title: Human liver peroxisomal alanine:glyoxylate aminotransferase: characterization of the two allelic forms and their pathogenic variants.
abstract: The hepatic peroxisomal alanine:glyoxylate aminotransferase (AGT) is a pyridoxal 5'-phosphate (PLP)-enzyme whose deficiency is responsible for Primary Hyperoxaluria Type 1 (PH1), an autosomal recessive disorder. In the last few years the knowledge of the characteristics of AGT and the transfer of this information into some pathogenic variants have significantly contributed to the improvement of the understanding at the molecular level of the PH1 pathogenesis. In this review, the spectroscopic features, the coenzyme's binding affinity, the steady-state kinetic parameters as well as the sensitivity to thermal and chemical stress of the two allelic forms of AGT, the major (AGT-Ma) and the minor (AGT-Mi) allele, have been described. Moreover, we summarize the characterization obtained by means of biochemical and bioinformatic analyses of the following PH1-causing variants in the recombinant purified forms: G82E associated with the major allele, F152I encoded on the background of the minor allele, and the G41 mutants which co-segregate either with the major allele (G41R-Ma and G41V-Ma) or with the minor allele (G41R-Mi). The data have been correlated with previous clinical and cell biology results, which allow us to (i) highlight the functional differences between AGT-Ma and AGT-Mi, (ii) identify the structural and functional molecular defects of the pathogenic variants, (iii) improve the correlation between the genotype and the enzymatic phenotype, (iv) foresee or understand the molecular basis of the responsiveness to pyridoxine treatment of patients bearing these mutations, and (v) pave the way for new treatment strategies. This article is part of a Special Issue entitled: Pyridoxal Phospate Enzymology.
authors.affiliation: Dipartimento di Scienze della Vita e della Riproduzione, Sezione di Chimica Biologica, Facoltà di Medicina e Chirurgia, Università degli Studi di Verona, Strada Le Grazie, 8 37134 Verona, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Cellini
authors.forename: Riccardo
authors.initials: R
authors.lastname: Montioli
authors.forename: Carla Borri
authors.initials: CB
authors.lastname: Voltattorni
mesh_terms: D000483:Alleles; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000201:enzymology*; D008958:Models, Molecular; D020675:Peroxisomes / Q000201:enzymology*; D011487:Protein Conformation; D000637:Transaminases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D007527:Isoenzymes; D000637:Transaminases; C019635:Alanine-glyoxylate transaminase