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Literature summary for 1.4.1.3 extracted from
- The glutamate dehydrogenase pathway and its roles in cell and tissue biology in health and disease (2017), Biology, 6, 11 .
Activating Compound
| Activating Compound | Comment | Organism | Structure |
|---|---|---|---|
| ADP | activation is markedly diminished at lower pH values | Homo sapiens |  |
Application
| Application | Comment | Organism |
|---|---|---|
| medicine | 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 | Homo sapiens |
Inhibitors
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| Mg2+ | at 1.0-2.0 mM; at 1.0-2.0 mM | Homo sapiens | |
KM Value [mM]
| KM Value [mM] | KM Value Maximum [mM] | Substrate | Comment | Organism | Structure |
|---|---|---|---|---|---|
| additional information | - |
additional information | when assayed in triethanolamine buffer, pH 8.0, at 1.0 mM ADP, hGDH1 and hGDH2 show similar catalytic properties (Vmax and Kms for 2-oxoglutarate, ammonia and glutamate), kinetics, overview | Homo sapiens |
Localization
| Localization | Comment | Organism | GeneOntology No. | Textmining |
|---|---|---|---|---|
| mitochondrion | - |
Homo sapiens | 5739 | - |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| L-glutamate + H2O + NAD(P)+ | Homo sapiens | - |
2-oxoglutarate + NH3 + NAD(P)H + H+ | - |
r | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | P00367 | - |
- |
| Homo sapiens | P49448 | - |
- |
Source Tissue
| Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|
| astrocyte | - |
Homo sapiens | - |
| brain | - |
Homo sapiens | - |
| carcinoma cell | upregulation of hGDH1/2 expression occurs in cancer | Homo sapiens | - |
| cerebral cortex | - |
Homo sapiens | - |
| glioma cell | gene expression profiling reveals that GLUD2 is selectively and consistently upregulated in glioma cells harboring IDH mutations | Homo sapiens | - |
| kidney | - |
Homo sapiens | - |
| liver | - |
Homo sapiens | - |
| additional information | neoplastic cell | Homo sapiens | - |
| Sertoli cell | - |
Homo sapiens | - |
| testis | - |
Homo sapiens | - |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| L-glutamate + H2O + NAD(P)+ | - |
Homo sapiens | 2-oxoglutarate + NH3 + NAD(P)H + H+ | - |
r | |
| additional information | in vitro, the thermodynamic equilibrium of mammalian GDH favors glutamate synthesis. Because the GDH-catalyzed reaction is reversible, its direction is expected to depend on the concentration of the substrates and the affinity of the enzyme (Km value) for these substrates. In addition to substrate concentrations, the GDH catalysis is affected by the pH, the ionic strength and the composition of the buffer | Homo sapiens | ? | - |
- |
|
Subunits
| Subunits | Comment | Organism |
|---|---|---|
| homohexamer | 6 * 56000, about, dimer of trimers | Homo sapiens |
| More | structure overview | Homo sapiens |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| GDH | - |
Homo sapiens |
| hGDH1 | - |
Homo sapiens |
| hGDH2 | - |
Homo sapiens |
pH Optimum
| pH Optimum Minimum | pH Optimum Maximum | Comment | Organism |
|---|---|---|---|
| 7.5 | - |
- |
Homo sapiens |
| 7.8 | 8 | - |
Homo sapiens |
Cofactor
| Cofactor | Comment | Organism | Structure |
|---|---|---|---|
| NAD+ | - |
Homo sapiens | |
| NADH | - |
Homo sapiens | |
| NADP+ | - |
Homo sapiens | |
| NADPH | - |
Homo sapiens | |
Expression
| Organism | Comment | Expression |
|---|---|---|
| Homo sapiens | upregulation of hGDH1/2 expression occurs in cancer | up |
General Information
| General Information | Comment | Organism |
|---|---|---|
| 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 | Homo sapiens |
| 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 | Homo sapiens |
| malfunction | deregulation of hGDH1/2 is implicated in the pathogenesis of several human disorders | Homo sapiens |
| 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 | Homo sapiens |
| 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 | Homo sapiens |
| 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 | Homo sapiens |
| 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 | Homo sapiens |
| 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 | Homo sapiens |
| 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 | Homo sapiens |
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