Synthesis of macrocyclic peptide thiolactones as models of the metastable binding sites of .alpha.2-macroglobulin and complement protein C3b

The Structure of Bovine Complement Component 3 Reveals the Basis for Thioester Function

“…The pyroGlu-containing structure is the thermodynamically stable structure and isomerization proceeds much faster than hydrolysis. 24 In native C3, the cyclic thioester structure hydrolyzes very slowly (t 1/2 of 186 h), 25 and isomerization takes place only upon denaturation. Hence, in native C3, the thioester is protected from both hydrolysis and isomerization.…”

Catalysis by human leukocyte elastase. Rate-limiting deacylation for specific p-nitroanilides and amides

“…If deacylation is in fact rate limiting for the hydrolysis of MeOSuc-Ala-Ala-Pro-Val-pNA, then addition of an appropriate nucleophile to solutions of this substrate and HLE should, in accord with Scheme I, provide the acyl-enzyme with an alternate, low-energy pathway for decomposition and result in enhancement of fcc.7 As shown in Figure 1, enhancement of kc was indeed observed for reaction solutions containing the nucleophilic species L-phenylalaninamide.8 Enhancement was more pronounced at pH 9 than at pH 7 indicating that these rate effects are due to the unprotonated, basic form of Phe-NH2. From these data it is possible to calculate a pKa of 7.7 for Phe-NH2, identical with (5) The alternative that both substrates hydrolyze with rate-limiting acylation seems improbable to us. Due to large electronic differences between p-nitrophenol and p-nitroaniline, expressed at least in part by kJKm, chemical processes involved in acyl-enzyme formation for their two substrates, such as the nucleophilic addition of the serine hydroxyl to the substrate carbonyl, will have quite different activation energies and thus cannot be considered as candidates for the common rate-limiting reaction.…”

The structure and function of thioester-containing proteins in arthropods

“…Thioester bonds are labile to hydrolysis or nucleophilic attack by amine and hydroxyl functional groups. In a synthetic model peptide, and the protein under denaturing conditions, substitution by the peptide nitrogen to form a lactam is preferred (Khan and Erickson 1981; 1982; Khan et al 1986) resulting in autolytic cleavage of the peptide bond (Fig. 1e) (Sim and Sim 1981).…”