ArticleProceedings of the National Academy of Sciences of the United States of America2010
Molecular defects of the glycine 41 variants of alanine glyoxylate aminotransferase associated with primary hyperoxaluria type I.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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28 citing papers in PubMed, 69 citations in OpenAlex.
- Impact of Ser81 phosphorylation on alanine: glyoxylate aminotransferase associated with Primary hyperoxaluria type I.Molecular biomedicine · 2026Article
- 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
- Enzymatic reactions towards aldehydes: An overview.Flavour and fragrance journal · 2023Review
- Phosphorylation of Thr9 Affects the Folding Landscape of the N-Terminal Segment of Human AGT Enhancing Protein Aggregation of Disease-Causing Mutants.Molecules (Basel, Switzerland) · 2022Article
- Identification of Human Alanine-Glyoxylate Aminotransferase Ligands as Pharmacological Chaperones for Variants Associated with Primary Hyperoxaluria Type 1.Journal of medicinal chemistry · 2022Article
- Structural dynamics shape the fitness window of alanine:glyoxylate aminotransferase.Protein science : a publication of the Protein Society · 2022Article
- Development and characterization of a glycine biosensor system for fine-tuned metabolic regulation in Escherichia coli.Microbial cell factories · 2022Article
- Dimerization Drives Proper Folding of Human Alanine:Glyoxylate Aminotransferase But Is Dispensable for Peroxisomal Targeting.Journal of personalized medicine · 2021Article
- 'Frontiers in microbiology · 2021Article
- Pyridoxine Responsiveness in a Type 1 Primary Hyperoxaluria Patient With a Rare (Atypical)Kidney international reports · 2020Article
- Molecular basis of primary hyperoxaluria: clues to innovative treatments.Urolithiasis · 2019Review
- Correlation between the molecular effects of mutations at the dimer interface of alanine-glyoxylate aminotransferase leading to primary hyperoxaluria type I and the cellular response to vitamin BJournal of inherited metabolic disease · 2018Article
- Two novel AGXT mutations identified in primary hyperoxaluria type-1 and distinct morphological and structural difference in kidney stones.Scientific reports · 2016Article
- Effects of alanine:glyoxylate aminotransferase variants and pyridoxine sensitivity on oxalate metabolism in a cell-based cytotoxicity assay.Biochimica et biophysica acta · 2016Article
- Phenotype-Genotype Correlations and Estimated Carrier Frequencies of Primary Hyperoxaluria.Journal of the American Society of Nephrology : JASN · 2015Article
- Molecular recognition of PTS-1 cargo proteins by Pex5p: implications for protein mistargeting in primary hyperoxaluria.Biomolecules · 2015Article
- Phosphorylation in the catalytic cleft stabilizes and attracts domains of a phosphohexomutase.Biophysical journal · 2015Article
- S81L and G170R mutations causing Primary Hyperoxaluria type I in homozygosis and heterozygosis: an example of positive interallelic complementation.Human molecular genetics · 2014Article
- Innovative strategies to treat protein misfolding in inborn errors of metabolism: pharmacological chaperones and proteostasis regulators.Journal of inherited metabolic disease · 2014Review
- Allele-specific characterization of alanine: glyoxylate aminotransferase variants associated with primary hyperoxaluria.PloS one · 2014Article
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8 authors at 3 institutions in 1 country.
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Abstract
G41 is an interfacial residue located within the alpha-helix 34-42 of alanine:glyoxylate aminotransferase (AGT). Its mutations on the major (AGT-Ma) or the minor (AGT-Mi) allele give rise to the variants G41R-Ma, G41R-Mi, and G41V-Ma causing hyperoxaluria type 1. Impairment of dimerization in these variants has been suggested to be responsible for immunoreactivity deficiency, intraperoxisomal aggregation, and sensitivity to proteasomal degradation. However, no experimental evidence supports this view. Here we report that G41 mutations, besides increasing the dimer-monomer equilibrium dissociation constant, affect the protein conformation and stability, and perturb its active site. As compared to AGT-Ma or AGT-Mi, G41 variants display different near-UV CD and intrinsic emission fluorescence spectra, larger exposure of hydrophobic surfaces, sensitivity to Met53-Tyr54 peptide bond cleavage by proteinase K, decreased thermostability, reduced coenzyme binding affinity, and catalytic efficiency. Additionally, unlike AGT-Ma and AGT-Mi, G41 variants under physiological conditions form insoluble inactive high-order aggregates (approximately 5,000 nm) through intermolecular electrostatic interactions. A comparative molecular dynamics study of the putative structures of AGT-Mi and G41R-Mi predicts that G41 --> R mutation causes a partial unwinding of the 34-42 alpha-helix and a displacement of the first 44 N-terminal residues including the active site loop 24-32. These simulations help us to envisage the possible structural basis of AGT dysfunction associated with G41 mutations. The detailed insight into how G41 mutations act on the structure-function of AGT may contribute to achieve the ultimate goal of correcting the effects of these mutations.
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