Lactate dehydrogenase 5: identification of a druggable target to reduce oxaluria

Abstract

Excessive excretion of oxalate in the urine results in the formation of calcium oxalate crystals and subsequent kidney stone formation. Severe forms of hyperoxaluria, including genetic forms and those that result from ethylene glycol poisoning, can result in end-stage renal disease. Therapeutic interventions are limited and often rely on dietary intervention. In this issue of the JCI, Le Dudal and colleagues demonstrate that the lactate dehydrogenase 5 inhibitor (LDH5) stiripentol reduces urinary oxalate excretion. Importantly, stiripentol treatment of a single individual with primary hyperoxaluria reduced the urinary oxalate excretion. Together, these results support further evaluation of LDH5 as a therapeutic target for hyperoxaluria.

Figure 1. Multicompartment glyoxylate-oxalate metabolism.

Multiple metabolic pathways converge to produce glyoxylate before conversion to oxalate. Defects in enzymes responsible for metabolism of glyoxylate and its precursors (denoted in blue) underlie specific forms of primary hyperoxaluria (PH) and lead to accumulation of glyoxylate and consequently to increased oxalate production which leaves the hepatocyte via SLC26a1 on its basolateral membrane. Mutations in AGT1 associate with PH1, mutations in GR are linked to PH2, and HOGA mutations underlie PH3. Inhibition of LDH5 by the drug stiripentol decreases enzymatic conversion of glyoxylate to oxalate and decreases urinary oxalate levels. Vitamin B6 (also known as pyridoxal phosphate) has been shown to increase enzymatic activity and decrease oxalate production in PH1. PH1, primary hyperoxaluria type I; PH2, primary hyperoxaluria type II; PH3, primary hyperoxaluria type III; ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase; GR, glycolate reductase; GO, glycolate oxidase; LDH5, lactate dehydrogenase 5; OH-OG, 4-hydroxy-2-oxoglutarate; HOGA, 4-hydroxy-2-oxoglutarate aldolase; AGT1, alanine glyoxylate aminotransferase 1; AGT₂, alanine glyoxylate aminotransferase 2; DAO, D-amino oxidase; B6, vitamin B6/pyridoxal phosphate.