title: Molecular identification of hydroxylysine kinase and of ammoniophospholyases acting on 5-phosphohydroxy-L-lysine and phosphoethanolamine.
abstract: The purpose of the present work was to identify the catalytic activity of AGXT2L1 and AGXT2L2, two closely related, putative pyridoxal-phosphate-dependent enzymes encoded by vertebrate genomes. The existence of bacterial homologues (40-50% identity with AGXT2L1 and AGXT2L2) forming bi- or tri-functional proteins with a putative kinase belonging to the family of aminoglycoside phosphotransferases suggested that AGXT2L1 and AGXT2L2 acted on phosphorylated and aminated compounds. Vertebrate genomes were found to encode a homologue (AGPHD1) of these putative bacterial kinases, which was therefore likely to phosphorylate an amino compound bearing a hydroxyl group. These and other considerations led us to hypothesize that AGPHD1 corresponded to 5-hydroxy-L-lysine kinase and that AGXT2L1 and AGXT2L2 catalyzed the pyridoxal-phosphate-dependent breakdown of phosphoethanolamine and 5-phosphohydroxy-L-lysine. The three recombinant human proteins were produced and purified to homogeneity. AGPHD1 was indeed found to catalyze the GTP-dependent phosphorylation of 5-hydroxy-L-lysine. The phosphorylation product made by this enzyme was metabolized by AGXT2L2, which converted it to ammonia, inorganic phosphate, and 2-aminoadipate semialdehyde. AGXT2L1 catalyzed a similar reaction on phosphoethanolamine, converting it to ammonia, inorganic phosphate, and acetaldehyde. AGPHD1 and AGXT2L2 are likely to be the mutated enzymes in 5-hydroxylysinuria and 5-phosphohydroxylysinuria, respectively. The high level of expression of AGXT2L1 in human brain, as well as data in the literature linking AGXT2L1 to schizophrenia and bipolar disorders, suggest that these diseases may involve a perturbation of brain phosphoethanolamine metabolism. AGXT2L1 and AGXT2L2, the first ammoniophospholyases to be identified, belong to a family of aminotransferases acting on ω-amines.
authors.affiliation: Laboratory of Physiological Chemistry, de Duve Institute and Université Catholique de Louvain, B-1200 Brussels, Belgium. maria.veiga@uclouvain.be
authors.forename: Maria
authors.initials: M
authors.lastname: Veiga-da-Cunha
authors.forename: Farah
authors.initials: F
authors.lastname: Hadi
authors.forename: Thomas
authors.initials: T
authors.lastname: Balligand
authors.forename: Vincent
authors.initials: V
authors.lastname: Stroobant
authors.forename: Emile
authors.initials: E
authors.lastname: Van Schaftingen
mesh_terms: D000818:Animals; D001419:Bacteria / Q000201:enzymology / Q000235:genetics; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001714:Bipolar Disorder / Q000201:enzymology / Q000235:genetics; D004983:Ethanolamines / Q000737:chemistry / Q000378:metabolism; D016680:Genome, Bacterial / Q000502:physiology*; D015894:Genome, Human / Q000502:physiology*; D006801:Humans; D006901:Hydroxylysine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D009154:Mutation; D012559:Schizophrenia / Q000201:enzymology / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D000637:Transaminases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D004983:Ethanolamines; D006901:Hydroxylysine; C065432:O-phosphohydroxylysine; C005448:phosphorylethanolamine; D000637:Transaminases; C019635:Alanine-glyoxylate transaminase