Primary hyperoxaluria type III—a model for studying perturbations in glyoxylate metabolism
- 476 Downloads
Perturbations in glyoxylate metabolism lead to the accumulation of oxalate and give rise to primary hyperoxalurias, recessive disorders characterized by kidney stone disease. Loss-of-function mutations in HOGA1 (formerly DHDPSL) are responsible for primary hyperoxaluria type III. HOGA1 is a mitochondrial 4-hydroxy-2-oxoglutarate aldolase catalyzing the fourth step in the hydroxyproline pathway. We investigated hydroxyproline metabolites in the urine of patients with primary hyperoxaluria type III using gas chromatography–mass spectroscopy. Significant increases in concentrations of 4-hydroxy-2-oxoglutarate and its precursor and derivative 4-hydroxyglutamate and 2,4-dihydroxyglutarate, respectively, were found in all patients as compared to carriers of the corresponding mutations or healthy controls. Despite a functional block in the conversion of hydroxyproline to glyoxylate—the immediate precursor of oxalate—the production of oxalate increases. To explain this apparent contradiction, we propose a model of glyoxylate compartmentalization in which cellular glyoxylate is normally prevented from contact with the cytosol where it can be oxidized to oxalate. We propose that HOGA1 deficiency results in the accumulation of 4-hydroxy-2-oxoglutarate in the mitochondria and its transport into the cytosol where it is converted to glyoxylate by a different cytosolic aldolase. In human hepatocyte cell lines, we detected a cytosolic 4-hydroxy-2-oxoglutarate aldolase activity not due to HOGA1. These studies provide a diagnostic tool for primary hyperoxaluria type III and shed light on glyoxylate metabolism and the pathogenesis of primary hyperoxalurias.
KeywordsHOGA1 PHIII Hydroxyproline pathway Glyoxylate Oxalate DHDPSL
The authors are indebted to Prof. Hanna Mandel for helpful advice. Sections of this work were supported by the Victorian Government's Operational Infrastructure Support Program.
Conflict of interest
The authors declare that no conflict of interest exists.
- 2.Monico CG, Rossetti S, Belostotsky R, Cogal AG, Herges RM, Seide BM, Olson JB, Bergstrahl EJ, Williams HJ, Haley WE et al (2011) Primary hyperoxaluria type III gene HOGA1 (formerly DHDPSL) as a possible risk factor for idiopathic calcium oxalate urolithiasis. Clin J Am Soc Nephrol 6:2289–2295PubMedCrossRefGoogle Scholar
- 4.Williams EL, Bockenhauer D, Van't Hoff WG, Johri N, Laing C, Sinha MD, Unwin R, Viljoen A, Rumsby G (2012) The enzyme 4-hydroxy-2-oxoglutarate aldolase is deficient in primary hyperoxaluria type 3. Nephrol Dial Transplant (in press)Google Scholar
- 7.Dijcker JC, Plantinga EA, van Baal J, Hendriks WH (2011) Influence of nutrition on feline calcium oxalate urolithiasis with emphasis on endogenous oxalate synthesis. Nutr Res Rev 22:1–15Google Scholar
- 18.Alaux S, Kusk M, Sagot E, Bolte J, Jensen AA, Bräuner-Osborne H, Gefflaut T, Bunch L (2005) Chemoenzymatic synthesis of a series of 4-substituted glutamate analogues and pharmacological characterization at human glutamate transporters subtypes 1-3. J Med Chem 48:7980–7992PubMedCrossRefGoogle Scholar
- 21.Danpure CJ, Fryer P, Jennings PR, Allsop J, Griffiths S, Cunningham A (1994) Evolution of alanine:glyoxylate aminotransferase 1 peroxisomal and mitochondrial targeting. A survey of its subcellular distribution in the livers of various representatives of the classes Mammalia, Aves and Amphibia. Eur J Cell Biol 64:295–313PubMedGoogle Scholar