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.

Keywords: alanine; amino acid metabolism; aminotransferase; glyoxylate; methylarginine.

Figure 1

Some of the aminotransferase activities of AGXT2. In addition to its alanine-glyoxylate aminotransferase activity (A), AGXT2 catalyzes several additional aminotransferase reactions, including BAIB-pyruvate aminotransferase activity (B), ADMA-glyoxylate aminotransferase activity (C), and alanine-DOVA aminotransferase (DOVA transaminase) activity.

Figure 2. β-lyase activity of AGXT2

Figure 3

Role of AGXT2 in thymine metabolism. D-β-aminoisobutyric acid (BAIB) is a product of thymine catabolism, which is subsequently converted to methylmalonate semialdehyde by AGXT2 and then to proprionyl-CoA by methylmalonate semialdehyde dehydrogenase.

Figure 4. Role of AGXT2 in ADMA metabolism

Asymmetric N^G, N^G–dimethyl–L–arginine (ADMA), derived from hydrolysis of proteins containing methylarginine, can be converted either to citrulline by dimethylarginine dimethylaminohydrolase (DDAH) in the cytoplasm or to α-keto-δ-(NG, NG-dimethylguanidino) valeric acid (DMGV) by AGXT2 in the mitochondrion.

Figure 5

Potential role of AGXT2 in heme synthesis. The heme precursor molecule δ-aminolevulinic acid (ALA) is produced from succinyl-CoA in the mitochondrion by the enzyme ALA synthase. An alternative source of ALA in the mitochondrion has been proposed to be mediated by the DOVA transaminase activity of AGXT2.