Protein binding covalent

Whilst chloramines are less reactive than HOC1, they are longer-lived and so can diffuse away from their site of production. Those formed from lipophilic amines are especially toxic because they can permeate membranes. Chloramines are toxic for a number of reasons they can oxidise sulphydryl or sulphur-ether groups, they are unstable and can be hydrolysed to release chlorine in the form of HOC1 or NH2C1, they can react with iodide to form iodine and they can covalently bind proteins. 

The metabolic control is exercised on certain key regulatory enzymes of a pathway called allosteric enzymes. These are enzymes whose catalytic activity is modulated through non-covalent binding of a specific metabolite at a site on the protein other than the catalytic site. Such enzymes may be allosterically inhibited by ATP or allosterically activated by ATP (some by ADP and/or AMP). 

The resolution of these columns for protein mixtures, however, was comparably poor. The peak capacity for human serum albumin was near 3 during 20 min gradient elution. Improvement has been reached by covalent binding of PEI (M = 400-600) onto a 330 A silica of 5 pm particle size [38], The peak capacities of ovalbumin and 2a -arid glycoprotein were 30-40 (tgradienl = 20 min). Enhanced peak capacity and resolution probably were due to the more diffuse structure of PEI coupled to silane moieties than that of strictly adsorbed on silica and cross-linked (see Sect, 2.2). Other applications of covalently adsorbed PEI are discussed in Sect. 4.1. 

FIG. 8 Electron micrographs of freeze-etched preparations of whole cells from (a, b) Bacillus sphaericus CCM 2120 exhibiting a square S-layer lattice or from (c, d) Thermoanaerobacter ther-mohydrosulfuricus Llll-69 carrying a hexagonally ordered S-layer lattice, (a, c) Native S-layer lattices (b, d) S-layer lattices after covalent binding of ferritin to carbodiknide-activated carboxylic acid groups of the S-layer protein. Bars, 100 nm. 

The first is cell injury (cytotoxicity), which can be severe enough to result in cell death. There are many mechanisms by which xenobiotics injure cells. The one considered here is covalent binding to cell macromol-ecules of reactive species of xenobiotics produced by metabolism. These macromolecular targets include DNA, RNA, and protein. If the macromolecule to which the reactive xenobiotic binds is essential for short-term cell survival, eg, a protein or enzyme involved in some critical cellular function such as oxidative phosphorylation or regulation of the permeability of the plasma membrane, then severe effects on cellular function could become evident quite rapidly. 

Increased covalent binding to vascular matrix proteins... 

Poli, G., Cheeseman, K.H., Biasi, F., Chiarpotto, E., Dianzani, M.U., Esterbauer, H. and Slater, T.F. (1989a). Promethazine inhibits the formation of aldehydic products of the lipid peroxidation that is stimulated by carbon tetrachloride, but does not inhibit covalent binding of metabolites of carbon tetrachloride to microsomal lipid protein. Biochem. J. 264, 527-532. 

Walle, T. Vincent, T. S. Walle, U. K. Evidence of covalent binding of the dietary flavonoid quercetin to DNA and protein in human intestinal and hepatic cells. Biochem. Pharmacol. 2003, 65, 1603-1610. 

Fluorescent labels based on oxo-squaraines were described in numerous articles and patents [45, 52]. Mono-reactive hydrophobic (32a) and hydrophilic (32b) squaraine labels containing one NHS ester group were synthesized by Terpetschnig et al. [62]. The initially low quantum yields and short fluorescence lifetime of 32b in aqueous solutions significantly increase after covalent binding to proteins. 

Zhou, S., Chan, E., Duan, W. et al. (2005) Drug bioactivation, covalent binding to target proteins and toxicity relevance. Drug Metabolism Reviews, 1, 41-213. 

Lactam antibiotics, such as cephalosporins, and penicillins, such as ampicillin (11) and aztreonam, covalently modify their protein targets. Alkyne-functionalized versions of these antibiotics, for example, AmpN (12), were used to probe various penicillin-binding proteins in vitro and in vivo using CC-ABPP [36,37],... 

The presence of chemically reactive structural features in potential drug candidates, especially when caused by metabolism, has been linked to idiosyncratic toxicity [56,57] although in most cases this is hard to prove unambiguously, and there is no evidence that idiosyncratic toxicity is correlated with specific physical properties per se. The best strategy for the medicinal chemist is avoidance of the liabilities associated with inherently chemically reactive or metabolically activated functional groups [58]. For reactive metabolites, protein covalent-binding screens [59] and genetic toxicity tests (Ames) of putative metabolites, for example, embedded anilines, can be employed in risky chemical series. 

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