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: Maria Veiga-da-Cunha, Farah Hadi, Thomas Balligand, Vincent Stroobant, Emile Van Schaftingen
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 287 Issue 10 Pg. 7246-55 (Mar 02 2012) ISSN: 1083-351X [Electronic] United States
• PMID: 22241472 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bacterial Proteins
• Ethanolamines
• Hydroxylysine
• O-phosphohydroxylysine
• phosphorylethanolamine
• Transaminases
• Alanine-glyoxylate transaminase

Topics

• Animals
• Bacteria (enzymology, genetics)
• Bacterial Proteins (chemistry, genetics, metabolism)
• Bipolar Disorder (enzymology, genetics)
• Ethanolamines (chemistry, metabolism)
• Genome, Bacterial (physiology)
• Genome, Human (physiology)
• Humans
• Hydroxylysine (analogs & derivatives, chemistry, metabolism)
• Mutation
• Schizophrenia (enzymology, genetics)
• Sequence Homology, Amino Acid
• Transaminases (chemistry, genetics, metabolism)