ArticleThe Journal of biological chemistry2008
In vivo and in vitro examination of stability of primary hyperoxaluria-associated human alanine:glyoxylate aminotransferase.
Article in The Journal of biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 50 citations in OpenAlex.
- A Minor Haplotype Variant Determines the Pathogenicity of the p.Ile279Thr Substitution in the Primary Hyperoxaluria Type 1 Gene, AGXT.Journal of inherited metabolic disease · 2025Article
- Four novel variants identified in primary hyperoxaluria and genotypic and phenotypic analysis in 21 Chinese patients.Frontiers in genetics · 2023Article
- Identification of Human Alanine-Glyoxylate Aminotransferase Ligands as Pharmacological Chaperones for Variants Associated with Primary Hyperoxaluria Type 1.Journal of medicinal chemistry · 2022Article
- Review
- Structural dynamics shape the fitness window of alanine:glyoxylate aminotransferase.Protein science : a publication of the Protein Society · 2022Article
- Perspectives in primary hyperoxaluria - historical, current and future clinical interventions.Nature reviews. Urology · 2022Review
- Molecular therapy of primary hyperoxaluria.Journal of inherited metabolic disease · 2017Review
- Effects of alanine:glyoxylate aminotransferase variants and pyridoxine sensitivity on oxalate metabolism in a cell-based cytotoxicity assay.Biochimica et biophysica acta · 2016Article
- Allele-specific characterization of alanine: glyoxylate aminotransferase variants associated with primary hyperoxaluria.PloS one · 2014Article
- Emerging novel concept of chaperone therapies for protein misfolding diseases.Proceedings of the Japan Academy. Series B, Physical and biological sciences · 2014Review
- Therapeutic potential of proteasome inhibitors in congenital erythropoietic porphyria.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
- Article
- Update on oxalate crystal disease.Current rheumatology reports · 2013Review
- 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.The Journal of biological chemistry · 2013Article
- Protein homeostasis defects of alanine-glyoxylate aminotransferase: new therapeutic strategies in primary hyperoxaluria type I.BioMed research international · 2013Review
- Primary hyperoxaluria type III--a model for studying perturbations in glyoxylate metabolism.Journal of molecular medicine (Berlin, Germany) · 2012Article
- Article
- An update on primary hyperoxaluria.Nature reviews. Nephrology · 2012Review
- Molecular requirements for peroxisomal targeting of alanine-glyoxylate aminotransferase as an essential determinant in primary hyperoxaluria type 1.PLoS biology · 2012Article
- Biochemical analyses are instrumental in identifying the impact of mutations on holo and/or apo-forms and on the region(s) of alanine:glyoxylate aminotransferase variants associated with primary hyperoxaluria type I.Molecular genetics and metabolism · 2012Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Primary hyperoxaluria type I is a severe kidney stone disease caused by mutations in the protein alanine:glyoxylate aminotransferase (AGT). Many patients have mutations in AGT that are not deleterious alone but act synergistically with a common minor allele polymorphic variant to impair protein folding, dimerization, or localization. Although studies suggest that the minor allele variant itself is destabilized, no direct stability studies have been carried out. In this report, we analyze AGT function and stability using three approaches. First, we describe a yeast complementation growth assay for AGT, in which we show that human AGT can substitute for function of yeast Agx1 and that mutations associated with disease in humans show reduced growth in yeast. The reduced growth of minor allele mutants reflects reduced protein levels, indicating that these proteins are less stable than wild-type AGT in yeast. We further examine stability of AGT alleles in vitro using two direct methods, a mass spectrometry-based technique (stability of unpurified proteins from rates of H/D exchange) and differential scanning fluorimetry. We also examine the effect of known ligands pyridoxal 5'-phosphate and aminooxyacetic acid on stability. Our work establishes that the minor allele is destabilized and that pyridoxal 5'-phosphate and aminooxyacetic acid binding significantly stabilizes both alleles. To our knowledge, this is the first work that directly measures relative stabilities of AGT variants and ligand complexes. Because previous studies suggest that stabilizing compounds (i.e. pharmacological chaperones) may be effective for treatment of primary hyperoxaluria, we propose that the methods described here can be used in high throughput screens for compounds that stabilize AGT mutants.
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Registered trials
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