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The Journey through the Gene: a Focus on Plant Anti-pathogenic Agents Mining in the Omics Era
Published in Mahendra Rai, Chistiane M. Feitosa, Eco-Friendly Biobased Products Used in Microbial Diseases, 2022
José Ribamar Costa Ferreira-Neto, Éderson Akio Kido, Flávia Figueira Aburjaile, Manassés Daniel da Silva, Marislane Carvalho Paz de Souza, Ana Maria Benko-Iseppon
Plants and their compounds represent an extraordinary source of agents showing antimicrobial activity. Such organisms are traditional sources or substrates used in popular medicine. These days, the majority of pharmaceutically bioactive molecules are isolated from plants because their chemical synthesis is sometimes profitless. Omics and bioinformatics are currently the methods of choice for understanding plants’ physiological dynamics, helping to identify relevant candidates for biotechnological applications. Thus, adopting new procedures/routines for PAAs mining is very necessary, meaningful and applicable.
Finding a Target
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
The reaction profile in Figure 2.1 illustrates how the energy difference between the substrate and the transition state at the top of the curve, which is the activation energy, is lowered in formation of an enzyme-substrate complex. Less energy is required for the reaction to proceed, so more encounters between the enzyme and the substrate will lead to a successful reaction, hence rate is increased. The mechanism for hydrolysis of a peptide bond explains how the catalytic process operates. The negative charge of the carboxylate pushes electron density onto the electronegative oxygen atom of the water molecule, making it a strong nucleophile. Meanwhile, the electronegative nitrogen atom of a second amino acid residue pulls electron density from the C=O bond, creating a partial positive charge on the carbon, making it very susceptible to nucleophilic attack from the oxygen lone pair of electrons, hence the reaction proceeds quickly.
Laboratory Procedures and Management
Published in Jeremy R. Jass, Understanding Pathology, 2020
Contrasting with the empirical approach employing natural and synthetic dyes derived from the textile industry is ‘designer’ staining utilising predicted biochemical reactions between specific reagents (reactive agents) and substrates (biochemical components within the cell upon which reagents act). This may be likened to the controlled biochemistry within a test tube except that the reaction (described as histochemistry) occurs within a tissue section. The substrates may include all manner of biological molecules, for example enzymes, carbohydrates, hormones and even DNA. Histochemistry permits the visual demonstration of molecules in their normal location by means of coloured reagents. The intensity of the colour reaction may even indicate the amount of cellular substrate, as well as its exact site of production within the cell.
Safety considerations in the management of hepatitis C and HIV co-infection
Published in Expert Opinion on Drug Safety, 2023
Vicente Soriano, Víctor Moreno-Torres, Ana Treviño, Pablo Barreiro, Fernando de Jesus, Octavio Corral, Carmen de Mendoza
P-glycoprotein (P-gp), also known as multidrug-resistant protein 1 (MDR1), is an efflux protein coded by the ATP-binding cassette sub-family B member 1 (ABCB1) gene. It is expressed in the intestinal epithelium, hepatocytes, renal proximal tubular cells, and brain capillary endothelial cells. P-gp acts as a transporter reducing drug accumulation within cells. Among the most important substrates are anticancer drugs, HIV protease inhibitors, calcium channel blockers, antibiotics, etc. Whereas P-gp inhibitors (i.e. most HIV protease inhibitors) increase drug substrate concentrations, P-gp inducers (i.e. rifampicin) reduce drug exposure [47,67,68]. The clinical relevance of DDI due to P-gp modulation is controversial, although it clearly contributes to resistance to some anticancer agents and influences the activity of oral anticoagulants or digoxin. In addition, P-gp displays considerable genetic heterogeneity, which may further influence drug metabolism.
Reliable chromatographic assay for measuring of indoleamine 2,3-dioxygenase 1 (IDO1) activity in human cancer cells
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Ilona Sadok, Kamila Rachwał, Ilona Jonik, Magdalena Staniszewska
Next, we investigated substrate amount effect on IDO1 activity by changing the concentration of ʟ-Trp in the reaction mixture between 0 to 400 µM. The experiment was carried out in parallel with SK-OV-3 and MDA-MB-231 cells in order to identify universal conditions for different cancer cells. The peak area of ʟ-Kyn generated by cellular enzyme was assessed to determine optimal substrate concentration (Figure 2). Increasing the ʟ-Trp amount in the reaction mixture up to 50 µM resulted in enhancement of ʟ-Kyn production by SK-OV-3 cancer cells, however the ʟ-Kyn signal decreased for 200 and 400 µM (Figure 2(A)). In the case of MDA-MB-231 cells, an impact of ʟ-Trp concentration on ʟ-Kyn production by IDO1 activity was significantly lower (Figure 2(B)), although a slight increase of ʟ-Kyn signal was observed from 20 to 400 µM (Figure 2(B)). It shows the importance of using the optimal substrate concentration to yield accurate results, in particular in cells with high IDO1 activity like SK-OV-3. This is due to reaching an optimal enzyme velocity in presence of the balanced ratio of substrate to enzyme. After a certain optimal substrate concentration, an enzyme becomes saturated and a further increase in ʟ-Trp amount decreases enzyme activity. This substrate-inhibition was proposed to be an aftereffect of ʟ-Trp binding in an inhibitory site of the enzyme41,42. We concluded based on the obtained results that100 µM ʟ-Trp is the optimal concentration and it was chosen for further experiments.
Network-based strategies in metabolomics data analysis and interpretation: from molecular networking to biological interpretation
Published in Expert Review of Proteomics, 2020
Leonardo Perez De Souza, Saleh Alseekh, Yariv Brotman, Alisdair R Fernie
The most basic approach is to simply search for the shortest paths between two nodes [97]. Whilst simple, shortest path search is severely limited by the frequent presence of side compounds such as energy carriers and proton donors leading to the detection of many irrelevant pathways [98]. A great deal of effort in this field concentrates toward finding alternative ways of dealing with this issue. Removing such compounds may help to mitigate the issue and there are procedures to identify them based on network topology, however they introduce other drawbacks. Common assumptions to define side compounds such as the use of node degree in the network may also apply to other highly connected relevant metabolites such as pyruvate and acetyl-CoA [4]. Additionally, certain metabolites such as ATP that are often a side compound can act as a substrate/product in other specific pathways. Alternatively, it is possible to use the topological features to weight the nodes or edges and search for the ‘lightest pathway,’ hence avoiding the exclusion of side compounds [99].