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.

原发性高草酸尿症 (PH) 是一种罕见的代谢紊乱，导致草酸内源性过度合成和草酸钙肾结石复发。缺乏 1 型 PH 的丙氨酸乙醛酸氨基转移酶 (AGT) 是限制乙醛酸氧化为草酸的关键酶。AGT 对其共底物丙氨酸的亲和力很低，表明其代谢活性在体内可能不是最佳的。为了检验这一假设，我们检查了草酸盐合成在细胞培养物和在原发性高草酸盐类型1（小鼠模型L-丙氨酸补充的效果Agxt KO），2型（GRHPRKO）和野生型小鼠。我们的结果表明，当与乙醇酸一起孵育时，细胞中 L-丙氨酸的增加会降低草酸的合成并增加表达 GO 和 AGT 的细胞的活力。在野生型和Grhpr KO 雄性和雌性小鼠中，与基线水平相比，补充 10% 的膳食 L-丙氨酸显着降低了尿草酸排泄约 30%。该研究表明，增加 L-丙氨酸的可用性可以提高 AGT 的代谢效率并减少草酸合成。