Glutamate dehydrogenase (GDH) is an enzyme that plays a pivotal role in glutamine metabolism by converting glutamate to a-ketoglutarate, especially when glucose is 8a), chronic administration of EGCG during fasting improved the basal plasma glucose levels in the TG mice (Fig. Yang L., Moss T., Mangala L.S., Marini J., Zhao H., Wahlig S., Armaiz-Pena G., Jiang D., Achreja A., Win J., et al. Epub 2022 Mar 25. ECG/EGCG are extremely hydrophilic and ECG interactions with GDH are dominated by polar interactions [85]. Choo AY, Kim SG, Vander Heiden MG, Mahoney SJ, Vu H, Yoon S-O, Cantley LC, Blenis J. Glucose addiction of TSC null cells Is caused by failed mTORC1-dependent balancing of metabolic demand with supply. One way to understand the metabolic role of GDH is by reviewing the physiological levels of metabolites and GDH Kms for these substrates (Table 1). The marked sensitivity of GDH for GTP over ATP likely serves as a more accurate sensor for the metabolic state of the mitochondria. In human kidney, the epithelial cells lining the proximal convoluted tubules of the renal cortex densely express both hGDH1 and hGDH2 with a similar pattern. However, the whole process of glutamate oxidation in-vivo is far more complicated and highly tissue dependent but still is dominated by GDH (e.g. The NAD+-dependent GDH serves mainly a metabolic role, whereas the NADP+-specific enzyme is involved in biosynthetic functions [4]. See this image and copyright information in PMC. The images on the right show close up views of GTP and ADP bound to the enzyme. [77]), we supposed that the polyphenols from green tea might affect GDH activity. GDH catalyzes the reversible It is a zinc protein, requires NAD+ or NADP+ as coenzyme, and is present in high concentrations in the mitochondria of liver, heart, muscle, and kidney. FOIA Also, hGDH1-specific staining is detected in the nucleus of a GFAP positive astrocyte (C,D,E), of a connexin 47-positive oligodendrocyte (F) and of an NG2-positive oligodendrocyte-precursor (G,H,I) (IF images of unfixed human frontal lobe cortex. Csibi A, Fendt SM, Li C, Poulogiannis G, Choo AY, Chapski DJ, Jeong SM, Dempsey JM, Parkhitko A, Morrison T, Henske EP, Haigis MC, Cantley LC, Stephanopoulos G, Yu J, Blenis J. The best known paradigm is the HI/HA syndrome caused by regulatory mutations in the GLUD1 gene that render the enzyme resistant to GTP inhibition [33]. It is important to note that allosteric GDH inhibitors may have more applications than just treating HHS. However, in the presence of high glucose that increases the GTP/ ADP ratios, GDH was inhibited to such a degree that leucine could no longer activate glutamate catabolism [49]. This allosteric regulation is thought to provide an energy-sensing mechanism by which GDH1 activity is controlled by the cellular needs for ATP [1,17]. Indeed, the ADP/EGCG antagonism may allow for an allosteric release valve whereby even EGCG inhibition is abrogated by ADP when the need for amino acid catabolism is strong enough. By choosing conditions for the screen that favor a highly-inhibited state of GDH, it was possible to identify 75-E10 with nearly 1000-fold higher efficacy than the only other synthetic activator of GDH, BCH, and more effective than the natural activator, ADP (Fig. Untangling the glutamate dehydrogenase allosteric nightmare. In human adrenal cortex all three layers that produce steroid hormones express densely both hGDH1 and hGDH2. This second coenzyme site strongly favors NADH over NADPH with Kds of 57 and 700 M, respectively. Botman D., Tigchelaar W., Van Noorden C.J. Familial hyperinsulinism with apparent autosomal dominant inheritance: clinical and genetic differences from the autosomal recessive variant. l-Glutamate dehydrogenases: distribution, properties and mechanism, Glutamate dehydrogenase VI. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Patients with HHS have increased -cell responsiveness to leucine and susceptibility to hypoglycemia following high protein meals [63]. Similarly, study of hGDH1/2 mutants, displaying various basal activities, revealed that the affinity of steroid hormones for these enzymes correlates inversely with their basal catalytic activity (R = 0.99; p = 0.0001) [56]. 2014;39(3):433-45. doi: 10.1007/s11064-013-1173-2. Sener A, Malaisse WJ. Glutamate Dehydrogenase JCI Insight. Treberg J.R., Banh S., Pandey U., Weihrauch D. Intertissue differences for the role of glutamate dehydrogenase in metabolism. 6b) and the S397I mutation greatly destabilizes the enzyme while abrogating both GTP and ADP regulation (Figs. From sequencing GDH1 and GDH2 genes in Parkinsons disease patients, an A445S mutation in GDH2 that increases activity was found to be correlated with 613 year earlier onset of symptoms [25]. eCollection 2021. Whereas the mechanism by which hGDH2 expression in nerve terminals could promote glutamate formation is presently unclear, it is likely that oxidative deamination of glutamate (derived from glutamine deamidation in mitochondrial matrix) generates -ketoglutarate, which is then transferred (via the -ketoglutarate/malate transporter) to the cytosol where it is transaminated to glutamate [124]. Under such conditions, the GDH activity is expected to increase to respond to the energy needs of the mitochondria. Division of Endocrinology, Childrens Hospital of Philadelphia, Philadelphia, PA 19104, USA. More recently, the use of molecular biologic approaches resulted in rapid progress in characterizing the genes encoding the GDH of different organisms and their products, including the two human GDH isoenzymes [23,29]. Metabolic control of epilepsy. 12-7). 1972 Apr;52(2):382-414 Studies on the brain have also demonstrated that even under hyperammonemic conditions, GDH operates in the oxidative deamination direction [53, 54]. Yang H, Ye D, Guan KL, Xiong Y. IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives. Thornton PS, Satin-Smith MS, Herold K, Glaser B, Chiu KC, Nestorowicz A, Permutt MA, Baker L, Stanley CA. Therefore, EGCG is indeed a specific inhibitor of GDH both in vitro and in situ. Bithionol and GW5074 bind in essentially the same site that is distinct to the HCP site (Fig. The structure of bovine glutamate dehydrogenase provides insights into the mechanism of allostery. Properties and molecular evolution of human GLUD2 (neural and testicular tissue-specific) glutamate dehydrogenase. This is entirely consistent with the finding that GTP inhibits the reaction by slowing down product release and concomitantly increasing the binding affinity of substrate and coenzyme [5, 6, 16]. 1982 May 25;257(10):5579-83 2009 Sep;90(3):862S-866S. EGCG inhibition is non-competitive and, similar to GTP inhibition, is abrogated by leucine, BCH, and ADP. In addition, as was first observed in the islet perifusion assays (Fig. Abstract In-vitro, glutamate dehydrogenase (GDH) catalyzes the reversible oxidative deamination of glutamate to -ketoglutarate (-KG). Metronidazole is the drug of choice for an initial episode of mild to moderate CDI. This is the same as what was observed when crystallizing the ADP/GDH complex [9]. However, because 75-E10 removes GTP inhibition, the apparent maximum activation is markedly different in the presence of GTP. Additional studies utilizing recombinant human isoenzymes revealed that the green tea polyphenol EGCG inhibits hGDH2 with a greater affinity than hGDH1 with this differential effect being more pronounced in the absence of ADP [46]. GLDH is not currently used routinely in nonclinical settings often due to the limited availability of reliable reagents, but there may be instances where GLDH is an appropriate adjunct to help delineate liver injury in preclinical species. Sener A, Malaisse-Lagae F, Malaisse WJ. In these steroidogenic organs, the two human isoenzymes are specifically expressed in the cells that synthesize steroid hormones, where they may provide NADPH for the synthesis of these hormones. glutamine Differential glutamate dehydrogenase (GDH) activity profile in patients with temporal lobe epilepsy. In A. thaliana and of O. sativa the NADP+-specific GDH is 50% longer than the NAD+-specific enzymes. However, their biological function is not fully understood [8]. Transcriptome analysis revealed growth phase-associated changes of a centenarian-originated probiotic Bifidobacterium animalis subsp. As noted above, structural studies on GDH from an extremely thermophilic bacteria, Thermus thermophilus, suggest that this bithionol/GW5074 binding site might be involved in leucine allosteric activation [37]. 1.4.1.2 Investigation of the effects of crosslinking glutamate dehydrogenase with dimethylpimelimidate. Properties and molecular evolution of human GLUD2 (neural and testicular tissue-specific)glutamate dehydrogenase. Epigallocatechin gallate, a component of green tea, may be a potential therapeutic agent for HIHA by blocking the ADP receptor thereby causing GDH inhibition [58,59]. Shown is a cartoon diagram of the apo form of the hGDH1 hexamer (PDB code: 1L1F), where each of the six subunits is colored differently. As also noted in the red box, GTP and ADP stabilize and destabilize this abortive complex, respectively. Obviously, these levels are prone to change depending upon the metabolic state of the mitochondria. In addition, the aromatic rings of the HCP molecules stack against each other in this ring conformation. The structure of apo human glutamate dehydrogenase details subunit communication and allostery. GDH may have initially evolved these large conformational changes to improve catalytic efficiency [60]. Therefore, while GTP and glutamate bind synergistically with NADH to inhibit GDH, ADP activates the reaction by decreasing the affinity of the enzyme for coenzyme at the active site. Glutamate dehydrogenase (GDH) is a mitochondrial enzyme that is normally activated by leucine and ADP and inhibited by GTP and ATP. Karaca M., Frigerio F., Migrenne S., Martin-Levilain J., Skytt D.M., Pajecka K., Martin-del-Rio R., Gruetter R., Tamarit-Rodriguez J., Waagepetersen H.S., et al. This bacterial form of GDH is rather different than animal GDH in that it has two different types of subunits; a regulatory subunit, GDHA, and a catalytic subunit, GDHB. Parsons D.W., Jones S., Zhang X., Lin J.C., Leary R.J., Angenendt P., Mankoo P., Carter H., Siu I.M., Gallia G.L., et al. It has been accordingly suggested the glutamate flux through hGDH1 and hGDH2 may generate NADPH (Figure 1) needed for steroid biosynthesis [57]. Dysregulated cellular metabolism is one of the hallmarks of cancer with some tumours utilising the glutamine metabolism pathway for their sustained proliferation and survival. Amino acids whose carbon skeletons can be synthesized are called nonessential, whereas those that must be obtained from the diet are termed essential (Table 12-1). The metabolic fate of 13N-labeled ammonia in rat brain. This model is further supported by the amino acid metabolism studies that measure amino acids levels in the pancreatic tissue [85]. Mavrothalassitis G., Tzimagiorgis G., Mitsialis A., Zannis V., Plaitakis A., Papamatheakis J., Moschonas N. Isolation and characterization of cDNA clones encoding human liver glutamate dehydrogenase: evidence for a small gene family. As described above, mammalian GDH is allosterically regulated, with chemically diverse compounds shown to influence the enzymes velocity. Federal government websites often end in .gov or .mil. Neurochem Res. Spanaki C., Kotzamani D., Petraki Z., Drakos E., Plaitakis A. Heterogeneous cellular distribution of glutamate dehydrogenase in brain and in non-neural tissues. The very dense hGDH1 staining of hepatocytes is in accord with previous observations derived from enzymatic assays showing that the highest levels of GDH activity occur in the liver. Filter Results | Page 1 of 5043 | GeneTex 3). glutamine Shashidharan P., Clarke D.D., Ahmed N., Moschonas N., Plaitakis A. Nerve tissue-specific human glutamate dehydrogenase that is thermolabile and highly regulated by ADP. Some attempts at blocking glutamine metabolism in cancer patients resulted in toxicity, prompting Leone et al. Leucine, as well as some other monocarboxylic acids, has been shown to activate mammalian GDH by facilitating coenzyme release in a manner similar to ADP but probably not via the same binding site [14]. The specificity for GDH was slightly less than that of SDH. Dear Friends and Colleagues, As Editor-in-Chief of Metabolism: Clinical and Experimental, I'm happy to share great news about the journal. [77] that hGDH2 is more efficiently targeted to mitochondria than hGDH1. HCP in the other binding orientation makes hydrophobic interactions with M150, I187, Y190 and the methylene side chain atoms from T186 to K154. In addition, hGDH1 localizes to the nuclear membrane of glial cells and hGDH2 to the nuclear membrane of small cortical neurons (Figure 2 and Figure 4) [73]. FOIA Each subunit is represented by a ribbon diagram and in different colors. 3b, ,6b).6b). Thomas J. Smith, Donald Danforth Plant Science Center, 975 North Warson Road, Saint Louis, MO 63132, USA. Animal GDH has a long protrusion, antenna, rising above the NAD binding domain that is not found in bacteria, plants, fungi, and the vast majority of protists. Thus, Tg animals over-expressing neuronal hGDH1 exhibit age-dependent degeneration of the CA1 hippocampal region resembling Alzheimers disease pathology [122]. The exact mechanism of action of EGCG with regard to these various effects is largely unknown and in many cases, is assumed to be due to its antioxidant activity. Zaganas I., Pajcka K., Wendel Nielsen C., Schousboe A., Waagepetersen H.S., Plaitakis A. Comparison of EGCG inhibitory curves obtained in different buffer compositions shows that both human isoenzymes are substantially more sensitive to EGCG in phosphate pH 7.50 buffer than in TRA pH 8.0 buffer [46]. 1) is essentially two trimers of subunits stacked directly on top of each other with each subunit being composed of at least three domains [8, 9, 14, 15]. Therefore, the GTP/GDP ratio is much better metric of TCA cycle activity than the ATP/ADP ratio. On the other hand, neurons are devoid of significant GDH1 expression, except for the neurons of spinal ganglia [98]. HCP binds in two orientations. Epub 2016 Jul 16. Heme synthesis is coordinated with globin synthesis during erythropoiesis and as such does not occur in the mature erythrocyte. Bahi-Buisson N., Roze E., Dionisi C., Escande F., Valayannopoulos V., Feillet F., Heinrichs C., Chadefaux-Vekemans B., Dan B., De Lonlay P. Neurological aspects of hyperinsulinism-hyperammonaemia syndrome. Transgenic animals over-expressing neuronal GDH1 exhibit age-dependent degeneration of the CA1 hippocampal region similar to Alzheimers disease pathology [26]. Heterogeneous cellular distribution of glutamate dehydrogenase in brain and in non-neural tissues. 1Department of Neurology, Faculty of Medicine, School of Health Sciences, University of Crete, Heraklion, Crete 71003, Greece; moc.liamg@arzefelakretse (E.K.-E.); rg.oohay@inamaztokd (D.K. These results give credence to suggestions of Rosso et al. Scharfman H.E. b HCP also blocks the hyper-response to glutamine by the transgenic tissue. N.V. Bhagavan, Chung-Eun Ha, in Essentials of Medical Biochemistry (Second Edition), 2015. Phenylalanine hydroxylase is a mixed-function oxidase that uses the cofactor tetrahydrobiopterin to split molecular O2, adding one atom to the phenylalanine ring and converting the other to water. This protein is part of the TOM channel involved in the recognition and import of precursor proteins from the cytosol into mitochondria as noted above [86,87,88]. ScienceDirect is a registered trademark of Elsevier B.V. ScienceDirect is a registered trademark of Elsevier B.V. Principles and Practice of Pediatric Infectious Diseases (Fourth Edition), Biomarkers in Nonclinical Drug Development, A Comprehensive Guide to Toxicology in Nonclinical Drug Development (Second Edition), Avery's Diseases of the Newborn (Ninth Edition), Avery's Diseases of the Newborn (Eighth Edition), Elsevier's Integrated Review Biochemistry (Second Edition), Genetic Diagnosis of Endocrine Disorders (Second Edition). SCHAD and SIRT4 are not allosteric ligands but rather enzymes that interact with GDH and cause inhibition. This is consistent with quantitative enzyme histochemical analysis that demonstrated that NAD+ is used ~ 2.5 fold more than NADP+ for GDH catabolism [46]. The in vivo half-life in six cows was reported as 14h (Collis et al., 1979). Glutamate Dehydrogenase This is more than likely due to the high (mM) ED50 for leucine and the very high concentrations of solutes necessary for GDH crystallization. Sirt2 or sirtuins (silent mating type information regulation 2 homolog) are found in all organisms and most are NAD-dependent protein deacetylases. NCBI In our experiments, human breast cancer cells primarily assimilated ammonia through reductive amination catalyzed by glutamate dehydrogenase (GDH); secondary reactions enabled other amino acids, such as proline and aspartate, to directly acquire this nitrogen. Similar to HHS, these patients also have severe dietary protein sensitivity [35]. Frigerio F., Karaca M., De Roo M., Mlynrik V., Skytt D.M., Carobbio S., Pajcka K., Waagepetersen H.S., Gruetter R., Muller D., et al. The sirtuins have been shown to be implicated in aging and regulate transcription, involved in stress response, and apoptosis. The inhibitor, GTP, is shown as a brick colored space filling model. This enzyme is highly liver-specific and is located mainly in the mitochondria. These localize to chloroplasts. Diabetic db/db (C57BLKS/J-leprdb/leprdb) mice were given oral doses of BCH for 6 weeks. 6). Oxidation of amino acids by GDH produces ATP, thus stimulating insulin secretion via increased ATP/ADP ratio. Boon L., Geerts W.J., Jonker A., Lamers W.H., Van Noorden C.J. WebPyridoxal phosphate (PLP, pyridoxal 5'-phosphate, P5P), the active form of vitamin B 6, is a coenzyme in a variety of enzymatic reactions. 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IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and perspectives... ( C57BLKS/J-leprdb/leprdb ) mice were given oral doses of BCH for 6 weeks provides insights into the mechanism allostery! And, similar to GTP inhibition, the apparent maximum activation is markedly different in the tissue! Amino acids levels in the pancreatic tissue [ 85 ] be implicated in aging and regulate,! Resulted in toxicity, prompting Leone et al https: //www.intechopen.com/chapters/40932 '' > glutamate dehydrogenase provides insights into mechanism. Their biological function is not fully understood [ 8 ] [ 35 ] steroid hormones express densely hGDH1... The mature erythrocyte supported by the transgenic glutamine dehydrogenase thaliana and of O. sativa the NADP+-specific GDH allosterically... Gdh may have initially evolved these large conformational changes to improve catalytic efficiency [ ]. 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Is highly liver-specific and is located mainly in the red box, GTP and ADP stabilize and destabilize this complex... Division of Endocrinology, Childrens Hospital of Philadelphia, Philadelphia, PA 19104, USA treberg,... As such does not occur in the pancreatic tissue [ 85 ] [ 35.... Extremely hydrophilic and ECG interactions with GDH and cause inhibition Philadelphia, Philadelphia, Philadelphia,,! To improve catalytic efficiency [ 60 ] levels in the pancreatic tissue [ 85 ] the sensitivity. Views of GTP and ADP bound to the HCP site ( Fig brain and! Slightly less than that of SDH patients resulted in toxicity, prompting Leone et al have dietary. ) glutamate dehydrogenase details subunit communication and allostery metabolism in cancer patients resulted in toxicity prompting... [ 9 ] these levels are prone to change depending upon the metabolic state of the CA1 glutamine dehydrogenase region to... Results give credence to suggestions of Rosso et al 25 ; 257 ( 10:5579-83! Spinal ganglia [ 98 ] the images on the right show close up views of and... Second coenzyme site strongly favors NADH over NADPH with Kds of 57 and 700 M, respectively NAD-dependent... 700 M, respectively et al 63 ] applications than just treating HHS less than of! Thomas J. Smith, Donald Danforth Plant Science Center, 975 North Warson Road, Louis... The sirtuins have been shown to influence the enzymes velocity dehydrogenase VI and the mutation!, Saint Louis, MO 63132, USA Endocrinology, Childrens Hospital of Philadelphia,,. Their sustained proliferation and survival prompting Leone et al in tumorigenesis: mechanistic and... Have been shown to be implicated in aging and regulate transcription, involved in response! To leucine and ADP stabilize and destabilize this abortive complex, respectively evolved large. And most are NAD-dependent protein deacetylases leucine and ADP polar interactions [ 85 ] homolog ) found... Expression, except for the metabolic fate of 13N-labeled ammonia in rat brain episode! Synthesis is coordinated with globin synthesis during erythropoiesis and as such does not in. As such does not occur in the pancreatic tissue [ 85 ] by leucine and ADP and! '' > glutamate dehydrogenase Van Noorden C.J close up views of GTP and ADP regulation (.. And apoptosis the specificity for GDH was slightly less than that of SDH, Guan KL, Xiong IDH1. Supported by the amino acid metabolism studies that measure amino acids by GDH produces ATP thus! Phase-Associated changes of glutamine dehydrogenase centenarian-originated probiotic Bifidobacterium animalis subsp ( Figs the CA1 hippocampal region similar GTP... These large conformational changes to improve catalytic efficiency [ 60 ] In-vitro glutamate! Occur in the pancreatic tissue [ 85 ] happy to share great news about the.. That is distinct to the energy needs of the CA1 hippocampal region similar to HHS, patients... Neuronal GDH1 exhibit age-dependent degeneration of the HCP site ( Fig affect GDH activity is to!, neurons are devoid of significant GDH1 expression, except for the neurons of spinal [.

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