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AGXT2

Official Full Name
alanine--glyoxylate aminotransferase 2
Background
The protein encoded by this gene is a class III pyridoxal-phosphate-dependent mitochondrial aminotransferase. It catalyzes the conversion of glyoxylate to glycine using L-alanine as the amino donor.
Synonyms
AGXT2; alanine--glyoxylate aminotransferase 2; alanine glyoxylate aminotransferase 2; alanine--glyoxylate aminotransferase 2, mitochondrial; AGT2; beta ALAAT II; beta alanine pyruvate aminotransferase; beta-ALAAT II; beta-alanine-pyruvate aminotransferase; im:7153274; zgc:114195; alanine-glyoxylate aminotransferase 2

Alanine-glyoxylate aminotransferase 2 (AGXT2) is one of the endogenous asymmetric dimethylarginine (ADMA) hydrolases, and its loss of expression or activity may affect the level of ADMA in vivo, while multiple single nucleotides polymorphism of AGXT2 is significantly associated with the level of symmetric dimethylarginine (SDMA) in vivo. ADMA and SDMA are independent predictors of cardiovascular and cerebrovascular disease or cardiovascular events.

AGXT2 is a pyridoxal phosphate (PLP)-dependent enzyme and is only found in the mitochondria of all tested mammalian species. Human AGXT2 is encoded by a nuclear gene located on chromosome 5. Upon synthesis in the cytoplasm, AGXT2 is transported to the mitochondria where its 41 amino acid N-terminal mitochondrial targeting sequence is cleaved, resulting in the formation of a mature form of the enzyme. AGXT2 is mainly expressed in the kidney and liver.

AGXT is an aminotransferase that relies on pyridoxal 5-phosphate, with L-alanine as the amino donor, irreversibly converting glyoxylate to glycine. There are two subtypes of AGXT, AGXT1 and AGXT2. AGXT1 is mainly distributed in peroxisomes, and has the activities of two aminotransferases, alanine-glyoxylic acid and serine-pyruvate. The gene mutation causes the activity to decrease or the expression is absent, which can attribute to the type I Primary hyperoxaluria (PH1). AGXT2 exerts physiological effects without the activity of serine-pyruvate transaminase, but participates in the metabolism of ADMA.

AGXT2 Figure 1. Comparison of the intracellular distribution and biochemical activity of human AGXT1 and AGXT2. (Hu, X.L., et al. 2017)

AGXT2 and ADMA Metabolism

Rodionov et al. found that ADMA levels in the liver and plasma of mice overexpressing human AGXT2 were significantly reduced, which indirectly promoted NO synthesis in vascular endothelial cells. Caplin et al. found that plasma ADMA levels were significantly elevated in AGXT2 knockout mice, while plasma levels of DMGV, a metabolite, were significantly reduced. The β-aminoisobutyrate (BAIB), a substrate for AGXT2, competes with ADMA for AGXT2 and is metabolized to methyl oxopropionate (2-methyl-). 3-oxopropanoate) and alanine (alanine) by AGXT2 in the presence of pyruvate. After perfusion of BAIB into C57/BL6 mice by micro pump, it was found that the levels of plasma ADMA and SDMA were significantly increased, while the level of DMGV was significantly decreased. These studies all suggest an important role for AGXT2 in ADMA metabolism.

An increase in plasma ADMA and SDMA may also occur after systemic infusion of BAIB in mice, possibly due to competitive inhibition of methyl arginine activity by AGXT2. Finally, ADMA and SDMA levels were found to be negatively correlated with AGXT2 expression in allografts of kidney transplant recipients, suggesting that AGXT2 also regulates human methylarginine metabolism. Caplin et al. also provided experimental evidence that the AGXT2 isolated from mouse kidney mitochondria can metabolize ADMA at physiological concentrations.

The kidney appears to be the main site of ADMA metabolism in AGXT2. A research suggest that renal clearance of ADMA may have two mechanisms: a direct mechanism by which ADMA is directly excreted into the urine, and an indirect mechanism by which ADMA is first metabolized by AGXT2 and then excreted as DMGV or DMGB into the urine. It is shown that clearance of ADMA by the AGXT2-mediated mechanism is more efficient than direct excretion of ADMA. AGXT2 is specifically localized to the epithelial cells of the Henle ring, further confirming the possible role of AGXT2 in renal ADMA metabolism and clearance.

The discovery that endogenous AGXT2 regulates systemic levels of methylarginine suggests that AGXT2 protects against cardiovascular disease. This hypothesis is consistent with the finding that up-regulation of AGXT2 protects against ADMA-mediated NO production damage to cultured endothelial cells, as well as endothelial dysfunction and hypertension phenotype observed in AGXT2 knockout mice. This is also consistent with a study showing a link between the AGXT2 locus and plasma SDMA levels and heart rate variability in young adults.

AGXT2 Gene Polymorphism and Cardiovascular Diseases

Due to the important role of AGXT2 in the metabolism of endogenous active substances such as ADMA and BAIB, recent studies on the clinical relevance of AGXT2 gene genetic variation have also been carried out. Suhre et al. performed a genome wide association study (GWAS) on 59 metabolites in human urine, and found that the non-synonymous polymorphism rs37369 (Val140Ile) of AGXT2 was highly correlated with urine BAIB levels. Rhee et al. subsequently found a very significant association between the AGXT2 rs37370 locus and plasma BAIB levels. There were also GWAS studies that found that the T allele at the rs37369 locus can increase the level of diastolic blood pressure (P = 0.0552).

In addition, researchers have found that AGXT2 loci rs37369 and rs16899974 polymorphisms is significantly correlated to serum SDMA water and a heart rate variability (HRV), rs37369 polymorphism also with ADMA / SDMA ratio is associated. In a study of 394 stroke patients, the rs28305, rs40200, and rs37369 polymorphic loci of the AGXT2 gene were associated with levels of SDMA in vivo, and the rs40200 polymorphism predicted stroke patients to some extent. The study found that the rs37369 polymorphism is related to the risk of coronary heart disease in Chinese Han smokers, the GG genotype (Val140Val) can increase the risk of coronary heart disease in individuals with diabetes and diabetes. Its mechanism may be related to smoking status It is associated with elevated levels of ADMA in the plasma.

References:

  1. Rodionov, Roman, N., Jarzebska, Natalia, Weiss, & Norbert, et al. (2014). Agxt2: a promiscuous aminotransferase. Trends in Pharmacological Sciences, 35(11), 575.
  2. Hu, X. L., Li, M. P., Song, P. Y., Tang, J., & Chen, X. P. (2017). Agxt2: an unnegligible aminotransferase in cardiovascular and urinary systems. Journal of Molecular & Cellular Cardiology, 113, 33.
  3. Kittel, A., Maas, R., König, J., Mieth, M., Weiss, N., & Jarzebska, N., et al. (2013). In vivo, evidence that agxt2 can regulate plasma levels of dimethylarginines in mice. Biochem Biophys Res Commun, 430(1), 84-89.
  4. Seppälä, I., Kleber, M. E., Lyytikäinen, L. P., Hernesniemi, J. A., Mäkelä, K. M., & Oksala, N., et al. (2013). Genome-wide association study on dimethylarginines reveals novel agxt2 variants associated with heart rate variability but not with overall mortality. European Heart Journal, 35(8), 524-31.
  5. Zhou, J. P., Bai, Y. P., Hu, X. L., Kuang, D. B., Shi, R. Z., & Xiong, Y., et al. (2014). Association of the agxt2 v140i polymorphism with risk for coronary heart disease in a chinese population. Journal of Atherosclerosis & Thrombosis, 21(10), 1022.

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