Limits...
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.

Show MeSH
Model of the inhibition of ACE by TPTQQS.The model shows that TPTQQS moves the zinc ion away from the active site to inhibit ACE.
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pone-0037077-g007: Model of the inhibition of ACE by TPTQQS.The model shows that TPTQQS moves the zinc ion away from the active site to inhibit ACE.

Mentions: These results suggest that the inhibition of ACE by TPTQQS is non-competitive, and a non-competitive inhibition model of TPTQQS to ACE can be built (Fig. 7). When ACE is in the unbound form, the zinc ion and HEXXH motif compose the complete active site of ACE, and HHL can enter the active site and be converted into HA [29], [32]. After TPTQQS enters ACE, the Thr1, Thr3 and Gln4 residues of TPTQQS allow the peptide to interact with the lid structure of tACE, and the C-terminal Ser6 pulls the zinc ion away from the active site through the coordination bonds between the Ser and the zinc ion, resulting in the non-competitive inhibition of ACE by TPTQQS. Although HHL could bind to the active site, it could not be converted into the product, HA, because the conformation of the active site had changed. This model supports the non-competitive inhibition mechanism. In conclusion, this study provides a new inhibitory model and mechanism of ACE by a peptide which broads our knowledge for drug designing against enzyme targets.


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)

Model of the inhibition of ACE by TPTQQS.The model shows that TPTQQS moves the zinc ion away from the active site to inhibit ACE.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0037077-g007: Model of the inhibition of ACE by TPTQQS.The model shows that TPTQQS moves the zinc ion away from the active site to inhibit ACE.
Mentions: These results suggest that the inhibition of ACE by TPTQQS is non-competitive, and a non-competitive inhibition model of TPTQQS to ACE can be built (Fig. 7). When ACE is in the unbound form, the zinc ion and HEXXH motif compose the complete active site of ACE, and HHL can enter the active site and be converted into HA [29], [32]. After TPTQQS enters ACE, the Thr1, Thr3 and Gln4 residues of TPTQQS allow the peptide to interact with the lid structure of tACE, and the C-terminal Ser6 pulls the zinc ion away from the active site through the coordination bonds between the Ser and the zinc ion, resulting in the non-competitive inhibition of ACE by TPTQQS. Although HHL could bind to the active site, it could not be converted into the product, HA, because the conformation of the active site had changed. This model supports the non-competitive inhibition mechanism. In conclusion, this study provides a new inhibitory model and mechanism of ACE by a peptide which broads our knowledge for drug designing against enzyme targets.

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