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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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The inhibitory activity of the modified peptides from TPTQQS.The concentration of each peptide was 0.25 mmol/L.
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pone-0037077-g004: The inhibitory activity of the modified peptides from TPTQQS.The concentration of each peptide was 0.25 mmol/L.

Mentions: According to the results of the docking of TPTQQS onto ACE, TPTQQS forming coordination bonds with the zinc in the active site and the H-bonds with other amino acids outside of the active site played a key role in the inhibitory effect of TPTQQS. We chemically modified the key amino acids and changed the length of TPTQQS to investigate the non-competitive inhibition mechanism of TPTQQS further. First, we confirmed the effect of Ser6 by deleting the residue and changing it to an alanine in the peptide. The results showed that the inhibition rate of the peptide significantly decreased from 72.55% to 26.36% when the Ser was deleted as a result of the lack of interaction between the Ser and the active site of ACE. When Ser6 was replaced with Ala6, the interaction force decreased because Ala contains only two oxygen ions that can interact with the active site of ACE; the inhibition rate decreased to 48.61% (Fig. 4).


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)

The inhibitory activity of the modified peptides from TPTQQS.The concentration of each peptide was 0.25 mmol/L.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0037077-g004: The inhibitory activity of the modified peptides from TPTQQS.The concentration of each peptide was 0.25 mmol/L.
Mentions: According to the results of the docking of TPTQQS onto ACE, TPTQQS forming coordination bonds with the zinc in the active site and the H-bonds with other amino acids outside of the active site played a key role in the inhibitory effect of TPTQQS. We chemically modified the key amino acids and changed the length of TPTQQS to investigate the non-competitive inhibition mechanism of TPTQQS further. First, we confirmed the effect of Ser6 by deleting the residue and changing it to an alanine in the peptide. The results showed that the inhibition rate of the peptide significantly decreased from 72.55% to 26.36% when the Ser was deleted as a result of the lack of interaction between the Ser and the active site of ACE. When Ser6 was replaced with Ala6, the interaction force decreased because Ala contains only two oxygen ions that can interact with the active site of ACE; the inhibition rate decreased to 48.61% (Fig. 4).

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