Metabolic pathways enzyme-mediated covalent

However, this does not apply to the special situation when (1) the enzyme is a synthetase which catalyzes the formation of a covalent bond between the metabolite (or antimetabolite) and a second substrate, and (2) the second substrate is available only in a limited amount. In this case, the antimetabolite competes with the metabolite not only for the enzyme but also for the second substrate, with which it will combine covalently to form an inert product. Although this enzyme-mediated reaction of the antimetabolite is reversible by the corresponding metabolite in a competitive manner, due to its potentially crucial metabolic effect, (i.e., the elimination of another, limiting metabolite which is required for the same reaction step of the metabolic pathway), this reaction per se could be responsible for the over-all inhibitory effect of the antimetabolite. That is, in such particular cases, the metabolic target of the inhibitory action of the antimetabolite may be an enzymic reaction step in which it actually plays the role of a substrate. One might think that this type of situation is a rather special and unusual one, as it may be indeed however, it so happens that the first descovered and still important class of classical and semi-classical antimetabolites, the sulfonamides, appears to act in this manner, as indicated by the results of a recent study8 (see Section 3.2.). 

The herbicide alachlor (4.146, Fig. 4.7) also displayed species-dependent toxicity, since it induced nasal tumors in rats but not in mice. Its metabolic scheme in rats and mice (Fig. 4.7) shows that alachlor can be transformed into 2,6-diethylaniline (4.149) by two different pathways, one of which proceeds via formation of 4.147. The other pathway implies glutathione (GSH) conjugation, followed by /3-lyase-mediated liberation of the thiol, followed by S-methylation to produce the methylsulfide 4.148. The two secondary amides 4.147 and 4.148 were hydrolyzed by microsomal arylamidases, but alachlor itself was not a substrate for this enzyme. The hydrolytic product 2,6-diethylaniline (4.149) was oxidized in nasal tissues to the electrophilic quinonimine metabolite 4.150, which can bind covalently to proteins. Aryl-... 

Several enzyme systems exist as cellular defense (detoxification) pathways against the chemically reactive metabolites generated by GYP metabolism (91,92,102,103). These include GST, epoxide hydrolase, and quinone reductase, as well as catalase, glutathione peroxidase, and superoxide dismutase, which detoxify the peroxide and superoxide by-products of metabolism. The efficiency of the bioinactivation process is dependent on the inherent chemical reactivity of the electrophilic intermediate, its affinity and selectivity of the reactive metabolite for the bioinactivation enzymes, the tissue expression of these enzymes, and the rapid upregulation of these enzymes and cofactors mediated by the cellular sensors of chemical stress. The reactive metabolites that can evade these defense systems may damage target proteins and nucleic acids by either oxidation or covalent modification. 

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