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Omega-3 Fatty Acids and NO from Flax Intervention in Atherosclerosis and Chronic Systemic Inflammation
Published in Robert Fried, Richard M. Carlton, Flaxseed, 2023
Robert Fried, Richard M. Carlton
L-arginine, a semi-essential α-amino acid, part of the biosynthesis of proteins, is naturally found in red meat, poultry, fish, dairy, beans and nuts and seeds. It is a precursor of NO essential to blood vessel and heart function, to brain and nervous system function and to immune system function. Each of these functions has its own dedicated form (isoforms) of catalyst synthase enzyme. These enzymes convert L-arginine to citrulline, producing NO in the process. Oxygen and NADPH are necessary cofactors.
Glutamine synthetase deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
Concentrations of glutamine were low in plasma, urine, and CSF. Concentrations of ammonia were moderately elevated. Deficient activity of glutamine synthetase (Figure 33.1) was found in immortalized lymphocytes derived from the initial patient [2]. Each infant was homozygous for an arginine to cysteine substitution in exon 6, p.R324C and p.R341C. A third patient has been reported [3] with a somewhat more attenuated course who had a p.R324S mutation. Glutamine synthase is the only reaction in which glutamine is synthesized. So, its deficiency makes glutamine an essential amino acid.
Consideration of Glutamine Synthetase as a Multifunctional Protein
Published in James F. Kane, Multifunctional Proteins: Catalytic/Structural and Regulatory, 2019
The amino acid glutamine is not only essential for protein synthesis but also as a precursor for other nitrogen-containing compounds in cells. The enzyme responsible for glutamine production, glutamine synthetase, is widely distributed in microorganisms, plants, and animals and catalyzes the conversion of glutamate and ammonia to glutamine with the cleavage of ATP to ADP and Pi Glutamine synthetase occupies a central position in cell physiology, because it forms an intersection of pathways for carbon metabolism, ammonia assimilation, amino acid synthesis, and the availability of glutamate and glutamine as precursors for other cell constituents. Many microorganisms use glutamate synthase, which converts glutamine and α-ketoglutarate to two glutamates, as the primary route for glutamate production. For these organisms, glutamine synthetase has the interesting physiological role of using glutamate as a substrate to make glutamine, which serves as a product for other cell metabolism and as a precursor for producing more glutamate. In this role, glutamine synthetase is in a cyclic reaction necessary for making one of its substrates.
Inhibitors of glucosamine-6-phosphate synthase as potential antimicrobials or antidiabetics – synthesis and properties
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Joanna Stefaniak, Michał G. Nowak, Marek Wojciechowski, Sławomir Milewski, Andrzej S. Skwarecki
In GlcN-6-P synthase, there is not any single defined active centre but two active centres located at GAH and ISOM domains, respectively, are connected through the intramolecular, solvent inaccessible channel25. The only catalytic residue at GAH, namely N-terminal Cys1, catalyses the hydrolysis of l-Gln amide and three residues, namely Glu488, His504 and Lys603 (E. coli GlcN-6-P synthase numbering), participate in ketose-aldose isomerisation of fructosamine-6-P intermediate at ISOM26. All the catalytic residues and another five involved in substrate binding are highly conserved among GlcN-6-P synthases of different sources18. The molecular mechanism of GlcN-6-P synthase catalytic action is complex and involves three main steps: hydrolysis of glutamine at GAH, transfer of ammonia from GAH to ISOM and isomerisation of the resulting fructosamine-6-P at ISOM. At first, the Fru-6-P molecule binds to ISOM and the opening of its hexose ring triggers the conformational changes of two domains, namely closing access to the ISOM active site and promoting rearrangement of Cys1 at GAH into an active conformation. The subsequent binding of l-Gln at GAH induces another conformational change of the enzyme molecule, which ensures hydrolysis of glutamine amide and ammonia transfer through the intramolecular channel to ISOM. In the third step, the fructosamine-6-P is isomerised through the cis-enamine intermediate and finally, the reaction products, i.e. GlcN-6-P and l-Glu are released (Scheme 2)27.
The mechanisms and therapeutic targets of ferroptosis in cancer
Published in Expert Opinion on Therapeutic Targets, 2021
Long Ye, Fengyan Jin, Shaji K. Kumar, Yun Dai
LPO is a well-defined driver of ferroptosis (Figure 1C). Peroxidized PUFAs can be catabolized into toxic aldol compounds containing epoxy-, oxy-, or aldehyde radicals. These radicals disrupt membrane integrity, thereby inducing mitochondrial contraction and cell membrane rupture[1]. The main PUFAs subjected to LPO include arachidonic acid (AA) and adrenaline (AdA). Acyl coenzyme A synthase long chain family member 4 (ACSL4) catalyzes the linkage of CoA to AA or AdA to form CoA-AA or CoA-AdA intermediates, which in turn form phosphatidylethanolamine(PE)-AA or PE-AdA by lysophosphatidylcholine acyltransferase 3 (LPCAT3). In the presence of lipoxygenases (LOXs), PE-AA or PE-AdA undergoes peroxidation, thus leading to ferroptosis[15]. Moreover, PUFAs also participate in ferroptosis through non-enzymatic autoxidation[4]. In this context, both decreased biosynthesis and increased degradation of PUFAs can inhibit ferroptosis. For example, monounsaturated FAs (MUFAs) antagonize ferroptosis by competing with PUFAs. In contrast, β-oxidation mediates the degradation of PUFAs, while its disruption leads to lipid accumulation[16].
Fever-range hyperthermia promotes cGAS-STING pathway and synergizes DMXAA-induced antiviral immunity
Published in International Journal of Hyperthermia, 2021
Inam Ullah Khan, Gabriel Brooks, Nina Ni Guo, Junsong Chen, Fang Guo
Cyclic GMP-AMP Synthase (cGAS) triggers the reaction of GTP and ATP to form cGAMP. To test if the increased expression of cGAS and hence FRT, could also increase the production of cGAMP in the cells; cells with and without htDNA transfection were heated at 39.5 °C and the synthesis of cGAMP was assessed by its ability to induce IRF3 phosphorylation and thus its dimerization, using native gel electrophoresis. HT at 39.5 °C showed higher IRF3 phosphorylation in htDNA transfected cells indicating increased production of cGAMP as compared to 37 °C. No significant difference in the degree of phosphorylation was seen in cells with or without htDNA transfection at 37 °C or in cells at 39.5 °C without DNA transfection showing no increased production of cGAMP (Figure 3(A). As expected, cGAS−/− did not show such difference in the degree of phosphorylation among the four groups with or without htDNA (Figure 3(B)).