Mechanisms of chemical action

Chemical Mechanism of Action of Pteridine-Synthesising or -Transforming Enzymes 959... 

Riboflavin synthase catalyzes the dismutation of 8-D-ribityl-6,7-dimethyllumazine to form the flavin ring system and the general features of the mechanism of this reaction have been known for some time. Recent X-ray structural studies of the enzyme from archaeal organisms such as methanobacteria have shown that the chemical mechanism of action is similar to that of enzymes from eubacteria and eukaryotes although the structures of the enzymes differ greatly <2006JBC1224>. 

The substrate specificities for these enzyme reactions were originally based only on electronic effects of substituents 12,13) the chemical mechanism of action depending on the electron-withdrawing ability of aromatic substituents has been postulated as being expressible by biphasic Hammett plots such as Fig. 1 for the reactions of Eq. 12. Eq. 9 and 10 clearly indicate the significance not only of electronic but also of steric and hydrophobic effects. 

Wilson VS, Keshava N, Hester S, Segal D, Chiu W, Thompson CM, Euling SY (2013) Utilizing toxicogenomic data to understand chemical mechanism of action in risk assessment. Toxicol Appl Pharmacol 271(3) 299-308. 

The currently accepted chemical mechanism of action of EAL, shown in Figure 17 for the reaction of ( 5)-2-aminopropanol, follows the pattern of other coenzyme Bi2-dependent isomerases. The chemical mechanism begins by homolytic scission of the Co—C5 bond in adenosylcobalamin with the substrate bound at its site translocation of the ribosyl moiety of the 5 -deoxyadenosyl radical by torsion about the ALribosyl linkage to place the 5 -methylene radical in contact with Cl of the substrate, in analogy with DDH ° abstraction of C 1-hydrogen from the substrate by the 5 -deoxyadenosyl radical to form 5 -deoxyadenosine and the... 

This textbook for advanced courses in enzyme chemistry and enzyme kinetics covers the field of steady-state enz5mie kinetics from the basic principles inherent in the Michaelis-Menten equation to the expressions that describe the multi-substrate enzyme reactions. The purpose of this book is to provide a simple but comprehensive framework for the study of enzymes with the aid of kinetic studies of enzyme-catalyzed reactions. The aim of enzyme kinetics is twofold to study the kinetic mechanism of enz5mie reactions, and to study the chemical mechanism of action of enzymes. 

By chemical mechanism of action of enzyme, we understand (a) the identification of any intermediates, (b) the identification of any groups on the enzyme acting as acid-base catalysts, (c) the roles of any cofactors, and (d) the nature of the transition state for the chemical reaction catalyzed by enzyme. 

The use of pH studies to determine chemical mechanisms of action of enzyme-catalyzed reactions is probably their most important application in enzymology... 

Although the cephalosporins have a similar chemical mechanism of action as the penicillins, the presence of a six-membered ring rather than a five-membered ring in the penicillins relieves ring strain and renders the cephalosporins less chemically reactive. However, upon attack of the C-8 carbonyl by nucleophiles, suitable sub-stimtions at C-3 can act as an electron sink (Fig. 22.22) and increase the reactivity of the P-lactam ring. The acetoxy substituent extending from the dihydrothiazine ring in cephalosporin C and cephalothin is a classical example. 

B.M. (1998) Use of competitive deadend inhibitors to determine the chemical mechanism of action of yeast alcohol dehydrogenase. Mol. Cell. Biochem., 178, 219 227. 

Antibiotics have a wide diversity of chemical stmctures and range ia molecular weight from neat 100 to over 13,000. Most of the antibiotics fall iato broad stmcture families. Because of the wide diversity and complexity of chemical stmctures, a chemical classification scheme for all antibiotics has been difficult. The most comprehensive scheme may be found ia reference 12. Another method of classifyiag antibiotics is by mechanism of action (5). However, the modes of action of many antibiotics are stiU unknown and some have mixed modes of action. Usually within a stmcture family, the general mechanism of action is the same. For example, of the 3-lactams having antibacterial activity, all appear to inhibit bacterial cell wall biosynthesis. 

Knowledge of the mechanism of action and investigations on the physico-chemical characteristics of the therapeutically used dalbaheptides has stimulated the transformation of natural antibiotics into new derivatives using both chemical and biosynthetic modification. 

Other Radioprotective Chemicals. The bis-methylthio- and methylthioamino-derivatives of 1-methylquinolinium iodide and l-methylpyridinium-2-dithioacetic acid provide reasonable protection to mice at much lower doses than the aminothiols, which suggests a different mechanism of action (139). One of these compounds, the 2-(methylthio)-2-piperidino derivative of the l-methyl-2-vinyl quinolinium iodide (VQ), interacts with supercoUed plasmic DNA primarily by intercalation. Minor substitutions on the aromatic quinolinium ring system markedly influence this interaction. Like WR-1065, VQ is positively charged at physiological pH, and the DNA-binding affinities of VQ and WR-1065 appear to be similar. 

The sulfated compounds MM 13902 (3, n = (5) and MM 17880 (4) are also broad-spectmm agents, but not as potent as thienamycia and all lack any significant activity against Pseudomonas (73). Many carbapenems are excellent inhibitors of isolated P-lactamases, particularly the olivanic acid sulfoxide MM 4550 (3, n = 1) (3). The possible mechanism of action of the carbapenems as inhibitors of P-lactamases has been discussed in some detail (74). Other carbapenems such as PS-5 (5) (75), the carpetimycins (76), asparenomycins (77), and pluracidomycins (8) are all highly active as antibiotics or P-lactamase inhibitors. The parent nucleus itself (1, X = CH2) is intrinsically active, but chemically unstable (9). 

A second problem concerns delimiting the mechanisms of action which should be included in the definition, to exclude effects which are a secondary consequence of overt toxicity in other body systems. For example, disruption to the endocrine system caused by general metabolic disturbance, such as in severe liver damage, should not be grounds for calling a chemical an ED. 

Table 1 Examples of chemicals suspected of causing endocrine disruption listed according to suspected mechanism of action...

Chang, S. I., and Hamme.s, G. G., 1990. Structure and mechanism of action of a mnltifnnctional enzyme Fatty acid. syndia.se. Accounts of Chemical Research 23 363—369. 

There are several hundred reported NF-kB inhibitors (see www.nf-kb.org for a complete and updated list). These inhibitors include natural products, chemicals, metabolites, and synthetic compounds. A large majority of these products, in particular commonly used antiinflammatory drugs such as corticosteroids and the nonsteroidal antiinflammatory drugs (NSADDs) aspirin, sulindac, ibuprofen and sulphasalazine, have the ability to partially inhibit NF-kB activity in cell culture. However, the precise mechanism of action and the specific molecular targets of most of these inhibitors remain unclear. 

Papp E, Csermely P (2006) Chemical chaperones mechanisms of action and potential use. Handb. Exp. Pharmacol. 172 405-l 6... 

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