oxalates and Genetic-Diseases--Inborn

Topics: alpha 1-Antitrypsin Deficiency; Amyloidosis; Bone Marrow Transplantation; Fabry Disease; Gaucher Disease; Genetic Diseases, Inborn; Gout; Granulomatous Disease, Chronic; Hemoglobinopathies; Hemophilia A; Hepatolenticular Degeneration; Humans; Immunologic Deficiency Syndromes; Kidney Transplantation; Leukodystrophy, Metachromatic; Liver Transplantation; Lymphocytes; Metabolism, Inborn Errors; Mucopolysaccharidoses; Nephritis, Hereditary; Niemann-Pick Diseases; Osteopetrosis; Oxalates; Oxalic Acid; Transplantation; Tyrosine; Uremia

Human liver peroxisomal alanine:glyoxylate aminotransferase (AGT) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that converts glyoxylate into glycine. AGT deficiency causes primary hyperoxaluria type 1 (PH1), a rare autosomal recessive disorder, due to a marked increase in hepatic oxalate production. Normal human AGT exists as two polymorphic variants: the major (AGT-Ma) and the minor (AGT-Mi) allele. AGT-Mi causes the PH1 disease only when combined with some mutations. In this study, the molecular basis of the synergism between AGT-Mi and F152I mutation has been investigated through a detailed biochemical characterization of AGT-Mi and the Phe(152) variants combined either with the major (F152I-Ma, F152A-Ma) or the minor allele (F152I-Mi). Although these species show spectral features, kinetic parameters, and PLP binding affinity similar to those of AGT-Ma, the Phe(152) variants exhibit the following differences with respect to AGT-Ma and AGT-Mi: (i) pyridoxamine 5'-phosphate (PMP) is released during the overall transamination leading to the conversion into apoenzymes, and (ii) the PMP binding affinity is at least 200-1400-fold lower. Thus, Phe(152) is not an essential residue for transaminase activity, but plays a role in selectively stabilizing the AGT-PMP complex, by a proper orientation of Trp(108), as suggested by bioinformatic analysis. These data, together with the finding that apoF152I-Mi is the only species that at physiological temperature undergoes a time-dependent inactivation and concomitant aggregation, shed light on the molecular defects resulting from the association of the F152I mutation with AGT-Mi, and allow to speculate on the responsiveness to pyridoxine therapy of PH1 patients carrying this mutation.

Topics: Alleles; Amino Acid Substitution; Genetic Diseases, Inborn; Glycine; Glyoxylates; Humans; Hyperoxaluria; Liver; Mutation, Missense; Oxalates; Peroxisomes; Transaminases

Topics: Arrhythmias, Cardiac; Barbiturates; Butyrylcholinesterase; Drug Synergism; Drug Tolerance; Dysautonomia, Familial; Genetic Diseases, Inborn; Humans; Hyperbilirubinemia, Hereditary; Jaundice; Kidney Calculi; Malignant Hyperthermia; Metabolism, Inborn Errors; Narcotics; Nephrocalcinosis; Osteogenesis Imperfecta; Oxalates; Paralyses, Familial Periodic; Pharmacogenetics; Porphyrias; Succinylcholine