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Inhibition mechanism and model of an angiotensin I-converting enzyme (ACE)-inhibitory hexapeptide from yeast (Saccharomyces cerevisiae).

Ni H, Li L, Liu G, Hu SQ - PLoS ONE (2012)

Bottom Line: The hexapeptide was found to inhibit ACE in a non-competitive manner, as supported by the structural model.The displacement of the zinc ion from the active site resulted in the inhibition of ACE activity.This study provides a new inhibitory mechanism of ACE by a peptide which broads our knowledge for drug designing against enzyme targets.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

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Lineweaver–Burk plot of ACE activity in the presence of the hexapeptide.Control (•), 100 µg/mL of the hexapeptide (▴), and 200 µg/mL of the hexapeptide (▪).
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pone-0037077-g001: Lineweaver–Burk plot of ACE activity in the presence of the hexapeptide.Control (•), 100 µg/mL of the hexapeptide (▴), and 200 µg/mL of the hexapeptide (▪).

Mentions: To determine the inhibitory mechanism, Lineweaver-Burk plots were determined for the ACE-inhibitory peptide from yeast (TPTQQS). As shown in Fig. 1, the lines intersection at the 1/[s] axis, indicate that the peptide is a non-competitive inhibitor [17]. Thus, the peptide can combine with the ACE molecule to produce a dead-end complex, regardless of whether a substrate molecule is bound or not. The complex between ACE and TPTQQS can prevent the formation of the reaction product, HA. Competitive inhibition of ACE is more frequently reported, including the common hypertension drugs, such as captopril, enalapril, and lisinopril; these drugs compete with the substrate for binding to the active site of ACE [18]. Some non-competitive inhibitory peptides have also been found in foods such as chickpeas [19], sardines [20], oysters [21], and tuna [22]; however, the inhibition mechanism and the binding site on ACE of these non-competitive inhibitors have not previously been investigated.


Inhibition mechanism and model of an angiotensin I-converting enzyme (ACE)-inhibitory hexapeptide from yeast (Saccharomyces cerevisiae).

Ni H, Li L, Liu G, Hu SQ - PLoS ONE (2012)

Lineweaver–Burk plot of ACE activity in the presence of the hexapeptide.Control (•), 100 µg/mL of the hexapeptide (▴), and 200 µg/mL of the hexapeptide (▪).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3351391&req=5

pone-0037077-g001: Lineweaver–Burk plot of ACE activity in the presence of the hexapeptide.Control (•), 100 µg/mL of the hexapeptide (▴), and 200 µg/mL of the hexapeptide (▪).
Mentions: To determine the inhibitory mechanism, Lineweaver-Burk plots were determined for the ACE-inhibitory peptide from yeast (TPTQQS). As shown in Fig. 1, the lines intersection at the 1/[s] axis, indicate that the peptide is a non-competitive inhibitor [17]. Thus, the peptide can combine with the ACE molecule to produce a dead-end complex, regardless of whether a substrate molecule is bound or not. The complex between ACE and TPTQQS can prevent the formation of the reaction product, HA. Competitive inhibition of ACE is more frequently reported, including the common hypertension drugs, such as captopril, enalapril, and lisinopril; these drugs compete with the substrate for binding to the active site of ACE [18]. Some non-competitive inhibitory peptides have also been found in foods such as chickpeas [19], sardines [20], oysters [21], and tuna [22]; however, the inhibition mechanism and the binding site on ACE of these non-competitive inhibitors have not previously been investigated.

Bottom Line: The hexapeptide was found to inhibit ACE in a non-competitive manner, as supported by the structural model.The displacement of the zinc ion from the active site resulted in the inhibition of ACE activity.This study provides a new inhibitory mechanism of ACE by a peptide which broads our knowledge for drug designing against enzyme targets.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

Show MeSH