Protein Synthesis, Targeting, and Turnover

In chapter 29, Protein Synthesis, Targeting, and Turnover, the processes of protein synthesis and transport are described. First the process whereby amino acids are ordered and polymerized into polypeptide chains is described. Next, posttranslational alterations of newly synthesized polypeptides is considered. This is followed by a discussion of the targeting processes whereby proteins migrate from their site of synthesis to their target sites of function. Finally, proteolytic reactions that result in the return of proteins to their starting materials, the amino acids, are considered. 

Aspirin covalently modifies COX-1 and COX-2, irreversibly inhibiting COX activity. This is an important distinction from all the NSAIDs because the duration of aspirin s effects is related to the turnover rate of COX in different target tissues. The duration of effect of nonaspirin NSAIDs, which competitively inhibit the active sites of the COX enzymes, relates more directly to the time course of drug disposition. The importance of enzyme turnover in relief from aspirin action is most notable in platelets, which, being anucleate, have a markedly limited capacity for protein synthesis. Thus, the consequences of inhibition of platelet COX (COX-1) last for the lifetime of the platelet. Inhibition of platelet COX-1-dependent TXA formation, therefore, is cumulative with repeated doses of aspirin (at least as low as 30 mg/day) and takes roughly 8-12 days (the platelet turnover time) to recover once therapy has been stopped. 

Time-dependent inhibition defined mainly by mechanism-based inhibition (MBI), which includes CYP suicide inactivation (irreversible inhibition, the more widely studied process) and metabolite-intermediate (MI) complex formation (quasi-irreversible inhibition), is responsible for most clinically significant DDIs (Silverman, 1995 Waley, 1980 Zhou et al., 2005). Suicide inactivation involves the formation of a reactive intermediate that irreversibly inactivates the CYP in the process of catalytic turnover. Quasi-irreversible inhibition occurs when the CYP produces a metabolite (e.g., nitroso intermediate) with the capacity to bind tightly to the CYP heme. TDI (time-dependent inhibition) can be characterized (1) to be dose dependent, (2) to be preincubation time dependent, (3) to have bioactivation of the inhibitor that is required for inactivation of the target enzyme, (4) to have de novo protein synthesis that is required to recover metabolic capacity, and (5) to have potentially slow onset of the effects but be more profound than reversible inhibition. If present, then TDI is the major component of overall enzyme inhibition and frequently leads to clinically relevant DDIs. Table 4.5 contains a list of inhibitors of TDI observed in vitro and in vivo. 

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