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drug target
the ADP-ribosylation of glutamate dehydrogenase is catalyzed by Sirt4, and downregulates the TCA cycle. In the ternary complex model of Sirt4-NAD+-GDH, the acetylated lysine 171 of GDH is located close to NAD+. This suggests a possible mechanism underlying the ADP-ribosylation at cysteine 172, which may occur through a transient intermediate with ADP-ribosylation at the acetylated lysine 171
evolution
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while GDH in most mammals is encoded by a single GLUD1 gene, humans and other primates have acquired a GLUD2 gene with distinct tissue expression profile
evolution
GDH is a widely distributed enzyme among all domains of life. Mammalian GDH is regulated allosterically by multiple metabolites, in which the antenna helix plays a key role to transmit the allosteric signals. In contrast, bacterial GDH is believed not to be regulated allosterically because it lacks the antenna helix
evolution
hGDH2 emerged recently via retroposition during primate evolution, being only present in humans and some closely related great apes. Functional evolution of hGDH isoenzymes, overview. Reflecting the very recent emergence of hGDH2 from hGDH1, the two human proteins show very high amino acid sequence homology (about 97%), differing in only 15 of 505 amino acids in their mature forms. Despite this similarity, hGDH2 has unique enzymatic and regulatory properties. These include GTP resistance and low basal activity amenable to activation by ADP and/or L-leucine, lower optimal pH and relative sensitivity to thermal inactivation. These properties are to a large extent associated with only two of the 15 amino acid substitutions that occurred in the course of hGDH2 evolution. In particular, the Gly456 to Ala substitution confers GTP resistance, whereas the Arg443 to Ser change is associated with lower basal activity, though still permitting activation by ADP
evolution
reflecting the very recent emergence of hGDH2 from hGDH1, the two human proteins show very high amino acid sequence homology (about 97%), differing in only 15 of 505 amino acids in their mature forms. Despite this similarity, hGDH2 has unique enzymatic and regulatory properties
evolution
while most mammals possess a single GDH1 protein (hGDH1 in the human) that is highly expressed in the liver, humans and other primates have acquired, via duplication, an hGDH2 isoenzyme with distinct functional properties and tissue expression profile. hGDH2 underwent rapid evolutionary adaptation, acquiring unique properties that enable enhanced enzyme function under conditions inhibitory to its ancestor hGDH1. These are thought to provide a biological advantage to humans with hGDH2 evolution occurring concomitantly with human brain development
evolution
while most mammals possess a single GDH1 protein (hGDH1 in the human) that is highly expressed in the liver, humans and other primates have acquired, via duplication, an hGDH2 isoenzyme with distinct functional properties and tissue expression profile. hGDH2 underwent rapid evolutionary adaptation, acquiring unique properties that enable enhanced enzyme function under conditions inhibitory to its ancestor hGDH1. These are thought to provide a biological advantage to humans with hGDH2 evolution occurring concomitantly with human brain development. A major evolutionary adaptation of hGDH2 is the ability of the enzyme to downregulate its activity in the absence of allosteric effectors
malfunction
deregulation of hGDH1/2 is implicated in the pathogenesis of several human disorders
malfunction
deregulation of hGDH1/2 is implicated in the pathogenesis of several human disorders. Glioma cells with the R132H IDH1 mutation show selective inhibition of GLUD2 expression markedly slows cell growth. xpression of GLUD2 (but not GLUD1) promotes tumor expansion, suggesting that R132H IDH1 glioma cells proliferate by utilizing enhanced glutamate flux through the GLUD2 pathway
malfunction
growth analysis of the aprth knockout strain (Tt27DELTAAPRTh) and aprth-overexpressing strain (Tt27NStHisAPRTh) of Thermus thermophilus in minimal medium. The Tt27DELTAAPRTh strain exhibits delayed growth and requires approximately 36 h to reach the early stationary phase, whereas the wild-type strain reaches this phase after 21 h of cultivation. The overexpressing Tt27NStHisAPRTh strain exhibits better growth than even the wild-type strain
metabolism
GDH1 is the protein partner for pyridoxamine 5'-phosphate-form of the mitochondrial branched chain aminotransferase (PMP-BCATm). Facilitating the recycling of BCATm to form metabolon, GDH1 acts as a catalytic machine
metabolism
glutamate dehydrogenase pathway and its roles in cell and tissue biology in health and disease, , glutamate dehydrogenase (GDH) pathway and the Krebs cycle function, oxidative deamination of glutamate by hGDH1 and hGDH2 generates 2-oxoglutarate, ammonia and NADH orNADPH, regulation of the isozymes, detailed overview
metabolism
glutamate dehydrogenase pathway and its roles in cell and tissue biology in health and disease, glutamate dehydrogenase (GDH) pathway and the Krebs cycle function, oxidative deamination of glutamate by hGDH1 and hGDH2 generates 2-oxoglutarate, ammonia and NADH orNADPH, regulation of the isozymes, detailed overview
metabolism
the enzyme is involved in the nitrogen distribution during primary assimilation, photorespiratory re-assimilation and translocation in Arabidopsis thaliana, overview. Traditional route of glutamate formation via the 2-oxoglutarate amination with NH4+ is persued by mitochondrial NADH-glutamate dehydrogenase
metabolism
the original published sequence of bovine GDH contains a few mistakes. Lysine is the correct amino acid identity of residue 387 in the allosteric NADH binding site, not asparagine. The thermodynamic impact of this mistake is shown to be +5 kcal/mol per NADH binding site. Four other residues are corrected in the bovine GDH sequence, specifically G47S, A248V, V271I, and A272T. Allostery at site R459 depends upon the expansion and contraction between subunits within the trimer as the catalytic site closes and opens, respectively
physiological function
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influence of alcohol on leukocyte GLDH activity, its diagnostic value, influence on metabolism and cells toxicity is analysed. Examination is conducted in 238 alcoholics and in 244 healthy persons. A fast increase of leukocyte GLDH activity after break in alcohol consumption is found. After 24 hours, activity increases by 21.8% (median 31.6%), after seven days by 33% (median 52%), yet after a short interval since last alcohol intake (up to 48 hours), it increases by 32% (median 36%)
physiological function
the glutamate dehydrogenase catalyzes the reversible interconversion of glutamate to 2-oxoglutarate and ammonia using NADP(H) and NAD(H) as cofactors, thus interconnecting amino acid and carbohydrate metabolism. Mammalian GDH is allosterically regulated, with GTP and ADP being the main negative and positive modulators, respectively
physiological function
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allosteric activation and inhibition is important for enzyme regulation, overview
physiological function
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the enzyme provides a pathway for ammonium assimilation
physiological function
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the enzyme provides a pathway for ammonium assimilation, although the activity for ammonium is low
physiological function
enzyme is able to complement an Escherichia coli glutamate auxotroph lacking glutamate dehydrogenase
physiological function
in a gene disruption strain of GDH, only threonine dehydrogenase activity is detected, indicating that activities toward Gln/Ala/Val/Cys are dependent on GDH. The disruption strain cannot grow in a medium in which growth is dependent on amino acid catabolism, GDH may be the only enzyme that can discharge the electrons (to NADP+/NAD+) released from amino acids in their oxidation to 2-oxoacids. In a medium containing excess pyruvate, the disprution strain displays normal growth, but higher degrees of amino acid catabolism are observed
physiological function
in transgenic Nicotiana tabacum the GDH protein accumulates in the mitochondria of mesophyll cells and in the mitochondria of the phloem companion cells. Overexpression induces major changes in carbon and nitrogen metabolite accumulation and a reduction in growth characterized by a decrease in the amount of sucrose, starch and glutamine in the leaves, and accompanied by an increase in the amount of nitrate and chlorophyl. There is an increase in the content of asparagine and a decrease in proline. Overexpressing the genes GDHA and GDHB individually or simultaneously induces a differential accumulation of glutamate and glutamine and a modification of the glutamate to glutamine ratio
physiological function
GDH catalyzes the synthesis and degradation of glutamate using NAD(P)(H). Bacterial GDH is believed not to be regulated allosterically because it lacks the antenna helix. TtGDH is activated by AMP in a complex with APRTh where APRTh is necessary for the AMP-mediated allosteric activation of TtGDH. L-Leucine is also required for allosteric regulation/activation of the enzyme
physiological function
in vitro, GDH catalyzes the reversible deamination of Glu to NH4 +, 2-oxoglutarate forming NADH. The reversible lethal phenotype of gltS mutants reveals that mitochondrial NADH-GDH is unable to re-assimilate photorespiratory NH3 produced within the same organelle although its amination activity. In vitro is several fold higher than the glutamate synthase isozyme Fd-GOGAT (EC 1.4.7.1) activity. The in vivo direction of reversible NADH-GDH reaction is controversial. NADH-GDH can exist as two homohexamers of either alpha subunit encoded by GDH1 or beta subunit encoded by GDH2 and five heterohexamers containing both alpha and beta subunits in Arabidopsis thaliana as observed in other plants
physiological function
isozyme hGDH2 is found in both human astrocytes and neurons, where it is thought to contribute to glutamate handling, both as a neurotransmitter and as a metabolic intermediate. It plays a putative role in early nervous system development, neurodegenerative processes, and oncogenesis. Regarding its role in cancer pathophysiology, hGDH2 promotes tumor cell survival especially under deprived conditions, such as glucose or glutamine depletion
physiological function
the enzyme catalyzes the reversible conversion of glutamate to 2-oxoglutarate and ammonia while reducing NAD(P)+ to NAD(P)H serving both catabolic and anabolic reactions. In mammalian tissues, oxidative deamination of glutamate via GDH generates 2-oxoglutarate, which is metabolized by the Krebs cycle, leading to the synthesis of ATP. In addition, the GDH pathway is linked to diverse cellular processes, including ammonia metabolism, acid-base equilibrium, redox homeostasis (via formation of fumarate), lipid biosynthesis (via oxidative generation of citrate), and lactate production. hGDH2 is co-expressed with hGDH1 in human brain, kidney, testis and steroidogenic organs, but not in the liver. In human cerebral cortex, hGDH1 and hGDH2 are expressed in astrocytes, the cells responsible for removing and metabolizing transmitter glutamate, and for supplying neurons with glutamine and lactate. In human testis, hGDH2 (but not hGDH1) is densely expressed in the Sertoli cells, known to provide the spermatids with lactate and other nutrients. In steroid producing cells, hGDH1/2 is thought to generate reducing equivalents (NADPH) in the mitochondria for the biosynthesis of steroidal hormones. Lastly, up-regulation of hGDH1/2 expression occurs in cancer, permitting neoplastic cells to utilize glutamine/glutamate for their growth. In addition to contributing to Krebs cycle anaplerosis and energy production, GDH function is linked to redox homeostasis and cell signaling processes. By regulating bioenergetics and redox homeostasis human GDH1/2 have emerged as key players in the pathogenesis of human neoplasias and as therapeutic targets for halting tumor development and expansion
physiological function
the enzyme catalyzes the reversible conversion of glutamate to 2-oxoglutarate and ammonia while reducing NAD(P)+ to NAD(P)H serving both catabolic and anabolic reactions. In mammalian tissues, oxidative deamination of glutamate via GDH generates 2-oxoglutarate, which is metabolized by the Krebs cycle, leading to the synthesis of ATP. In addition, the GDH pathway is linked to diverse cellular processes, including ammonia metabolism, acid-base equilibrium, redox homeostasis (via formation of fumarate), lipid biosynthesis (via oxidative generation of citrate), and lactate production. hGDH2 is co-expressed with hGDH1 in human brain, kidney, testis and steroidogenic organs, but not in the liver. In human cerebral cortex, hGDH1 and hGDH2 are expressed in astrocytes, the cells responsible for removing and metabolizing transmitter glutamate, and for supplying neurons with glutamine and lactate. In human testis, hGDH2 (but not hGDH1) is densely expressed in the Sertoli cells, known to provide the spermatids with lactate and other nutrients. In steroid producing cells, hGDH1/2 is thought to generate reducing equivalents (NADPH) in the mitochondria for the biosynthesis of steroidal hormones. Lastly, upregulation of hGDH1/2 expression occurs in cancer, permitting neoplastic cells to utilize glutamine/glutamate for their growth. In addition to contributing to Krebs cycle anaplerosis and energy production, GDH function is linked to redox homeostasis and cell signaling processes. By regulating bioenergetics and redox homeostasis human GDH1/2 have emerged as key players in the pathogenesis of human neoplasias and as therapeutic targets for halting tumor development and expansion
additional information
transgenic mice overexpressing the enzyme in brain have decreases in MAP2A labeling of dendrites and in synaptophysin labeling of presynaptic terminals, increasing in neuronal numbers and dendrite and presynaptic terminal labeling with advancing age, and show decreases in long-term potentiation of synaptic activity and in spine density in dendrites of CA1 neurons. Despite overexpression of Glud1 in all neurons of the central nervous system, the Tg mice suffer neuronal losses in select brain regions, e.g., the CA1 but not the CA3 region, dendrite structure and neuronal numbers in brains of transgenic mice, overview. The transgenic mice are significantly more resistant than wild-type mice to induction and duration of anesthesia produced by anesthetics that suppress Glu neurotransmission, phenotype, overview
additional information
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transgenic mice overexpressing the enzyme in brain have decreases in MAP2A labeling of dendrites and in synaptophysin labeling of presynaptic terminals, increasing in neuronal numbers and dendrite and presynaptic terminal labeling with advancing age, and show decreases in long-term potentiation of synaptic activity and in spine density in dendrites of CA1 neurons. Despite overexpression of Glud1 in all neurons of the central nervous system, the Tg mice suffer neuronal losses in select brain regions, e.g., the CA1 but not the CA3 region, dendrite structure and neuronal numbers in brains of transgenic mice, overview. The transgenic mice are significantly more resistant than wild-type mice to induction and duration of anesthesia produced by anesthetics that suppress Glu neurotransmission, phenotype, overview
additional information
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glutamate is bound to the active site of GdhB, the GdhB-Glu complex takes an open-like structure. No substrate is found in the active site of the GdhAGdhB-Leu complex, while six leucine molecules are found at the interfaces of three subunits
additional information
GDH1 has an advanced structure that also encompasses the antenna showing that the entire hexamer undergoes substantial conformational changes during each catalytic cycle. As the catalytic cleft opens the NAD+ domain moves away from the glutamate binding domain, twisting around the antenna in a clockwise direction along with concomitant clockwise rotation of the ascending alpha-helix of the antenna. In addition, the small alpha-helix of the antenna (at the end of its descending random coil) undergoes striking conformational changes as the catalytic mouth opens. The importance of this small helix is underscored by observations showing that mutation of amino acids located in this helix in hGDH1 attenuate GTP inhibition leading to hyperinsulinemia/hyperammonemia (HI/HA) syndrome
additional information
GDH1 has an advanced structure that also encompasses the antenna showing that the entire hexamer undergoes substantial conformational changes during each catalytic cycle. As the catalytic cleft opens the NAD+ domain moves away from the glutamate binding domain, twisting around the antenna in a clockwise direction along with concomitant clockwise rotation of the ascending alpha-helix of the antenna. In addition, the small alpha-helix of the antenna (at the end of its descending random coil) undergoes striking conformational changes as the catalytic mouth opens. The importance of this small helix is underscored by observations showing that mutation of amino acids located in this helix in hGDH1 attenuate GTP inhibition leading to hyperinsulinemia/hyperammonemia (HI/HA) syndrome
additional information
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GDH1 has an advanced structure that also encompasses the antenna showing that the entire hexamer undergoes substantial conformational changes during each catalytic cycle. As the catalytic cleft opens the NAD+ domain moves away from the glutamate binding domain, twisting around the antenna in a clockwise direction along with concomitant clockwise rotation of the ascending alpha-helix of the antenna. In addition, the small alpha-helix of the antenna (at the end of its descending random coil) undergoes striking conformational changes as the catalytic mouth opens. The importance of this small helix is underscored by observations showing that mutation of amino acids located in this helix in hGDH1 attenuate GTP inhibition leading to hyperinsulinemia/hyperammonemia (HI/HA) syndrome
additional information
glutamate dehydrogenase (GDH) from Thermus thermophilus is composed of two heterologous subunits, GdhA and GdhB. In the heterocomplex, GdhB acts as the catalytic subunit, whereas GdhA lacks enzymatic activity and acts as the regulatory subunit for activation by leucine. TTC1249 (APRTh), which is annotated as adenine phosphoribosyltransferase but lacks the enzymatic activity, forms a ternary complex with the enzyme heterodimer. The ternary complex exhibits GDH activity that is activated by leucine, as observed for the GdhA-GdhB binary complex
additional information
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glutamate dehydrogenase (GDH) from Thermus thermophilus is composed of two heterologous subunits, GdhA and GdhB. In the heterocomplex, GdhB acts as the catalytic subunit, whereas GdhA lacks enzymatic activity and acts as the regulatory subunit for activation by leucine. TTC1249 (APRTh), which is annotated as adenine phosphoribosyltransferase but lacks the enzymatic activity, forms a ternary complex with the enzyme heterodimer. The ternary complex exhibits GDH activity that is activated by leucine, as observed for the GdhA-GdhB binary complex
additional information
sequence comparisons and GDH structure homology modeling studies and docking analyses of NADPH, NADH, 2-oxoglutarate, and L-glutamate into the predictive model of GDH, loop modeling, overview
additional information
structure-function analysis, overview. Structure comparison with isozyme hGDH1, comparison of open, semi-closed and closed conformations from apo-hGDH1 (PDB ID 1L1F) and hGDH2 (PDB ID 6G2U)
additional information
structure-function analysis, overview. Structure comparison with isozyme hGDH1, comparison of open, semi-closed and closed conformations from apo-hGDH1 (PDB ID 1L1F) and hGDH2 (PDB ID 6G2U)
additional information
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structure-function analysis, overview. Structure comparison with isozyme hGDH1, comparison of open, semi-closed and closed conformations from apo-hGDH1 (PDB ID 1L1F) and hGDH2 (PDB ID 6G2U)
additional information
structure-function analysis, overview. Structure comparison with isozyme hGDH2, comparison of open, semi-closed and closed conformations from apo-hGDH1 (PDB ID 1L1F) and hGDH2 (PDB ID 6G2U)
additional information
structure-function analysis, overview. Structure comparison with isozyme hGDH2, comparison of open, semi-closed and closed conformations from apo-hGDH1 (PDB ID 1L1F) and hGDH2 (PDB ID 6G2U)
additional information
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structure-function analysis, overview. Structure comparison with isozyme hGDH2, comparison of open, semi-closed and closed conformations from apo-hGDH1 (PDB ID 1L1F) and hGDH2 (PDB ID 6G2U)
additional information
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transgenic mice overexpressing the enzyme in brain have decreases in MAP2A labeling of dendrites and in synaptophysin labeling of presynaptic terminals, increasing in neuronal numbers and dendrite and presynaptic terminal labeling with advancing age, and show decreases in long-term potentiation of synaptic activity and in spine density in dendrites of CA1 neurons. Despite overexpression of Glud1 in all neurons of the central nervous system, the Tg mice suffer neuronal losses in select brain regions, e.g., the CA1 but not the CA3 region, dendrite structure and neuronal numbers in brains of transgenic mice, overview. The transgenic mice are significantly more resistant than wild-type mice to induction and duration of anesthesia produced by anesthetics that suppress Glu neurotransmission, phenotype, overview
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