Strict reaction and substrate specificity of AGXT2L1, the human O‐phosphoethanolamine phospho‐lyase

Abstract

Dysregulated expression of the AGXT2L1 gene has been associated to neuropsychiatric disorders. Recently the gene product was shown to possess O-phosphoethanolamine phospholyase activity. We here analyze the specificity of AGXT2L1 in terms of both reaction and substrate. We show that the enzyme, despite having evolved from a transaminase ancestor, is at least 500-fold more active as a lyase than as an aminotransferase. Furthermore, the lyase reaction is very selective for O-phosphoethanolamine, strongly discriminating against closely related compounds, and we dissect the factors that contribute to such narrow substrate specificity. Overall, AGXT2L1 function appears to be rigidly confined to phospholipid metabolism, which is altered in neuropsychiatric disturbances. V C 2013 IUBMB Life, 65(7): [645][646][647][648][649][650] 2013

A subfamily of PLP-dependent enzymes specialized in handling terminal amines

“…For example, as observed in DGDA, the Arg that in most ATs interacts with the substrate α-carboxylic group is not conserved. This is in accordance with the low affinity of PEA-PL towards α-amino acids and with its ineffectiveness as a transaminase (for this enzyme, β-elimination is at least 500-fold more efficient than transamination) [85]. Again similar to DGD (and more generally to pyruvate specific ATs) the lyases also lack the Arg residues that in α-KG-specific ATs interact with the γ-carboxylate of the substrate (see Figs.…”

“…The structures of these two phospho-lyases are not known, but some hypotheses can be made about the structural changes that, during evolution, led to their emergence from some ancestor that was almost certainly a transaminase [85].…”

AGXT2L1 is down-regulated in heptocellular carcinoma and associated with abnormal lipogenesis

“…The alanine-glyoxylate aminotransferase 2-like 1 (AGXT2L1) gene, also called ethanolamine-phosphate phospholyase (ETNPPL) and mapped to 4q25 in the human genome, was initially found to be expressed in brain tissue 8. AGXT2L1 is called after alanine-glyoxylate aminotransferase 2 (AGXT2) as they share 36% sequence identity 8.…”

Vitamin B-6 Metabolism and Interactions with TNAP

“…Rats fed a high protein, vitamin B-6 deficient diet developed osteoporotic changes and markedly increased excretion of phosphoethanolamine with no changes in serum alkaline phosphatase activity (Benke et al 1972). Recently, AGXT2L1, a pyridoxal phosphate brain protein related to alanine glyoxylate aminotransferase, has been shown to be an ethanolamine-phosphate phospho-lyase (Veiga-da-Cunha et al 2012;Schiroli et al 2013). AGXT2L1 was the most consistently upregulated gene in the brains of deceased patients with schizophrenia or bipolar disorder (Shao and Vawter 2008) and was the most upregulated gene in mouse brain after treatment with lithium (McQuillin et al 2007).…”

“…Nam et al (2012) noted that specialist enzymes are frequently essential, maintain higher metabolic flux, and require more regulation to control metabolic flux in dynamic environments. Schiroli et al (2013) suggested that the need for strict regulation in the case of AGXT2L1 might result from the fact that the reaction is irreversible and generates potentially toxic products. They noted that phosphoethanolamine is a product of sphingolipid degradation and a substrate for glycerophospholipid biosynthesis.…”