Effect of alanine supplementation on oxalate synthesis

The Primary Hyperoxalurias (PH) are rare disorders of metabolism leading to excessive endogenous synthesis of oxalate and recurring calcium oxalate kidney stones. Alanine glyoxylate aminotransferase (AGT), deficient in PH type 1, is a key enzyme in limiting glyoxylate oxidation to oxalate. The affinity of AGT for its co-substrate, alanine, is low suggesting that its metabolic activity could be sub-optimal in vivo. To test this hypothesis, we examined the effect of L-alanine supplementation on oxalate synthesis in cell culture and in mouse models of Primary Hyperoxaluria Type 1 (Agxt KO), Type 2 (Grhpr KO) and in wild-type mice. Our results demonstrated that increasing L-alanine in cells decreased synthesis of oxalate and increased viability of cells expressing GO and AGT when incubated with glycolate. In both wild type and Grhpr KO male and female mice, supplementation with 10% dietary L-alanine significantly decreased urinary oxalate excretion ~30% compared to baseline levels. This study demonstrates that increasing the availability of L-alanine can increase the metabolic efficiency of AGT and reduce oxalate synthesis. •Deficiency in alanine:glyoxylate aminotransferase causes primary hyperoxaluria type 1.•Elevated urinary oxalate and calcium oxalate kidney stones are hallmarks of PH1.•Supplementation with L-alanine increased AGT activity in a cell model.•Alanine supplementation decreased urinary oxalate in Wt and Grhpr Ko mice.•L-alanine can increase AGT metabolic efficiency and thus reduce oxalate synthesis.