Issue 18, 2013

The role of imidazole in peptidecyclization 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-SCH2ϕ, 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.

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

Article information

Article type
Paper
Submitted
20 Dec 2012
Accepted
09 Mar 2013
First published
12 Mar 2013

Org. Biomol. Chem., 2013,11, 2979-2987

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

K. G. Byler, Y. Li, R. A. Houghten and K. Martinez-Mayorga, Org. Biomol. Chem., 2013, 11, 2979 DOI: 10.1039/C3OB27464K

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements