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Enzymes mechanism-based inactivation

Suicide Substrates —Mechanism-Based Enzyme Inactivators... [Pg.447]

Several drugs in current medical use are mechanism-based enzyme inactivators. Eor example, the antibiotic penicillin exerts its effects by covalently reacting with an essential serine residue in the active site of glycoprotein peptidase, an enzyme that acts to cross-link the peptidoglycan chains during synthesis of bacterial cell walls (Eigure 14.17). Once cell wall synthesis is blocked, the bacterial cells are very susceptible to rupture by osmotic lysis, and bacterial growth is halted. [Pg.447]

Silverman, R. B., 1988. Mechanism-Based Enzyme Inactivation Chemistry and Enzymology, Vols. I and II. Boca Raton, FL CRC Press. [Pg.459]

Further examples of the utility of the allylic sulfoxide-sulfenate interconversion in the construction of various biologically active natural products include intermediates such as the /Miydroxy-a-methylene-y-butyrolactones (e.g. 63)128 and tetrahydrochromanone derivative 64129. Interestingly, the facility and efficiency of this rearrangement has also attracted attention beyond the conventional boundaries of organic chemistry. Thus, a study on mechanism-based enzyme inactivation using an allyl sulfoxide-sulfenate rearrangement has also been published130 131. [Pg.733]

A new type of mechanism-based enzyme-inactivators, which are related to conduritol epoxides with respect to activation at the active site, was introduced by Tong and Ganem, " who prepared the aziridine 37 from the o-galacto analog of 1-deoxynojirimycin. Compound 37 proved to be a pp-... [Pg.371]

Walsh, C. T. Suicide substrates mechanism-based enzyme inactivators recent developments. Ann. Rev. Biochem. 1984, 53, 493-535. [Pg.378]

Silverman, R.B. (1995) Mechanism-based enzyme inactivators. Methods in Enzymology, 249, 240-283. [Pg.242]

Walsh, C.T. (1984) Suicide Substrates, Mechanism Based Enzyme Inactivators -Recent Developments. Annual Review of Biochemistry, 53, 493-535. [Pg.286]

Other useful targets for pharmaceutical agents are thymidylate synthase and dihydrofolate reductase, enzymes that provide the only cellular pathway for thymine synthesis (Fig. 22-49). One inhibitor that acts on thymidylate synthase, fluorouracil, is an important chemotherapeutic agent. Fluorouracil itself is not the enzyme inhibitor. In the cell, salvage pathways convert it to the deoxynucleoside monophosphate FdUMP, which binds to and inactivates the enzyme. Inhibition by FdUMP (Fig. 22-50) is a classic example of mechanism-based enzyme inactivation. Another prominent chemotherapeutic agent, methotrexate, is an inhibitor of dihydrofolate reductase. This folate analog acts as a competitive inhibitor the enzyme binds methotrexate with about 100 times higher affinity than dihydrofolate. Aminopterin is a related compound that acts similarly. [Pg.876]

C. Walsh, Suidde substrates mechanism-based enzyme inactivators, Tetrahedron 1982, 38, 871-909. [Pg.133]

The third requirement is not absolute, as a stoichiometric inactivation will occur if the condition [E] 4 [/] applies. Even if modifications occur less-frequently than in quenching, the modification can be ultimately completed after several catalytic turnovers. Since an excellent review has recently appeared on mechanism-based enzyme inactivators 48), we will mention a few selected examples here. [Pg.92]

C. T. Walsh. 1984. Suicide substrates, mechanism-based enzyme inactivators Recent developments Rev. Biochem. 53 493-535. (PubMed)... [Pg.355]

Mechanism-based enzyme inactivators are also powerful tools in the determination of enzyme mechanisms. Because some understanding of the enzyme mechanism is required for the design of an inactivator, the success of the compound provides support for the mechanistic hypothesis. Analysis of the intermediates and products of an inactivation reaction can be extremely useful in illuminating the normal mechanism of enzymic catalysis. For example, the covalent modification of an enzyme by a mechanism-based inactivator facilitates isolation of active site peptides and identification of cataiytically relevant amino acids. [Pg.215]

Since the initial description of a mechanism-based enzyme inactivator in the late 1960s, the field has been reviewed extensively from a variety of perspectives (Abeles and Maycock, 1976 Walsh, 1982, 1984 Rando, 1984 Silverman and Hoffman, 1984 Palfreyman et al., 1987 Silverman, 1988). Rather than to provide a comprehensive summary of the entire literature in this area, the goal of this chapter is to describe the classic approaches to inactivation of a variety of enzymes, drawing illustrations from the best understood examples. This review begins with a discussion of the criteria which define a mechanism-based enzyme inactivator and the strategies for design of such compounds. [Pg.215]

In order for a compound to be defined as a mechanism-based enzyme inactivator, its reaction with the target enzyme must meet a simple set of kinetic and mechanistic criteria. The kinetics of the inactivation reaction should conform to those expected for the minimal scheme shown in Eq. (1). [Pg.216]

Fig. I. (a) Typical lime-dependent inactivation kinetics for a mechanism-based enzyme inactivator. (b) Replot of inactivation kinetics. Fig. I. (a) Typical lime-dependent inactivation kinetics for a mechanism-based enzyme inactivator. (b) Replot of inactivation kinetics.
The second criterion for mechanism-based enzyme inactivation concerns the stoichiometry of enzyme modification. If mechanism-based inactivation of an enzyme is the result of specific covalent modification of an essential active site amino acid residue, then one radiolabeled inactivator molecule should be incorporated per active site. The stoichiometry of specific radiolabeling should also correlate with the extent of inactivation. In multimeric enzymes which display negative cooperativity, it is possible to observe complete inactivation following substoichiometric modification of the enzyme (Johnston et al., 1979). [Pg.217]


See other pages where Enzymes mechanism-based inactivation is mentioned: [Pg.132]    [Pg.862]    [Pg.876]    [Pg.450]    [Pg.450]    [Pg.95]    [Pg.862]    [Pg.876]    [Pg.213]    [Pg.214]    [Pg.215]    [Pg.215]    [Pg.216]    [Pg.217]    [Pg.217]   
See also in sourсe #XX -- [ Pg.95 ]




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