ArticlePloS one2011
Structural and biochemical studies of human 4-hydroxy-2-oxoglutarate aldolase: implications for hydroxyproline metabolism in primary hyperoxaluria.
Article in PloS one, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 60 citations in OpenAlex.
- Gene overexpression reduces inhibitory metabolites to enhance CHO cell growth and IgG1 production.NPJ systems biology and applications · 2026Article
- Urine microscopy revealing a metabolic disorder: a case report.BMC nephrology · 2026Article
- The new insight into the role of hydroxyproline in metabolism of cancer cells.Frontiers in cell and developmental biology · 2025Review
- HOGA1 variants in Chinese patients with primary hyperoxaluria type 3: genetic features and genotype-phenotype relationships.World journal of urology · 2023Article
- Nedosiran, a Candidate siRNA Drug for the Treatment of Primary Hyperoxaluria: Design, Development, and Clinical Studies.ACS pharmacology & translational science · 2022Review
- Genetic association-based functional analysis detectsFrontiers in genetics · 2022Article
- EHreact: Extended Hasse Diagrams for the Extraction and Scoring of Enzymatic Reaction Templates.Journal of chemical information and modeling · 2021Article
- Novel therapeutic approaches for the primary hyperoxalurias.Pediatric nephrology (Berlin, Germany) · 2021Review
- Genetics of kidney stone disease.Nature reviews. Urology · 2020Review
- Future treatments for hyperoxaluria.Current opinion in urology · 2020Review
- Specific Inhibition of Hepatic Lactate Dehydrogenase Reduces Oxalate Production in Mouse Models of Primary Hyperoxaluria.Molecular therapy : the journal of the American Society of Gene Therapy · 2018Article
- HOGA1 Gene Mutations of Primary Hyperoxaluria Type 3 in Tunisian Patients.Journal of clinical laboratory analysis · 2017Article
- Article
- Hydroxyproline metabolism in a mouse model of Primary Hyperoxaluria Type 3.Biochimica et biophysica acta · 2015Article
- Phenotype-Genotype Correlations and Estimated Carrier Frequencies of Primary Hyperoxaluria.Journal of the American Society of Nephrology : JASN · 2015Article
- Proline dehydrogenase 2 (PRODH2) is a hydroxyproline dehydrogenase (HYPDH) and molecular target for treating primary hyperoxaluria.The Biochemical journal · 2015Article
- Kidney stone analysis: "Give me your stone, I will tell you who you are!".World journal of urology · 2015Article
- Use of a novel microtitration protocol to obtain diffraction-quality crystals of 4-hydroxy-2-oxoglutarate aldolase from Bos taurus.Acta crystallographica. Section F, Structural biology communications · 2014Article
- Hereditary causes of kidney stones and chronic kidney disease.Pediatric nephrology (Berlin, Germany) · 2013Review
- Novel findings in patients with primary hyperoxaluria type III and implications for advanced molecular testing strategies.European journal of human genetics : EJHG · 2013Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
background4-hydroxy-2-oxoglutarate (HOG) aldolase is a unique enzyme in the hydroxyproline degradation pathway catalyzing the cleavage of HOG to pyruvate and glyoxylate. Mutations in this enzyme are believed to be associated with the excessive production of oxalate in primary hyperoxaluria type 3 (PH3), although no experimental data is available to support this hypothesis. Moreover, the identity, oligomeric state, enzymatic activity, and crystal structure of human HOGA have not been experimentally determined. METHODOLOGY/PRINCIPAL
findingsIn this study human HOGA (hHOGA) was identified by mass spectrometry of the mitochondrial enzyme purified from bovine kidney. hHOGA performs a retro-aldol cleavage reaction reminiscent of the trimeric 2-keto-3-deoxy-6-phosphogluconate aldolases. Sequence comparisons, however, show that HOGA is related to the tetrameric, bacterial dihydrodipicolinate synthases, but the reaction direction is reversed. The 1.97 Å resolution crystal structure of hHOGA bound to pyruvate was determined and enabled the modeling of the HOG-Schiff base intermediate and the identification of active site residues. Kinetic analyses of site-directed mutants support the importance of Lys196 as the nucleophile, Tyr168 and Ser77 as components of a proton relay, and Asn78 and Ser198 as unique residues that facilitate substrate binding. CONCLUSIONS/SIGNIFICANCE: The biochemical and structural data presented support that hHOGA utilizes a type I aldolase reaction mechanism, but employs novel residue interactions for substrate binding. A mapping of the PH3 mutations identifies potential rearrangements in either the active site or the tetrameric assembly that would likely cause a loss in activity. Altogether, these data establish a foundation to assess mutant forms of hHOGA and how their activity could be pharmacologically restored.
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