Aspartate kinase activation

Problems associated with identification of specific regulatory mechanisms can be illustrated by a brief consideration of changes in the apparent levels of aspartate kinase during plant growth. Aspartate kinase extracted from whole carrot roots, freshly sliced root tissue, or recently subcultured cell suspensions is predominantly sensitive to inhibition by the pathway product, threonine. However, when root slices are incubated in a growth stimulating medium or when suspension cultures are allowed to grow for a period of time, the bulk of the extractable aspartate kinase activity is sensitive to... 

Changes in Aspartate Kinase Activity during Growth of Carrot Root Celis"... 

Deiva K, Geeraerts T, Salim H, Leclerc P, Hery C, Hugel B, Freyssinet JM, Tardieu M (2004) Fractalkine reduces N-methyl-d-aspartate-induced calcium flux and apoptosis in human neurons through extracellular signal-regulated kinase activation. Eur J Neurosci 20(12) ... 

Aspartate kinase [EC 2.T.2.4], also known as asparto-kinase, catalyzes the reaction of aspartate with ATP to produce 4-phosphoaspartate and ADP. The enzyme isolated from E. coli is a multifunctional protein, also exhibiting the ability to catalyze the reaction of homoserine with NAD(P) to produce aspartate 4-semialdehyde and NAD(P)H (that is, the activity of homoserine dehydrogenase, EC 1.1.1.3). 

Chandler LJ, Sutton G, Dorairaj NR, Norwood D (2001) N-methyl D-aspartate receptor-mediated bidirectional control of extracellular signal-regulated kinase activity in cortical neuronal cultures. J Biol Chem 276 2627-2636... 

Fukunaga K, Soderling TR Activation of Ca Vcalmodulin-dependent protein kinase II in cerebellar granule cells by N-methyl-D-aspartate receptor activation. Mol Cell Neurosci 1 133-138, 1990... 

Zheng, X., Zhang, L., Wang, A. p., Bennett, M. V. L., Zukin, S. Protein kinase C potentiation of N-methyl-D-aspartate receptor activity is not mediated by phosphorylation of N-methyl-D-aspartate receptor subunits, Proc. Natl. Acad. Sci. USA 1999, 96, 15262-15267. 

A 59-year-old man took troglitazone 400 mg/day for 6 months and alcohol about 40 g/day. He developed weakness and muscle pain. He had mild liver damage. His HbAic concentration was 9.0%. All his muscles were tender, his creatine kinase activity was 10 570 IU/ml, and his myoglobin, aldolase, and aspartate transaminase were raised. Troglitazone was withdrawn. He improved biochemically and clinically. 

Marchetti L., Klein M., Schlett K., Pfizenmaier K., and Eisel U. L. M. (2004). Tumor necrosis factor (TNF)-mediated neuroprotection against glutamate-induced excitotoxicity is enhanced by N-metliyl-D-aspartate receptor activation-Essential role of a TNF receptor 2-mediated phosphatidylinositol 3-kinase-dependent NF-kB pathway. J. Biol. Chem. 279 32869-32881. 

The stress or growth pathways modulated by vanadium involve specialized effectors and often can be activated by excess ROS. Cytokines, small proteins that effect communication between cells or cell behavior, can be involved in the cellular stress response. Tumor necrosis factor a (TNFa) is a cytokine stress signal that binds to a membrane receptor (tumor necrosis factor receptor, or TNFR). This interaction stimulates kinase activity that leads to cell injury and inflammation and also to the activation of caspases, a family of cysteine-dependent aspartate-directed proteases that are involved in apoptosis. The mitogen-activated protein (MAP) kinase cascade regulates both mitosis and apoptosis signaling pathways. 

With prolonged bed rest, fluid retention occurs and plasma protein and albumin concentrations may be decreased by an average of 0.5 and 0.3g/dL, respectively. The concentrations of protein-bound constituents are also reduced, although mobilization of calcium from bones with an increased free ionized fraction compensates for the reduced protein-bound calcium, so serum total calcium is less affected. Serum aspartate aminotransferase activity is usually slightly less in individuals confined to bed than in those undertaking normal physical activity. Initially and paradoxically, creatine kinase (CK) activity is increased as a result of its release from skeletal muscles, but ultimately, CK activity may be less than in active, healthy individuals. Serum potassium may be reduced by up to 0.5mmol/L because of reduction of skeletal muscle mass. 

There is good evidence for de novo pyrimidine synthesis in cestodes. Five of the six enzymes needed for UMP synthesis are present in Hymenolepis diminuta and aspartate transcarbamoylase activity has been found in Moniezia benedeni (81). Salvage of preformed pyrimidines by a cestode was first reported in Mesocestoides corti (70). Thymidine kinase is the only cestode H. diminuta) pyrimidine salvage enzyme that has been characterized (114). 

Fig. 10. Schematic representation of the split biosynthetic pathway of L-lysine in wildtype Corynebacterium glutamicum including the branch point of aspartate semialdehyde distribution. The metabolites derived from the aldehyde via the synthase activity are D,L-di-aminopimelate and L-lysine, whereas that resulting from dehydrogenase activity are L-threo-nine, L-methionine, and L-isoleucine. The activity of the dehydrogenase is inhibited at elevated L-threonine concentrations and its synthesis is repressed by L-methionine. Accumulating intracellular lysine causes feedback inhibition of aspartate kinase and activates lysE transcription...

Marchetti L, Klein M, Schlett K, Pflzenmaier K, Eisel UL (2004) Tumor necrosis factor (TNE)-mediated neuroprotection against glutamate-induced exdtotoxicity is enhanced by iV-methyl-D-aspartate receptor activation. Essential role of a TNE receptor 2-mediated phos-phatidyUnositol 3-kinase-dependent NE-kappa B pathway. J Biol Chem 279 32869-32881 Mark RJ, Lovell MA, Markesbery WR, Uchida K, Mattson MP (1997) A role for 4-hydroxynonenal, an aldehydic produd of Upid peroxidation, in disruption of ion homeostasis and neuronal death induced by amyloid p-peptide. J Neurochem 68 255-264 Mattson MP, Meffert MK (2006) Roles for NF-kappaB in nerve cell survival, plasticity, and disease. Cell Death Differ 13 852-860... 

Inhibitor constants (A j) or the concentration of inhibitor required for half-maximal inhibition under specified assay conditions ffo.s) provide an indication of the quantitative sensitivity of an enzyme. Such indicators of plant aspartate kinase sensitivity are consistently below 1.0 mM and in several instances are less than 100 fiM (Table III). Even though the effective concentration of regulatory metabolites in plant cells is difficult to estimate (Section III,C), the demonstrable inhibitory effects of comparatively low concentrations of lysine or threonine on aspartate kinase i/t vitro suggest that enzyme activity is likely to be regulated by these pathway products in vivo. 

Several plant aspartate kinases are activated by other amino acids such as valine, alanine, and isoleucine (Table HI). Activation does not appear to be a general effect of hydrophobic amino acids, since neither methionine nor leucine influence the activity of the maize enzyme yet, leucine has been reported to activate the enzyme isolated from Sinapsis alba and inhibit the enzyme from Helianthus annus. Interaction of these secondary effectors with the various aspartate kinases has not been fully explored, but several observations suggest a considerable degree of complexity. Alanine partially relieves threonine inhibition of the enzyme isolated from pea seedlings (Aames and Rognes, 1974). Lysine inhibition of maize aspartokinase is diminished in the presence of isoleucine, alanine, or valine (Bryan e/ al., 1970) and threonine, even though it does not inhibit the maize enzyme, counteracts... 

Aspartate kinase is usually subject to very strong inhibition by lysine and/or threonine (Miflin et ai, 1979). Even if the worker can be certain that the activity that is measured is due to the action of asparagine synthetase, there is still no information on whether glutamine or ammonia is acting as the amino donor. It is for these reasons that the hydroxamate assay is not recommended. 

As noted, another possiblity is that the changes in essential amino add synthetic capadty in isolated plastids are due to fluctuations in the catalytic activity [1] of key regulatory enzymes (see Fig. 1). Indeed, in preliminary experiments we have found aspartate kinase [14] and homoserine dehydrogenase [15] activity in plastids from 8 day old pea plants to be 2-6 times greater than in those from 14 day old plants (data not shown). Nonetheless, additional purification and immunological studies will be required to confirm these results. 

This patient had non-spedfic symptoms and increased alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase activities and might have been wrongly thought to have had liver disease if muscle weakness and the increased creatinine kinase activity had been overlooked. 

Although LTP has been demonstrated in many parts of the mammalian CNS, hippocampal LTP is the most studied form. Hippocampal LTP requires synaptic glutamate NMDA (n-methyl-o-aspartate) receptor activation to constitutively activate key protein kinases and/or phosphatases [99]. There are two mechanistically distinct phases of LTP early-phase LTP (E-LTP related to short-term memory) and... 

A 71-year-old woman took sertraline 50 mg/day for depression and 2 months later was found to have markedly increased creatine kinase, lactate dehydrogenase, and aspartate aminotransferase activities and serum myoglobin concentration. These abnormalities resolved within 1 week of sertraline withdrawal, but recurred dramatically 2 weeks after re-introduc-tion of sertraline. Once again, everything resolved after withdrawal of sertraline. She was successfully treated with escitalopram without recurrence of the biochemical disturbances. 

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