The role of imidazole in peptide cyclization by transesterification: parallels to the catalytic triads of serine proteases

Abstract

The improved bioavailability, stability and selectivity of cyclic peptides over their linear counterparts make them attractive structures in the design and discovery of novel therapeutics. In our previous work, we developed an imidazole-promoted preparation of cyclic depsipeptides in which we observed that increasing the concentration of imidazole resulted in the concomitant increase in the yield of cyclic product and reduction in dimerization, but also resulted in the generation of an acyl-substituted side product. In this work, we used transition state analysis to explore the mechanism of the imidazole-catalyzed esterification of one such peptide, Ac-SAFYG-SCH 2 ϕ, and determined the acyl substitution product to be an intermediate in a competing reaction pathway involving acyl substitution of the thioester by imidazole. Our findings indicate that imidazole plays an essential role in this side-chain to C-terminal coupling, and by extension, in transesterifications in general, through a concerted mechanism wherein imidazole deprotonates the nucleophile as the nucleophile attacks the carbonyl. The system under study is identical to the histidine-serine portion of the catalytic triads in serine proteases and it is likely that these enzymes employ the same concerted mechanism in the first step of peptide cleavage. Additionally, relatively high concentrations of imidazole must be used to effectively catalyze reactions in aprotic solvents since the overall reaction involves imidazole acting both as an acid and as a base, existing in solution as an equilibrium distribution between the neutral form and its conjugate acid.

Alkaline Phosphatase-Mimicking Peptide Nanofibers for Osteogenic Differentiation

“…This mechanism is similar to the histidine-serine portion of the catalytic triad in serine proteases. 26 Free imidazole showed a much lower catalytic activity compared to peptide nanofibers, which illustrates the importance of histidine residue organization in the nanofibrous system ( Figure 2). Preorganization of a supramolecular system containing high densities of histidine residues increases the efficiency of catalysis compared to free and dispersed imidazole.…”

Dual‐Mode Optical Sensing of Histamine at Nanomolar Concentrations in Complex Biological Fluids and Living Cells

“…Although the interaction with 1 proceeded at much slower rate in this case, the addition of imidazole could improve the interaction rate (Figure d). This indicated the involvement of the imidazole group as a proton transfer catalyst in the overall sensing process . Nevertheless, the extent of spectral change observed in this case was less (ca.…”

“…This indicated the involvement of the imidazole group as ap roton transfer catalyst in the overall sensing process. [38,39] Nevertheless, the extent of spectral change observed in this case was less (ca. 2.25 fold) than for histamine ( Figure 2b), which indicated that there must be an additional role played by the imidazole group in the overall sensing process.…”

One‐pot emulsion templating for simultaneous hydrothermal carbonization and hydrogel synthesis: porous structures, nitrogen contents and activation

“…VIm could donate its lone sp 2 electron pair to a vacant boron p orbital in borax to form an amine–boron complex 95,96 . Imidazole, which can catalyze esterification reactions, 97 could also promote the esterification of the α ‐carbonyl aldehyde generated during HTC and thus interfere with the HTC process 91,98 . In addition, the formation of imidazole anions in the alkaline solution could promote salt formation and precipitation 99 .…”