BIOCHEMICAL CHARACTERIZATION OF HUMAN ENZYMES INVOLVED IN THE METABOLISM OF GLYOXYLATE: IMPLICATIONS FOR THE TREATMENT OF PRIMARY HYPEROXALURIA TYPE 1

Primary hyperoxaluria type 1 (PH1) is a severe hereditary disease occurring in 1 per 120,000 live births. It is caused by the functional deficiency of a single liver enzyme, named AGT1, that is in charge of the detoxification of glyoxylate. Glyoxylate is a reactive compound that, in the presence of functional AGT1, is mostly converted to the harmless amino acid glycine (see attached scheme). In PH1 patients, where AGT1 activity is deficient, glyoxylate cannot be properly metabolized and it is mainly converted to oxalate. Oxalate is less reactive than glyoxylate but it tends to form insoluble salts that precipitate in the kidney and in other tissues. This causes recurring kidney stones, kidney calcification and eventually end-stage renal disease. PH1 is caused by a great number of different mutations in the gene encoding for AGT1. This genetic heterogeneity complicates the development of an effective therapy, and in fact no generally valid cure (apart from the combined transplantation of kidney and liver) is currently known for PH1 patients. With this point in mind, we propose two approaches aimed at the identification of possible therapeutical targets for PH1. First, we plan to identify enzymes that may surrogate the role of AGT1 in the conversion of glyoxylate to glycine. If such enzymes do exist, stimulation of their activity could represent a viable therapeutical approach. Second, we plan to carry out a biochemical and structural characterization of HAOX1. This enzyme is capable of producing glyoxylate, and apparently also of its further oxidation to oxalate (see scheme). Development of specific inhibitors for this enzyme could be particularly useful to reduce oxalate accumulation.