Glutamic discovery

If 15N ammonium citrate was administered, and glutamate, aspartate, and glycine isolated from liver and intestinal wall protein, all showed 15N uptake. From the results of labeling studies, Schoenheimer finished his Edward K.Dunham lectures in Harvard in 1941 with the phrase— the structural materials [of the body] are in a steady state of flux. The classical picture must thus be replaced by one which takes account of the dynamic state of body structure —an idea which has become an integral part of biochemistry since that time, and which was almost totally dependent on the introduction of isotopes for its discovery. 

Trypsin inhibitors in cucumber were first found in a study by Walker-Simmons et /. " after wounding of leaves and treatment with proteinase inhibitor-inducing factor (PIIF). The amino acid sequence of two inhibitors isolated from Cucurhita maxima (winter squash) were determined by Wilusz et at The peptides named ITD I and ITD 111 each comprised a 29-residue sequence with six cysteine residues. The only difference between the two peptides is in position 9, which is lysine in ITD I and glutamic acid in ITD III. The reactive site is located at the peptide bond between Arg5 and Ile6. Owing to their discovery and distribution in Cucurbitaceae the inhibitor family has been named squash inhibitors. Since the initial discoveries many other members of the squash family have been found. 

Interest in the therapeutic potential of drugs acting on the NMDA receptor has risen with the discovery that epilepsy and related convulsive states may occur as a consequence of a sudden release of glutamate. Sustained seizures of the limbic system in animals result in brain damage that resembles the changes seen in glutamate toxicity. Similar changes are... 

To date, three of the four FDA-approved medications used in the treatment of the cognitive aspects of AD are acetylcholinesterase inhibitors, which increase overall levels of acetylcholine (the fourth reduces glutamate excitotoxicity via the NMD A receptor). The identification of compounds that reduce inflammation (and thus immune-mediated neuron loss) or increase the levels of acetylcholine are, therefore, also active areas of drug discovery. 

There are three types of ionotropic glutamate receptors NMDA, a-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA), and kainate receptors (Fig. 1). Each is principally activated by the agonist bearing its name and is permeable to cationic flux hence, their activation results in membrane depolarization. Ionotropic glutamate receptors were originally classified based on three selective, synthetic agonists quisqualate, kainate and NMDA. After the discovery of metabotropic receptors, it became clear that quisqualate also interacts with them. Since that time, quisqualate-sensitive ionotropic receptors have been classified by the more selective agonist AMPA. 

For several years after the discovery of cobalamin its biochemical function remained a mystery, a major reason being the extreme sensitivity of the coenzymes to decomposition by light. Progress came after Barker and associates discovered that the initial step in the anaerobic fermentation of glutamate by Clostridium... 

The discovery of D-glutamic acid cyclotransferase was foreshadowed by the observations of Ratner (23) who fed rats D,L-glutamate labeled with 15N in the amino group and deuterium attached to the a- and / -... 

Very recently, (3-lactam antibiotics have been shown to offer neuroprotection by increasing glutamate transporters expression via gene activation [15] in addition, the discoveries of new biologically active (3-lactams such as cholesterol acyl transferase inhibitors [16-18], thrombin inhibitors [19], human cytomegalovirus protease inhibitors [20], matrix-metallo protease inhibitors [21], inhibitors of human leukocyte elastase (HLE) [22, 23] and cysteine protease [24, 25], and apoptosis inductors [26, 27] have provided much needed motivation for continuous development of new (3-lactam systems. 

The discovery of potent and selective agonists and antagonists (Figs. 2.1, 2.2, and 2.3) has resulted in extensive information on the NMDA receptor-channel complex (Wood et al., 1990 Fagg and Baud, 1988). It consists of four domains (1) the transmitter recognition site with which NMDA and L-glutamate interact ... 

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