Publications

• Probing AGXT2 enzyme activity in mouse tissue by applying stable isotope-labeled asymmetric dimethyl arginine as substrate.

  Martens-Lobenhoffer J., Rodionov R.N., Bode-Boeger S.M.

  Asymmetric dimethylarginine (ADMA) is a metabolite of the amino acid L-arginine. It competitively inhibits the enzymatic production of the cell-signaling substance nitric oxide. Therefore, increased levels of ADMA are associated with a range of cardiovascular and other diseases. ADMA is biological ... >> More

  Asymmetric dimethylarginine (ADMA) is a metabolite of the amino acid L-arginine. It competitively inhibits the enzymatic production of the cell-signaling substance nitric oxide. Therefore, increased levels of ADMA are associated with a range of cardiovascular and other diseases. ADMA is biologically eliminated by direct renal excretion and hydrolysis by the enzyme DDAH. Recently, a further elimination pathway via the transamination by the enzyme AGXT2 to α-keto-δ-(N(G),N(G)-dimethylguanidino)valeric acid (DMGV) has come into the focus of biological research. In this work, we describe an assay for the AGXT2 activity in mouse liver and kidney tissue. It is based on the transformation of isotope-labeled ADMA-d(6) to DMGV-d(6). The quantification of the DMGV-d(6) produced by this reaction in tissue homogenate samples was accomplished by chromatographic separation on a porous graphitic carbon column and tandem mass spectrometric detection. DMGV-d(6) with the deuterium labels in different molecular positions was used as internal standard. The overall production rates of DMGV-d(6) in mice were 195.37 pmol/min/mg total protein in liver and 85.21 pmol/min/mg total protein in kidney tissue, with coefficients of variation of 6.31% and 11.25%, respectively. This method can be applied as a tool for the characterization of the ADMA elimination by the AGXT2 pathway. << Less

  J. Mass Spectrom. 47:1594-1600(2012) [PubMed] [EuropePMC]

• Alanine-Glyoxylate aminotransferase-2 metabolizes endogenous methylarginines, regulates NO, and controls blood pressure.

  Caplin B., Wang Z., Slaviero A., Tomlinson J., Dowsett L., Delahaye M., Salama A., Wheeler D.C., Leiper J.

  <h4>Objective</h4>Asymmetric dimethylarginine is an endogenous inhibitor of NO synthesis that may mediate cardiovascular disease. Alanine-glyoxylate aminotransferase-2 (AGXT2) has been proposed to degrade asymmetric dimethylarginine. We investigated the significance of AGXT2 in methylarginine meta ... >> More

  <h4>Objective</h4>Asymmetric dimethylarginine is an endogenous inhibitor of NO synthesis that may mediate cardiovascular disease. Alanine-glyoxylate aminotransferase-2 (AGXT2) has been proposed to degrade asymmetric dimethylarginine. We investigated the significance of AGXT2 in methylarginine metabolism in vivo and examined the effect of this enzyme on blood pressure.<h4>Methods and results</h4>In isolated mouse kidney mitochondria, we show asymmetric dimethylarginine deamination under physiological conditions. We demonstrate increased asymmetric dimethylarginine, reduced NO, and hypertension in an AGXT2 knockout mouse. We provide evidence for a role of AGXT2 in methylarginine metabolism in humans by demonstrating an inverse relationship between renal (allograft) gene expression and circulating substrate levels and an association between expression and urinary concentrations of the product. Finally, we examined data from a meta-analysis of blood pressure genome-wide association studies. No genome-wide significance was observed, but taking a hypothesis-driven approach, there was a suggestive association between the T allele at rs37369 (which causes a valine-isoleucine substitution and altered levels of AGXT2 substrate) and a modest increase in diastolic blood pressure (P=0.0052).<h4>Conclusions</h4>Although the effect of variation at rs37369 needs further study, these findings suggest that AGXT2 is an important regulator of methylarginines and represents a novel mechanism through which the kidney regulates blood pressure. << Less

  Arterioscler. Thromb. Vasc. Biol. 32:2892-2900(2012) [PubMed] [EuropePMC]

• Dimethylarginine:pyruvate aminotransferase in rats. Purification, properties, and identity with alanine:glyoxylate aminotransferase 2.

  Ogawa T., Kimoto M., Sasaoka K.

  Dimethylarginine:pyruvate aminotransferase, which plays a role in the metabolism of dimethylarginines, has been purified to homogeneity from rat kidney. The enzyme has a molecular weight of approximately 200,000 and an isoelectric point at about pH 6.3. The enzyme consists of four similar subunits ... >> More

  Dimethylarginine:pyruvate aminotransferase, which plays a role in the metabolism of dimethylarginines, has been purified to homogeneity from rat kidney. The enzyme has a molecular weight of approximately 200,000 and an isoelectric point at about pH 6.3. The enzyme consists of four similar subunits having a molecular weight of about 50,000. The enzyme catalyzes the effective transaminations of guanidino-N methylated L-arginines (e.g. NG,NG-dimethyl-L-arginine, NG,N'G-dimethyl-L-arginine and NG-monomethyl-L-arginine) and the alpha-amino group of L-ornithine to pyruvate or glyoxylate. The enzyme was always accompanied by the known alanine:glyoxylate amino-transferase activity with the ratios of their specific activities remaining constant during the purification steps. The physicochemical and immunological properties of the purified enzyme were shown to be identical with those of the isozyme of alanine:glyoxylate aminotransferase (EC 2.6.1.44), designated as alanine:glyoxylate aminotransferase 2 (Noguchi, T. (1987) in Peroxisomes in Biology and Medicine (Fahimi, H. D., and Sies, H., eds) pp. 234-243, Springer-Verlag, Heidelberg). The distribution profiles in tissues and the negative response to glucagon treatment further supported the identity of the two enzymes. The present data show that alanine:glyoxilate aminotransferase 2 functions in dimethylarginine metabolism in vivo in rats. << Less

  J. Biol. Chem. 265:20938-20945(1990) [PubMed] [EuropePMC]

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