransferase as an essential determinant in primary hyperoxaluria type 1. PLoS Biol. 2012 Apr;10(4):e1001309. Epub 2012 Apr 17. PMID:22529745 doi:10.1371/journal.pbio.1001309
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