AGXT2: a promiscuous aminotransferase

Abstract

Alanine-glyoxylate aminotransferase 2 (AGXT2) is a multifunctional mitochondrial aminotransferase that was first identified in 1978. The physiological importance of AGXT2 was largely overlooked for three decades because AGXT2 is less active in glyoxylate metabolism than AGXT1, the enzyme that is deficient in primary hyperoxaluria type I. Recently, several novel functions of AGXT2 have been “rediscovered” in the setting of modern genomic and metabolomic studies. It is now apparent that AGXT2 has multiple substrates and products and that altered AGXT2 activity may contribute to the pathogenesis of cardiovascular, renal, neurological and hematological diseases. This article reviews the biochemical properties and physiological functions of AGXT2, its unique role at the intersection of key mitochondrial pathways, and its potential as a drug target.

Dimethylguanidino valeric acid is a marker of liver fat and predicts diabetes

“…Patients returned to the clinic 2 and 6 months after their operation and had clinical parameters measured and plasma taken for clinical biochemistry (Table 6). At both 2 and 6 months after RYGB, patients had dramatic weight loss and also significant improvements in metabolic parameters, such as glucose levels, systolic blood pressure ate, ADMA, and alanine (25). Our group and others have previously reported associations between common variants in the AGXT2 gene with circulating metabolite levels in human blood (17,20,32) and urine (17).…”

“…AGXT2 was originally described in the context of transamination of alanine and glyoxylate, resulting in the formation of pyruvate and glycine (Supplemental Figure 3A) (24). However, subsequent studies have shown that this enzyme can catalyze the transamination of other previously unanticipated metabolite pairs, including β-aminoisobutyric acid (BAIBA) and pyruvate, asymmetric dimethylarginine (ADMA) and glyoxylate, as well as alanine and Υ,δ-dioxovaleric acid (DOVA) (25). Therefore, we sought to determine whether m/z 202.1185 was either a product or substrate of AGXT2-mediated transamination.…”

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

“…In this last case the Arg side chain is oriented away from the active site, leaving a large cavity behind. The wide size of the O-pocket may also explain the substantial substrate promiscuity not just of ω-PATs [18] but also of other pyruvate-specific transaminases such as AGXT2 [77].…”

“…This product is not released from the active site, however, and functions as the amino group donor in the second part of the reaction, to yield the final product 5-aminolevulinate. 11 Mammalian AGXT2 is a promiscuous mitochondrial transaminase that acts on a variety of substrates -in addition to D-3-aminoisobutyrate, these substrates include L-alanine, 5-aminolevulinate, β-alanine [77,98]. Accordingly, the enzyme can be assigned to different E.C.…”

Proteome analysis of the liver in the Chinese fire-bellied newt Cynops orientalis

“…HAL catalyzes the first reaction in histidine metabolism, the nonoxidative deamination of L-histidine to trans-urocanic acid. AGXT2 is a multifunctional mitochondrial aminotransferase, and takes part in L-alanine metabolism by transamination (Rodionov et al, 2014). Glutamate dehydrogenase required for urea synthesis, mainly exists in the liver, heart and kidney, and converts glutamate to a-ketoglutarate (Hamelin et al, 2007).…”