Medicinal Chemistry of Glutathione and Glutathione Analogs in the Mammalian Central Nervous System
Christopher A. Shaw in Glutathione in the Nervous System, 2018
Initial SAR studies are targeted to finding the pharmacophore or functional groups essential for the activity of GSH. The methodology often used with peptides is to test fragments of the peptide to find the active region. GSH contains only three residues and therefore presents a much simpler analysis in that we are able to look at the actions of the individual amino acids and some of the dipeptide combinations. GSH may be regarded as a longer analog of Glu, the backbone chain length being 11 atoms for the diacid of GSH as opposed to 5 for Glu (Fig. 4). The comparison is complicated, however, by the presence of the peptide linkages, which add polarity and the capacity for hydrogen bonding to the molecule. Finally, GSH contains the thiol group, which (as we shall see) appears essential to the actions of GSH as a neuromodulator. The actions of the individual amino acid residues are known, as are those of a variety of dipeptides. Glutamic acid itself is a potent excitant in the CNS. Cysteine is less well studied; however, in our investigations this compound produces NMDA-like depolarizations that are reversibly attenuated by AP5 (Table 1). Glycine is known to act at a site in the NMDA channel in various regions of the CNS and is necessary for activation of this channel by NMDA; glycine is known also to be an inhibitory neurotransmitter in the spinal cord.
Biochemical Effects in Animals
Stephen P. Coburn in The Chemistry and Metabolism of 4′-Deoxypyridoxine, 2018
In addition to the marked increase in blood urea, Beaton et al.36 observed that compared with rats receiving pyridoxine plus 100 pg deoxypyridoxine per day, those receiving only the By-deficient diet plus deoxypyridoxine showed a slight increase in plasma glutamic acid and a marked decrease in glutamine. Beare et al.34 found no consistent change in glutamic acid but confirmed the decrease in plasma glutamine. Plasma glutamic acid seemed to increase more in B6-deficient rats receiving deoxypyridoxine than in rats receiving a normal B6 intake plus deoxypyridoxine after injection with glutamic acid or lysine40 or alanine.33 Beaton et al.40 noted decreased formation or increased utilization of glutamine after treatment with glutamic acid.
Glutamate Sensing in Plants
Akula Ramakrishna, Victoria V. Roshchina in Neurotransmitters in Plants, 2018
Glutamic acid is one of the 20 protein-forming amino acids. It is commonly found as anion in neutral solutions, such as physiological fluids, which is usually referred to as glutamate. It is not one of the essential amino acids in humans, meaning the body can synthesize it. In mammals, Glu is a signal molecule essential for the normal development and function of the central nervous system (CNS), where it plays a major role in important activities, including cognition, learning, memory, and many other fundamental brain processes. In presynaptic cells, Glu is released from vesicles and then binds to ionotropic (ligand-gated cation channels, iGluRs) and/or metabotropic receptors (G-protein coupled, mGluR) on the plasma membrane, change the receptor conformation, and allows cations to flow through the plasma membrane, which usually leads to postsynaptic cell depolarization (Kew et al., 2005; Featherstone, 2010). The binding of Glu to some of its multiple ionotropic and metabotropic receptors initiates a cascade of signaling that culminates in cellular responses which include the normal neurotransmission of nerve impulses and the activation of proteases and caspases that lead to cell death, to mention some. These signaling pathways involve classic proteins and signaling molecules as G proteins, phospholipase C, Inositol 1,4,5-triphosphate, diacylglycerol, AMP cyclic, reactive oxygen species, calcium, and protein kinases of several types (MAPK, PKB, PKC, PDK1, TOR, IKK, CaMK), which control the expression of several genes implicated in the regulation of cell cycle, cell growth, and cell proliferation in different ways (Willard and Koochekpour, 2013).
Evaluation of anionic surfactants effects on the skin barrier function based on skin permeability
Published in Pharmaceutical Development and Technology, 2019
Mana Okasaka, Koji Kubota, Emi Yamasaki, Jianzhong Yang, Sadaki Takata
For amino acid surfactants other than those in the glutamate series (i.e. alaninate series, glycinate series, and taurate series), the Transmission Index values were ∼1 or less. Alanine and glycine are neutral amino acids, unlike glutamic acid. Taurine is not classified as an amino acid in the strictest sense; however, it has similar properties to natural amino acids and is known as an amino sulfonic acid. There is no notable alanine or glycine content in biological proteins relative to glutamic acid. Taurine is a biologically essential component functioning in the digestive and neurotransmitter systems. There is a little distribution of taurine in body surface tissues. Thus, the adsorption of the alaninate, glycinate, and taurate series on the skin is weaker than that of the glutamate series. Therefore, their effects on skin barrier function are very limited. The acidity of glutamic acid is another possible factor. Glutamic acid is an acidic amino acid possessing two carboxyl groups. One carboxyl group functions as the anion to form an ionic pair, whereas the other remains as a free acid. Therefore, glutamate surfactants may be acidic as sulfate-based surfactants.
Glutamatergic dysregulation in mood disorders: opportunities for the discovery of novel drug targets
Published in Expert Opinion on Therapeutic Targets, 2020
Panek Małgorzata, Kawalec Paweł, Malinowska Lipień Iwona, Tomasz Brzostek, Pilc Andrzej
Glutamate is the main stimulatory neurotransmitter in the central nervous system. Glu is the anion of glutamic acid and is the predominant form in physiological conditions. It plays an important role in the maturation of neurons, regulating their proliferation and migration processes during nervous system development. Additionally, it has a significant impact on cognition (e.g. learning and memory) as well as many other processes (e.g. it regulates the conduction of pain sensation in the spinal cord and brain). Glu is synthesized from glutamine in glutamatergic neurons by the mitochondrial enzyme glutaminase. With the aid of the vesicular glutamate transporter, Glu enters synaptic vesicles. During neuronal depolarization, the released Glu enters the synaptic space, stimulating numerous receptors. After its release, glutamate does not undergo enzymatic decomposition but is intercepted into the neighboring glial cells through the EAAT. Then, under the influence of the glutamine synthetase enzyme, it is converted into glutamine [13,25] Centelles et al. [25] depicted graphically the exact metabolism of glutamate)
An updated patent review of glutaminase inhibitors (2019–2022)
Published in Expert Opinion on Therapeutic Patents, 2023
Danni Wang, Xiaohong Li, Guangyue Gong, Yulong Lu, Ziming Guo, Rui Chen, Huidan Huang, Zhiyu Li, Jinlei Bian
In addition to Gln analogs derived from DON as GLS1 inhibitors, there is a class of oligopeptide Gln analogs that do not carry an azo structure. It was found that GLS1 inhibitors that cross the blood–brain barrier exhibit adverse effects on the central nervous system. Therefore, patent US20190309017 (Figure 5B) [83] reported a class of GLS1 inhibitors, which are oligopeptides of 2 to 6 amino acids that do not cross the blood–brain barrier. The parent nucleus was combined with each of the two carboxyl groups of glutamic acid to obtain two compounds. Both compounds were tested on IM-9 cells (multiple myeloma), which revealed that 1 mM compound 43 (compound 9) had a 58% lethal effect on day 4, while 0.25 mM compound 42 (compound 6) had an 87% lethal effect on day 3. Experiments involving pancreatic cancer cells indicated that treatment with 1 mM compound 43 (compound 9) resulted in cell death at a rate of only 6% on day 4, while treatment with 0.25 mM compound 42 (compound 6) resulted in a cell death of 50% on day 3, suggesting that compound 42 (compound 6) was superior in time and concentration. Thus, the activity was enhanced when the parent nucleus was bound to the non-α carboxyl group of glutamate.
Related Knowledge Centers
- Acid
- Amine
- Biosynthesis
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- Essential Amino Acid
- Nervous System
- Protein
- Amino Acid
- Neurotransmitter
- Γ-Aminobutyric Acid