Determination of equilibria constants of arginine:glycine amidinotransferase (AGAT)-catalyzed reactions using concentrations of circulating amino acids

Tsikas, Dimitrios

doi:10.1007/s00726-022-03218-5

Cited by 2 publications

(4 citation statements)

References 42 publications

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“…It is noteworthy that metabolites belonging to creatine metabolism were the ones most related to biguanides, especially metformin and buformin, according to our results during structural, physicochemical, and binding comparisons. Recently, has authors have reported the competitive inhibition of AGAT by a metformin treatment (3 × 1500 mg daily for 6 weeks) in individuals with Becker muscular dystrophy, leading to reduced concentrations of guanidinoacetic acid in both serum and urine [ 55 ]. Remarkably, decreased renal and pancreatic AGAT activity, but not decreased mRNA expression, have been reported after creatine supplementation in rats, suggesting that creatine can be involved in a negative feedback regulation mechanism [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

Metformin May Alter the Metabolic Reprogramming in Cancer Cells by Disrupting the L-Arginine Metabolism: A Preliminary Computational Study

Espinosa-Rodríguez

Treviño-Almaguer

Carranza-Rosales

et al. 2023

IJMS

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Metabolic reprogramming in cancer is considered to be one of the most important hallmarks to drive proliferation, angiogenesis, and invasion. AMP-activated protein kinase activation is one of the established mechanisms for metformin’s anti-cancer actions. However, it has been suggested that metformin may exert antitumoral effects by the modulation of other master regulators of cellular energy. Here, based on structural and physicochemical criteria, we tested the hypothesis that metformin may act as an antagonist of L-arginine metabolism and other related metabolic pathways. First, we created a database containing different L-arginine-related metabolites and biguanides. After that, comparisons of structural and physicochemical properties were performed employing different cheminformatic tools. Finally, we performed molecular docking simulations using AutoDock 4.2 to compare the affinities and binding modes of biguanides and L-arginine-related metabolites against their corresponding targets. Our results showed that biguanides, especially metformin and buformin, exhibited a moderate-to-high similarity to the metabolites belonging to the urea cycle, polyamine metabolism, and creatine biosynthesis. The predicted affinities and binding modes for biguanides displayed good concordance with those obtained for some L-arginine-related metabolites, including L-arginine and creatine. In conclusion, metabolic reprogramming in cancer cells by metformin and biguanides may be also driven by metabolic disruption of L-arginine and structurally related compounds.

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Section: Discussionmentioning

confidence: 99%

Metformin May Alter the Metabolic Reprogramming in Cancer Cells by Disrupting the L-Arginine Metabolism: A Preliminary Computational Study

Espinosa-Rodríguez

Treviño-Almaguer

Carranza-Rosales

et al. 2023

IJMS

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“…The urinary excretion rates of amino acids were corrected for the urinary excretion rate of creatinine, and these results are presented as µM analyte per mM creatinine. The equilibrium constant for the AGAT-catalyzed formation of GAA (i.e., K GAA ) from L-arginine (Arg) and glycine (Gly) was determined as described elsewhere (Tsikas 2022 ). The equilibrium constant for the AGAT-catalyzed formation of hArg (i.e., K harg ) from Arg and L-lysine (Lys) was determined similarly (Tsikas 2022 ).…”

Section: Methodsmentioning

confidence: 99%

“…The equilibrium constant for the AGAT-catalyzed formation of GAA (i.e., K GAA ) from L-arginine (Arg) and glycine (Gly) was determined as described elsewhere (Tsikas 2022 ). The equilibrium constant for the AGAT-catalyzed formation of hArg (i.e., K harg ) from Arg and L-lysine (Lys) was determined similarly (Tsikas 2022 ). Because of co-elution and interconversion (Hanff et al 2019 ), the sum concentration for the following amino acids is reported: leucine and isoleucine (Leu + Ile), glutamate and glutamine (Glu + Gln), ornithine and citrulline (Orn + Cit), aspartate and asparagine (Asp + Asn).…”

Section: Methodsmentioning

confidence: 99%

“…Valid analytical methods are required to determine deviations from “normal” values and intervals of certain metabolites in the blood, which may then be used in diagnosis and therapy. The determination of several biochemical parameters enables a more complex assessment of the imbalance caused by a disease or by other circumstances (Tsikas 2022 ). In Arg-involving pathways, the Arg bioavailability is of key importance and is dependent on many factors including its cellular transport (Kittel and Maas 2014 ) and the arginase (ARG) activity (Caldwell et al 2018 ).…”

Section: Introductionmentioning

confidence: 99%

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Amino acids, post-translational modifications, nitric oxide, and oxidative stress in serum and urine of long COVID and ex COVID human subjects

et al. 2023

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In this study, we investigated the status of amino acids, their post-translational modifications (PTM), major nitric oxide (NO) metabolites and of malondialdehyde (MDA) as a biomarker of oxidative stress in serum and urine samples of long COVID (LoCo, n = 124) and ex COVID (ExCo, n = 24) human subjects collected in 2022. Amino acids and metabolites were measured by gas chromatography–mass spectrometry (GC–MS) methods using stable-isotope labelled analogs as internal standards. There were no differences with respect to circulating and excretory arginine and asymmetric dimethylarginine (ADMA). LoCo participants excreted higher amounts of guanidino acetate than ExCo participants (17.8 ± 10.4 µM/mM vs. 12.6 ± 8.86 µM/mM, P = 0.005). By contrast, LoCo participants excreted lower amounts of the advanced glycation end-product (AGE) NG-carboxyethylarginine (CEA) than ExCo participants did (0.675 ± 0.781 µM/mM vs. 1.16 ± 2.04 µM/mM, P = 0.0326). The serum concentrations of MDA did not differ between the groups, indicating no elevated oxidative stress in LoCo or ExCo. The serum concentration of nitrite was lower in LoCo compared to ExCo (1.96 ± 0.92 µM vs. 2.56 ± 1.08 µM; AUC, 0.718), suggesting altered NO synthesis in the endothelium. The serum concentration of nitrite correlated inversely with the symptom anxiety (r = − 0.293, P = 0.0003). The creatinine-corrected urinary excretion of Lys and its metabolite L-5-hydroxy-Lys correlated positively with COVID toes (r = 0.306, P = 0.00027) and sore throat (r = 0.302, P = 0.0003). Our results suggest that amino acid metabolism, PTM and oxidative stress are not severely affected in long COVID. LoCo participants may have a lower circulating NO reservoir than ExCo.

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Determination of equilibria constants of arginine:glycine amidinotransferase (AGAT)-catalyzed reactions using concentrations of circulating amino acids

Cited by 2 publications

References 42 publications

Metformin May Alter the Metabolic Reprogramming in Cancer Cells by Disrupting the L-Arginine Metabolism: A Preliminary Computational Study

Metformin May Alter the Metabolic Reprogramming in Cancer Cells by Disrupting the L-Arginine Metabolism: A Preliminary Computational Study

Amino acids, post-translational modifications, nitric oxide, and oxidative stress in serum and urine of long COVID and ex COVID human subjects

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