Detection and quantification of α-keto-δ-(NG,NG-dimethylguanidino)valeric acid: A metabolite of asymmetric dimethylarginine

Martens‐Lobenhoffer, Jens; Rodionov, Roman N.; Drust, Andreas; Bode‐Böger, Stefanie M.

doi:10.1016/j.ab.2011.08.044

Cited by 29 publications

(27 citation statements)

References 17 publications

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“…ADMA was suggested as the potential candidate metabolite. While the chromatographic retention time (RT) as well as mass ruled out ADMA as the actual parent mass, we determined that the product of a transamination reaction (causing the substitution of an amine with a carbonyl group) (Figure 2A) of ADMA by AGXT2 would have an m/z within 1 ppm of our unknown metabolite, which is well within the acceptable mass error using this technology (26) (27,28).…”

Section: Resultsmentioning

confidence: 70%

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

O’Sullivan¹,

Morningstar²,

Yang³

et al. 2017

Journal of Clinical Investigation

124

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Unbiased, "nontargeted" metabolite profiling techniques hold considerable promise for biomarker and pathway discovery, in spite of the lack of successful applications to human disease. By integrating nontargeted metabolomics, genetics, and detailed human phenotyping, we identified dimethylguanidino valeric acid (DMGV) as an independent biomarker of CTdefined nonalcoholic fatty liver disease (NAFLD) in the offspring cohort of the Framingham Heart Study (FHS) participants. We verified the relationship between DMGV and early hepatic pathology. Specifically, plasma DMGV levels were correlated with biopsy-proven nonalcoholic steatohepatitis (NASH) in a hospital cohort of individuals undergoing gastric bypass surgery, and DMGV levels fell in parallel with improvements in post-procedure cardiometabolic parameters. Further, baseline DMGV levels independently predicted future diabetes up to 12 years before disease onset in 3 distinct human cohorts. Finally, we provide all metabolite peak data consisting of known and unidentified peaks, genetics, and key metabolic parameters as a publicly available resource for investigations in cardiometabolic diseases.

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Section: Resultsmentioning

confidence: 70%

“…DMGV has been measured in the blood of rats and humans in 2 prior studies (27,28), but it has never been correlated with metabolic disease and had not been added to biochemical databases. In our analyses, DMGV was an independent predictor of future T2D in the FHS, MDC, and JHS cohorts.…”

Section: Discussionmentioning

confidence: 99%

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

O’Sullivan¹,

Morningstar²,

Yang³

et al. 2017

Journal of Clinical Investigation

124

View full text Add to dashboard Cite

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“…ADMA can be transaminated by the enzyme alanine glyoxylate aminotransferase 2 to DMGV [α-keto-δ-(N (G),N(G)-dimethylguanidino)valeric acid], a mitochondrial aminotransferase expressed primarily in the kidney. 10 Now that we are able to determine DMGV in plasma, urine, and tissues, 11 the in vivo importance of this pathway for regulation of systemic ADMA levels can be shown. 12 In contrast to DDAHs, AGXT 2 can metabolize not only ADMA but also SDMA, which deserves further research in the future.…”

Section: Origin and Removal Of Adma And Sdmamentioning

confidence: 99%

Dimethylarginines ADMA and SDMA: The Real Water-Soluble Small Toxins?

Schepers

Speer

Bode‐Böger

et al. 2014

Seminars in Nephrology

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“…Methylarginine, amino acids, and dimethyl-guanidino valeric acid levels were quantified using liquid chromatography tandem mass spectrometry using a modification of methods previously described. 15,18 Briefly, an internal standard (deuterium [d7]-labeled ADMA, Cambridge Isotope Laboratories) was added to 50 or 100 µL of biological samples (plasma, urine, tissue lysate, enzyme assay) before precipitation in 5 volumes of methanol. After centrifugation (13 000 rpm for 10 minutes at 4ºC), 100 to 200 µL of the supernatant was vacuum dried for 2 hours using a refrigerated vacuum dryer.…”

Section: Biochemical Measurementsmentioning

confidence: 99%

“…ADGV is found in the plasma and urine. 15 Although AGXT2 has been reported to degrade exogenous ADMA in rats, 16 experimentally this occurs with a Michaelis constant (K m ) far higher than prevailing methylarginine concentrations. Recent evidence suggests that this enzyme will reduce endogenous circulating methylarginines after virus-mediated overexpression in mice.…”

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confidence: 99%

Alanine-Glyoxylate Aminotransferase-2 Metabolizes Endogenous Methylarginines, Regulates NO, and Controls Blood Pressure

Caplin

Wang

Slaviero

et al. 2012

ATVB

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Objective-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. Methods and Results-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 hypothesisdriven 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). Conclusion-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. (Arterioscler Thromb Vasc Biol. 2012;32:2892-2900.)Key Words: alanine-glyoxylate aminotransferase-2 ◼ asymmetric dimethylarginine ◼ hypertension ◼ kidney ◼ NO

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Detection and quantification of α-keto-δ-(NG,NG-dimethylguanidino)valeric acid: A metabolite of asymmetric dimethylarginine

Cited by 29 publications

References 17 publications

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

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

Dimethylarginines ADMA and SDMA: The Real Water-Soluble Small Toxins?

Alanine-Glyoxylate Aminotransferase-2 Metabolizes Endogenous Methylarginines, Regulates NO, and Controls Blood Pressure

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