Guangdong Province Key Laboratory for Green Processing of Natural Products and Product Safety, College of Light Industry and Food Sciences, South China University of Technology, Guangzhou, Guangdong, China.
PLoS One. 2012;7(5):e37077. doi: 10.1371/journal.pone.0037077. Epub 2012 May 14.
Angiotensin I-converting enzyme (ACE) has an important function in blood pressure regulation. ACE-inhibitory peptides can lower blood pressure by inhibiting ACE activity. Based on the sequence of an ACE-inhibitory hexapeptide (TPTQQS) purified from yeast, enzyme kinetics experiments, isothermal titration calorimetry (ITC), and a docking simulation were performed. The hexapeptide was found to inhibit ACE in a non-competitive manner, as supported by the structural model. The hexapeptide bound to ACE via interactions of the N-terminal Thr1, Thr3, and Gln4 residues with the residues on the lid structure of ACE, and the C-terminal Ser6 attracted the zinc ion, which is vital for ACE catalysis. The displacement of the zinc ion from the active site resulted in the inhibition of ACE activity. The structural model based on the docking simulation was supported by experiments in which the peptide was modified. This study provides a new inhibitory mechanism of ACE by a peptide which broads our knowledge for drug designing against enzyme targets.
血管紧张素转化酶（ACE）在血压调节中具有重要作用。ACE 抑制肽可通过抑制 ACE 活性来降低血压。基于从酵母中纯化的 ACE 抑制六肽（TPTQQS）的序列，进行了酶动力学实验、等温滴定量热法（ITC）和对接模拟。结构模型支持该六肽以非竞争性方式抑制 ACE。六肽通过 N 端 Thr1、Thr3 和 Gln4 残基与 ACE 盖结构上的残基相互作用与 ACE 结合，C 端 Ser6 吸引锌离子，锌离子对 ACE 催化至关重要。锌离子从活性位点的置换导致 ACE 活性的抑制。基于对接模拟的结构模型得到了肽修饰实验的支持。这项研究为肽抑制 ACE 的提供了新的机制，拓宽了我们对针对酶靶标的药物设计的认识。
