Protein homeostasis defects of alanine-glyoxylate aminotransferase: New therapeutic strategies in primary hyperoxaluria type i

16 pags, 5 figsAlanine-glyoxylate aminotransferase catalyzes the transamination between L-alanine and glyoxylate to produce pyruvate and glycine using pyridoxal 5′-phosphate (PLP) as cofactor. Human alanine-glyoxylate aminotransferase is a peroxisomal enzyme expressed in the hepatocytes, the main site of glyoxylate detoxification. Its deficit causes primary hyperoxaluria type I, a rare but severe inborn error of metabolism. Single amino acid changes are the main type of mutation causing this disease, and considerable effort has been dedicated to the understanding of the molecular consequences of such missense mutations. In this review, we summarize the role of protein homeostasis in the basic mechanisms of primary hyperoxaluria. Intrinsic physicochemical properties of polypeptide chains such as thermodynamic stability, folding, unfolding, and misfolding rates as well as the interaction of different folding states with protein homeostasis networks are essential to understand this disease. The view presented has important implications for the development of new therapeutic strategies based on targeting specific elements of alanine-glyoxylate aminotransferase homeostasis. © 2013 Angel L. Pey et al.This work was supported by the Spanish ministry of Science and Innovation (RYC2009-04147 and CSD2009-00088 to Angel L. Pey, SAF2011-23933 to Eduardo Salido, and CSD2006-00015 and BFU2011-25384 to Armando Albert), Junta de Andalucia (P11CTS-7187 A.L.P.), and European Union (FP7-REGPOT-CT2012-31637-IMBRAIN to E.S.)