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Regulation of human 4-hydroxy-2-oxoglutarate aldolase by pyruvate and α-ketoglutarate: implications for primary hyperoxaluria type-3
Journal article

Regulation of human 4-hydroxy-2-oxoglutarate aldolase by pyruvate and α-ketoglutarate: implications for primary hyperoxaluria type-3

  • Huang, Amadeus Maurice Wilkins Centre for Molecular Biodiscovery and School of Biological Sciences, University of Auckland, 3A Symonds St, Auckland 1010, New Zealand
  • Burke, Julia Maurice Wilkins Centre for Molecular Biodiscovery and School of Biological Sciences, University of Auckland, 3A Symonds St, Auckland 1010, New Zealand
  • Bunker, Richard D. Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland
  • Mok, Yee-Foong Department of Biochemistry and Molecular Biology, University of Melbourne, Australia
  • Griffin, Michael D. Department of Biochemistry and Molecular Biology, University of Melbourne, Australia
  • Baker, Edward N. Maurice Wilkins Centre for Molecular Biodiscovery and School of Biological Sciences, University of Auckland, 3A Symonds St, Auckland 1010, New Zealand
  • Loomes, Kerry M. ORCID Institute for Innovation in Biotechnology, University of Auckland, Auckland, New Zealand
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  • 2019-11-15
Published in:
  • Biochemical Journal. - Portland Press Ltd.. - 2019, vol. 476, no. 21, p. 3369-3383
Cell Biology
Biochemistry
Molecular Biology
English 4-hydroxy-2-oxoglutarate aldolase (HOGA1) is a mitochondrial enzyme that plays a gatekeeper role in hydroxyproline metabolism. Its loss of function in humans causes primary hyperoxaluria type 3 (PH3), a rare condition characterised by excessive production of oxalate. In this study, we investigated the significance of the associated oxaloacetate decarboxylase activity which is also catalysed by HOGA1. Kinetic studies using the recombinant human enzyme (hHOGA1) and active site mutants showed both these dual activities utilise the same catalytic machinery with micromolar substrate affinities suggesting that both are operative in vivo. Biophysical and structural studies showed that pyruvate was a competitive inhibitor with an inhibition constant in the micromolar range. By comparison α-ketoglutarate was a weak inhibitor with an inhibition constant in the millimolar range and could only be isolated as an adduct with the active site Lys196 in the presence of sodium borohydride. These studies suggest that pyruvate inhibits HOGA1 activity during gluconeogenesis. We also propose that loss of HOGA1 function could increase oxalate production in PH3 by decreasing pyruvate availability and metabolic flux through the Krebs cycle.
Language
  • English
Open access status
closed
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Persistent URL
https://sonar.ch/global/documents/232103
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