Mechanism-based substrates

J. E. Gready, Design of new mechanism-based substrates for dihydrofolate reductase, in ... 

P. L. Cummins and J. E. Gready, Novel mechanism-based substrates of dihydrofolate... 

The two examples show that the base-catalyzed proton abstraction occurs mostly at the ortho-position, i.e. the most acidic position in fluoroaromatics. However, the assumption has proved incorrect in some cases. Schlosser proposed a concept of regioselectivity through mechanism-based substrate-reagent matching [13] (an example is shown in Scheme 3.5). 

The 3 -substituent may also be a reactive functional group which may form a covalent linkage to viral reverse transcriptase. Two potential types of covalent, irreversible inhibitors have been proposed [27]. The first type is comprised of mechanism-based substrates whose reactive functionalities are unmasked as a consequence of their incorporation into the DNA chain. The two compounds 3 and 4 have peroxy and hydroxylamino groups at 3 which, once the nucleosides have been incorporated to DNA, could eventually be phosphorylated by the... 

Schlosser introdueed the eoneept of optional site selectivity through mechanism-based substrate reagent matching to describe the metalation of arenes carrying two different DMGs... 

FIGURE 26.6 Optional site selectivity through mechanism-based substrate reagent matching. 

Nemeria NS, Korotchkina LG, Chakraborty S et al (2(X)6) Acetylphosphinate is the most potent mechanism-based substrate-like inhibitor of both the human and Escherichia coli pyruvate dehydrogenase components of the pymvate dehydrogenase complex. Bioorg Chem 34 362-379... 

Affinity Labels. Active site-directed, irreversible inhibitors or affinity labels are usually substrate analogues that contain a reactive electrophilic functional group. In the first step, they bind to the active site of the target enzyme in a reversible fashion. Subsequentiy, an active site nucleophile in close proximity reacts with the electrophilic group on the substrate to form a covalent bond between the enzyme and the inhibitor, typically via S 2 alkylation or acylation. Affinity labels do not require activation by the catalysis of the enzyme, as in the case of a mechanism-based inhibitor. 

Primers for protective coatings may be divided into three broad classes based on the mechanism of substrate protection barrier primers that function by preventing the ingress of moisture and electrolytes, primers that protect the substrate galvanically in the presence of electrolytes, and primers that contain electrochemical inhibitors to passivate the substrate. Each of these approaches requires a distinct primer film structure due to the different mechanisms of protection. 

Suicide Substrates —Mechanism-Based Enzyme Inactivators... 

Rhinoviruses, which represent the single major cause of common cold, belong to the family of picornavimses that harbors many medically relevant pathogens. Inhibitors of the 3C protease, a cysteine protease, have shown good antiviral potential. Several classes of compounds were designed based on the known substrate specificity of the enzyme. Mechanism-based, irreversible Michael-acceptors were shown to be both potent inhibitors of the purified enzyme and to have antiviral activity in infected cells. 

Vaillancourt FH, G Labbe, NM Drouin, PD Fortin, LD Eltis (2002) The mechanism-based inactivation of 2,3-dihydroxybiphenyl 1,2-dioxygenase by catecholic substrates. J Biol Chem 277 2019-2027. 

The starting point for much of the work described in this article is the idea that quinone methides (QMs) are the electrophilic species that are generated from ortho-hydro-xybenzyl halides during the relatively selective modification of tryptophan residues in proteins. Therefore, a series of suicide substrates (a subtype of mechanism-based inhibitors) that produce quinone or quinonimine methides (QIMs) have been designed to inhibit enzymes. The concept of mechanism-based inhibitors was very appealing and has been widely applied. The present review will be focused on the inhibition of mammalian serine proteases and bacterial serine (3-lactamases by suicide inhibitors. These very different classes of enzymes have however an analogous step in their catalytic mechanism, the formation of an acyl-enzyme intermediate. Several studies have examined the possible use of quinone or quinonimine methides as the latent... 

The functionalized phenaceturates 16 (Fig. 11.10) are substrates of class A and C [3-lactamases, especially the class C enzymes, as observed with the parent unfunctionalized phenaceturates 15. They are also modest inhibitors of these enzymes and the serine DD-peptidase of Streptomyces R61. The inhibition of class C [3-lactamases is turnover dependent, as expected for a mechanism-based inhibitor. Inhibition is not very dependent on the nature of the leaving group, suggesting that the QM is generated in solution after the product phenol has been released from the active site. It therefore... 

Walsh, C. T. Suicide substrates mechanism-based enzyme inactivators recent developments. Ann. Rev. Biochem. 1984, 53, 493-535. 

P Schmeidlin-Ren, DJ Edwards, ME Fitzsimmons, K He, KS Lown, PM Woster, A Rahman, KE Thummel, JM Fisher, PF Hollenberg, PB Watkins. Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit constituents decreased enterocyte CYP3A4 concentration and mechanism-based inactivation by furanocoumarins. Drug Metab Dispos 25 1228-1233, 1997. 

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