Primary hyperoxaluria type III—a model for studying perturbations in glyoxylate metabolism

Abstract

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.

Hydroxyproline metabolism in a mouse model of Primary Hyperoxaluria Type 3

“…1) [14]. The finding of an elevation of two stereoisomers of DHG in that study suggests that more than one enzyme may be able to reduce HOG to DHG, but the identity and localization of these enzymes remain to be determined.…”

“…In summary, normal individuals and mice excrete very low levels of HOG in urine (Table 1) [5, 14]. HOG excretion is elevated in subjects with PH3 [5, 14], but not in Hoga1 KO mice until they are challenged with Hyp feeding.…”

“…HOG excretion is elevated in subjects with PH3 [5, 14], but not in Hoga1 KO mice until they are challenged with Hyp feeding. Female Hoga1 KO mice show the greatest response, and could be the model of choice for monitoring HOG production.…”

“…Individuals with PH3 have also been shown to synthesize significant amounts of 2,4-dihydroxyglutarate (DHG), presumably derived from the reduction of HOG (Fig. 1) [14]. The pathway that converts HOG to DHG requires investigation, as it could be exploited therapeutically to enhance the disposal of HOG to limit its conversion to oxalate.…”

Proline dehydrogenase 2 (PRODH2) is a hydroxyproline dehydrogenase (HYPDH) and molecular target for treating primary hyperoxaluria

“…PRODH2 and HOGA are unique to the pathway, while P5CDH and AspAT are ubiquitously expressed and involved in the proline catabolism pathway [19,26,28]. PH3 patient mutations in HOGA inactivate the enzyme and lead to a build-up of HOG in the blood and urine, which can inhibit GR and potentially contribute to a PH2-like phenotype [10,29]. Therefore, HOGA is also an inappropriate target.…”