Experimental evidence that maleic acid markedly compromises glutamate oxidation through inhibition of glutamate dehydrogenase and α-ketoglutarate dehydrogenase activities in kidney of developing rats

Roginski, Ana Cristina; Cecatto, Cristiane; Wajner, Simone Magagnin; Camera, Fernanda Dal’Maso; Castilho, Roger F.; Wajner, Moaçir; Amaral, Alexandre Umpierrez

doi:10.1007/s11010-019-03534-7

Cited by 9 publications

(10 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, up-regulation of hydroxyproline has been observed in response to many different kinds of stress, such as inflammatory and genotoxic stresses [ 62 , 63 ]. Elevated concentrations of malate were linked to kidney dysfunction in rats [ 64 ], and the increased concentration of malate observed in the kidneys of the birds administered CORT could indicate that the CORT treatment is a biomarker of renal dysfunction and this warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

Corticosterone-Mediated Physiological Stress Alters Liver, Kidney, and Breast Muscle Metabolomic Profiles in Chickens

Brown

Zaytsoff

Montina

et al. 2021

Animals

View full text Add to dashboard Cite

The impact of physiological stress on the metabolomes of liver, kidney, and breast muscle was investigated in chickens. To incite a stress response, birds were continuously administered corticosterone (CORT) in their drinking water at three doses (0, 10, and 30 mg L−1), and they were sampled 1, 5, and 12 days after the start of the CORT administration. To solubilize CORT, it was first dissolved in ethanol and then added to water. The administration of ethanol alone significantly altered branched chain amino acid metabolism in both the liver and the kidney, and amino acid and nitrogen metabolism in breast muscle. CORT significantly altered sugar and amino acid metabolism in all three tissues, but to a much greater degree than ethanol alone. In this regard, CORT administration significantly altered 11, 46, and 14 unique metabolites in liver, kidney, and breast muscle, respectively. Many of the metabolites that were affected by CORT administration, such as mannose and glucose, were previously linked to increases in glycosylation and gluconeogenesis in chickens under conditions of production stress. Moreover, several of these metabolites, such as dimethylglycine, galactose, and carnosine were also previously linked to reduced quality meat. In summary, the administration of CORT in chickens significantly modulated host metabolism. Moreover, results indicated that energy potentials are diverted from muscle anabolism to muscle catabolism and gluconeogenesis during periods of stress.

show abstract

Section: Discussionmentioning

confidence: 99%

Corticosterone-Mediated Physiological Stress Alters Liver, Kidney, and Breast Muscle Metabolomic Profiles in Chickens

Brown

Zaytsoff

Montina

et al. 2021

Animals

View full text Add to dashboard Cite

show abstract

“…Interestingly, maleic acid which accumulates during PAcidemia condition is reported to inhibit human kidney GDH activity. 22 The inhibition potency of maleic acid might be related to better positioning of the two carboxylate groups in the mammalian GDH active site due to presence of the cis double bond between C2 and C3. However, the fumarate (trans) and maleate (cis) act as weak inhibitors for AtGDH as compared to mammalian GDH.…”

Section: Discussionmentioning

confidence: 99%

“…21 Some of the metabolites are also reported to control the function of mammalian GDHs. Metabolic disorders such as propionic acidemia (PAcidemia), 22 ureagenesis and tumor growth 20,23,24 are linked with the function of GDH. In a metabolic organic acid disorder (organic aciduria) accumulation of metabolites such as fumarate, malonate are reported.…”

Section: Introductionmentioning

confidence: 99%

“…27 Similarly in PAcidemia, maleic acid along with other precursor organic acids such as propionic acid, 3-hydroxypropionic acid and 2methylcitric acids are also excessively excreted in urine (~5 mM). 22 Recently, a study showed that the maleic acid specifically inhibits the kidney mitochondrial NAD + linked GDH (K i = 1.93 mM) and AKG dehydrogenase (K i = 0.5 mM) by acting as competitive inhibitor. 22 Additionally, there are several metabolites of TCA cycle like fructose-1, 6-diphosphate, isocitrate, fumarate and non-metabolites which are known to affect the GDH activity.…”

Section: Introductionmentioning

confidence: 99%

“…22 Recently, a study showed that the maleic acid specifically inhibits the kidney mitochondrial NAD + linked GDH (K i = 1.93 mM) and AKG dehydrogenase (K i = 0.5 mM) by acting as competitive inhibitor. 22 Additionally, there are several metabolites of TCA cycle like fructose-1, 6-diphosphate, isocitrate, fumarate and non-metabolites which are known to affect the GDH activity. Caughey and his group reported in 1957 that the 5-carbon dicarboxylate anions, AKG and glutarate act as competitive inhibitors against the beef liver GDH.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Molecular insights into the inhibition of glutamate dehydrogenase (GDH) by the dicarboxylic acid metabolites

Godsora

Prakash

Punekar

et al. 2021

Preprint

View full text Add to dashboard Cite

Glutamate dehydrogenase (GDH) is a salient metabolic enzyme which catalyzes the NAD+- or NADP+-dependent reversible conversion of α-ketoglutarate (AKG) to L-glutamate; and thereby connects the carbon and nitrogen metabolism cycles in all living organisms. The function of GDH is extensively regulated by both metabolites (citrate, succinate, etc.) and non-metabolites (ATP, NADH, etc.) but sufficient molecular evidences are lacking to rationalize the inhibitory effects by the metabolites. We have expressed and purified NADP+-dependent Aspergillus terreus GDH (AtGDH) in recombinant form. Succinate, malonate, maleate, fumarate and tartrate independently inhibit the activity of AtGDH to different extents. The crystal structures of AtGDH complexed with the dicarboxylic acid metabolites and the coenzyme NADPH have been determined. Although AtGDH structures are not complexed with substrate; surprisingly, they acquire super closed conformation like previously reported for substrate and coenzyme bound catalytically competent Aspergillus niger GDH (AnGDH). These dicarboxylic acid metabolites partially occupy the same binding pocket as substrate; but interact with varying polar interactions and the coenzyme NADPH binds to the Domain-II of AtGDH. The low inhibition potential of tartrate as compared to other dicarboxylic acid metabolites is due to its weaker interactions of carboxylate groups with AtGDH. Our results suggest that the length of carbon skeleton and positioning of the carboxylate groups of inhibitors between two conserved lysine residues at the GDH active site might be the determinants of their inhibitory potency. Molecular details on the dicarboxylic acid metabolites bound AtGDH active site architecture presented here would be applicable to GDHs in general.

show abstract

Molecular insights into the inhibition of glutamate dehydrogenase by the dicarboxylic acid metabolites

et al. 2021

View full text Add to dashboard Cite

Glutamate dehydrogenase (GDH) is a salient metabolic enzyme which catalyzes the NAD + -or NADP + -dependent reversible conversion of α-ketoglutarate (AKG) to L-glutamate; and thereby connects the carbon and nitrogen metabolism cycles in all living organisms. The function of GDH is extensively regulated by both metabolites (citrate, succinate, etc.) and non-metabolites (ATP, NADH, etc.) but sufficient molecular evidences are lacking to rationalize the inhibitory effects by the metabolites. We have expressed and purified NADP + -dependent Aspergillus terreus GDH (AtGDH) in recombinant form. Succinate, malonate, maleate, fumarate, and tartrate independently inhibit the activity of AtGDH to different extents. The crystal structures of AtGDH complexed with the dicarboxylic acid metabolites and the coenzyme NADPH have been determined. Although AtGDH structures are not complexed with substrate; surprisingly, they acquire super closed conformation like previously reported for substrate and coenzyme bound catalytically competent Aspergillus niger GDH (AnGDH). These dicarboxylic acid metabolites partially occupy the same binding pocket as substrate; but interact with varying polar interactions and the coenzyme NADPH binds to the Domain-II of AtGDH. The low inhibition potential of tartrate as compared to other dicarboxylic acid metabolites is due to its weaker interactions of carboxylate groups with AtGDH. Our results suggest that the length of carbon skeleton and positioning of the carboxylate groups of inhibitors between two conserved lysine residues at the GDH active site might be the determinants of their inhibitory potency. Molecular details on the dicarboxylic acid metabolites bound AtGDH active site architecture presented here would be applicable to GDHs in general.

show abstract

Experimental evidence that maleic acid markedly compromises glutamate oxidation through inhibition of glutamate dehydrogenase and α-ketoglutarate dehydrogenase activities in kidney of developing rats

Cited by 9 publications

References 57 publications

Corticosterone-Mediated Physiological Stress Alters Liver, Kidney, and Breast Muscle Metabolomic Profiles in Chickens

Corticosterone-Mediated Physiological Stress Alters Liver, Kidney, and Breast Muscle Metabolomic Profiles in Chickens

Molecular insights into the inhibition of glutamate dehydrogenase (GDH) by the dicarboxylic acid metabolites

Molecular insights into the inhibition of glutamate dehydrogenase by the dicarboxylic acid metabolites

Contact Info

Product

Resources

About