Conformationally Regulated Peptide Bond Cleavage in Bradykinin

Journal of the American Chemical Society
Daniel R FullerD E Clemmer

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: Δ G‡ = 94.8 ± 0.2 kJ·mol-1, Δ H‡ = 79.8 ± 0.2 kJ·mol-1, and Δ S‡ = -50.4 ± 1.7 J·mol-1·K-1 for the trans → cis protonation event; and, Δ G‡ = 94.1 ± 9.2 kJ·mol-1, Δ H‡ = 107.3 ± 9.2 kJ·mol-1, and Δ S‡ = 44.4 ± 5.1 J·mol-1·K-1 for bond cleavage. Biological resistance to the most favored intri...Continue Reading

References

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Jun 28, 2015·Journal of the American Chemical Society·Liuqing ShiDavid E Clemmer
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Feb 8, 2018·Journal of the American Chemical Society·Liudmila VoroninaThomas R Rizzo

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Citations

Feb 19, 2019·European Journal of Mass Spectrometry·Daniel R FullerDavid E Clemmer
Jul 2, 2020·Mass Spectrometry Reviews·Jacob W McCabeDavid H Russell
Jan 29, 2020·Analytical Chemistry·Daniel W WoodallDavid E Clemmer
Mar 11, 2021·The Journal of Physical Chemistry. B·Zhi-Chao ZhangDavid E Clemmer
Apr 14, 2019·Journal of the American Society for Mass Spectrometry·Christopher R ConantDavid E Clemmer
Jul 25, 2019·Journal of the American Society for Mass Spectrometry·Yu-Fu LinLaurence A Angel
Aug 1, 2019·Journal of the American Society for Mass Spectrometry·Christopher J BrownDavid E Clemmer
Jul 17, 2021·The Journal of Physical Chemistry. B·Zhichao ZhangDavid E Clemmer
Oct 12, 2021·Chemistry : a European Journal·Julian Alexander HarrisonRenato Zenobi

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