Dataset Information

Conformationally Regulated Peptide Bond Cleavage in Bradykinin.

ABSTRACT: Ion mobility and mass spectrometry techniques are used to investigate the stabilities of different conformations of bradykinin (BK, Arg1-Pro2-Pro3-Gly4-Phe5-Ser6-Pro7-Phe8-Arg9). At elevated solution temperatures, we observe a slow protonation reaction, i.e., [BK+2H]2++H+ ? [BK+3H]3+, that is regulated by trans ? cis isomerization of Arg1-Pro2, resulting in the Arg1- cis-Pro2- cis-Pro3-Gly4-Phe5-Ser6- cis-Pro7-Phe8-Arg9 (all- cis) configuration. Once formed, the all- cis [BK+3H]3+ spontaneously cleaves the bond between Pro2-Pro3 with perfect specificity, a bond that is biologically resistant to cleavage by any human enzyme. Temperature-dependent kinetics studies reveal details about the intrinsic peptide processing mechanism. We propose that nonenzymatic cleavage at Pro2-Pro3 occurs through multiple intermediates and is regulated by trans ? cis isomerization of Arg1-Pro2. From this mechanism, we can extract transition state thermochemistry: ? G‡ = 94.8 ± 0.2 kJ·mol-1, ? H‡ = 79.8 ± 0.2 kJ·mol-1, and ? S‡ = -50.4 ± 1.7 J·mol-1·K-1 for the trans ? cis protonation event; and, ? G‡ = 94.1 ± 9.2 kJ·mol-1, ? H‡ = 107.3 ± 9.2 kJ·mol-1, and ? S‡ = 44.4 ± 5.1 J·mol-1·K-1 for bond cleavage. Biological resistance to the most favored intrinsic processing pathway prevents formation of Pro3-Gly4-Phe5-Ser6- cis-Pro7-Phe8-Arg9 that is approximately an order of magnitude more antigenic than BK.

SUBMITTER: Fuller DR

PROVIDER: S-EPMC6503673 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Conformationally Regulated Peptide Bond Cleavage in Bradykinin.

Fuller Daniel R DR Conant Christopher R CR El-Baba Tarick J TJ Brown Christopher J CJ Woodall Daniel W DW Russell David H DH Clemmer David E DE

Journal of the American Chemical Society 20180723 30

Ion mobility and mass spectrometry techniques are used to investigate the stabilities of different conformations of bradykinin (BK, Arg1-Pro2-Pro3-Gly4-Phe5-Ser6-Pro7-Phe8-Arg9). At elevated solution temperatures, we observe a slow protonation reaction, i.e., [BK+2H]2++H+ → [BK+3H]3+, that is regulated by trans → cis isomerization of Arg1-Pro2, ...[more]

PMID: 30028131

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Dataset Information

Conformationally Regulated Peptide Bond Cleavage in Bradykinin.

Publications

Conformationally Regulated Peptide Bond Cleavage in Bradykinin.

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