Inhibition Mechanism and Model of an Angiotensin I-Converting Enzyme (ACE)-Inhibitory Hexapeptide from Yeast (Saccharomyces cerevisiae)

Abstract

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.

Structural Characteristics and Antihypertensive Effects of Angiotensin-Iconverting Enzyme Inhibitory Peptides in the Renin-Angiotensin and Kallikrein Kinin Systems

“…This indicates that the presence of phenylalanine at C-terminus is also an utmost importance for the ACE inhibitory activity (Saiga et al, 2006). According to Ni et al, (2012), the peptides with phenylalanine at the C-terminal have high ACE inhibitory activity. Similar characteristic was observed for the peptide sequence of VECYGPNRPQF, with proline at the antepenultimate and phenylalanine at the C-terminal.…”

Purification and characterization of a novel angiotensin I-converting enzyme inhibitory peptide derived from abalone (Haliotis discus hannai Ino) gonads

“…Food-derived peptides which act as non-competitive inhibitor against aCE have recently been reported from Pleurotus cornucopiae and edible mushroom [40,41]. a hexapeptide (TPTQQS) which revealed non-competitive inhibition mechanism can bind to the catalytic area of aCE and consequently chelate zinc ion away from aCE active site [42]. However, other inhibitory peptides that function as noncompetitive inhibitors may not fit into this model because of different structures of peptides.…”

Molecular Recognition of Human Angiotensin-Coverting Enzyme I (hACE I) and Different Inhibitors

“…The molecular modeling is performed on the novel ketomethylene inhibitors with ACE, and the results show that tryptophan at the P2'position in the complex of ketomethylene and ACE significantly increased selectivity for the C-domian, while an aliphatic P2 group confers N-domian selectivity [36]. The complexes of oligopeptides and ACE are also studies using the molecular simulation, and the oligopeptides contain the ACE-inhibitory hexapeptide (TPTQQS) [37], tripeptides LKP and IKP [38], gonadotropin-releasing hormone (GnRH) [39]. The results of the studies show that the binding mode of the oligopeptides with ACE.…”