Conformationally Regulated Peptide Bond Cleavage in Bradykinin.
Conformationally Regulated Peptide Bond Cleavage in Bradykinin.
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构象调节的肽键裂解在心动激肽中。
DOI：
10.1021/jacs.8b04751
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发表时间：
2018-08-01
影响因子：
15
通讯作者：
Clemmer DE
中科院分区：
文献类型：
--
作者：
Fuller DR;Conant CR;El-Baba TJ;Brown CJ;Woodall DW;Russell DH;Clemmer DE
采用离子迁移率和质谱技术研究了缓激肽（BK，Arg 1-Pro2-Pro3-Gly 4-Phe 5-Ser 6-Pro7-Phe 8-Arg 9）不同构象的稳定性。在升高的溶液温度下，我们观察到缓慢的质子化反应，即，[BK+2H 2 ++H+ → [BK+3 H]3+，受Arg 1-Pro2的反式→顺式异构化调控，形成Arg 1-Cis-Pro2-cis-Pro3-Gly 4-Phe 5-Ser 6-cis-Pro7-Phe 8-Arg 9（all-cis）构型。一旦形成，全顺式[BK+3 H]3+自发地以完美的特异性切割Pro2-Pro3之间的键，该键在生物学上对任何人类酶的切割具有抗性。温度依赖性动力学研究揭示了内在肽加工机制的细节。我们建议，在Pro2-Pro3的非酶裂解发生通过多个中间体，并受Arg 1-Pro2的反式→顺式异构化。从该机理出发，我们可以得到过渡态热化学：对于反式→顺式质子化事件，ΔG_（？）= 94.8 ± 0.2 kJ·mol − 1，ΔH_（？）= 79.8 ± 0.2 kJ·mol−1，ΔS_（？）= −50.4 ± 1.7 J·mol−1·K−1;键断裂时，ΔG_（？）= 94.1 ± 9.2 kJ·mol-1，→H_（？）= 107.3 ± 9.2 kJ·mol-1，→S_（？）= 44.4 ± 5.1 J·mol-1·K-1。对最有利的内在加工途径的生物抗性阻止了Pro3-Gly 4-Phe 5-Ser 6-cis-Pro7-Phe 8-Arg 9的形成，其抗原性比BK高大约一个数量级。
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: ΔG‡ = 94.8 ± 0.2 kJ·mol−1, ΔH‡ = 79.8 ± 0.2 kJ·mol−1, and ΔS‡ = −50.4 ± 1.7 J·mol−1·K−1 for the trans → cis protonation event; and, ΔG‡ = 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.
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影响因子：
2.9
作者：
YOUNG, JK;HICKS, RP
通讯作者：
HICKS, RP
影响因子：
7.4
作者：
Benesch, JLP;Sobott, F;Robinson, CV
通讯作者：
Robinson, CV
影响因子：
2.9
作者：
DENYS, L;BOTHNERBY, AA;RYAN, JW
通讯作者：
RYAN, JW
DOI：
10.1139/o79-067
发表时间：
1979-01-01
期刊：
CANADIAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
REDMAN, LW;REGOLI, D;TUSTANOFF, ER
通讯作者：
TUSTANOFF, ER
影响因子：
15
作者：
Cong, Xiao;Liu, Yang;Laganowsky, Arthur
通讯作者：
Laganowsky, Arthur