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.

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The docking simulation of TPTQQS binding to ACE.A. The docking simulation of TPTQQS (green) binding to ACE (shown as a multi-colored cartoon). A zinc ion (gray) was present in the active site of tACE. B. The interaction between TPTQQS (shown as sticks) and the residues of tACE (shown as lines) is shown.
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pone-0037077-g003: The docking simulation of TPTQQS binding to ACE.A. The docking simulation of TPTQQS (green) binding to ACE (shown as a multi-colored cartoon). A zinc ion (gray) was present in the active site of tACE. B. The interaction between TPTQQS (shown as sticks) and the residues of tACE (shown as lines) is shown.

Mentions: To investigate the non-competitive inhibition mechanism of ACE by TPTQQS further, DS2.1 (a suitable a program for performing automated docking simulations of ligands to their macromolecular receptors) was used to carry out the docking simulation. Because tACE can completely perform the blood pressure regulation function of sACE, the three-dimensional structure of tACE (1O8A) was used as the macromolecular receptor in the docking simulation to investigate the inhibition mechanism of ACE by TPTQQS [14]. Fig. 3A showed the docking mode of TPTQQS, with the highest LibDock Score (188.439), onto the binding site of ACE. It was observed that this peptide had an expanded conformation and was deeply inserted into the binding pocket. The active cleft divides tACE into two structural subdomains: subdomain I and subdomain II. The peptide was adjacent to subdomain I, far from the active site, which includes the important positions S1′ and S2′, especially [16].


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 docking simulation of TPTQQS binding to ACE.A. The docking simulation of TPTQQS (green) binding to ACE (shown as a multi-colored cartoon). A zinc ion (gray) was present in the active site of tACE. B. The interaction between TPTQQS (shown as sticks) and the residues of tACE (shown as lines) is shown.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0037077-g003: The docking simulation of TPTQQS binding to ACE.A. The docking simulation of TPTQQS (green) binding to ACE (shown as a multi-colored cartoon). A zinc ion (gray) was present in the active site of tACE. B. The interaction between TPTQQS (shown as sticks) and the residues of tACE (shown as lines) is shown.
Mentions: To investigate the non-competitive inhibition mechanism of ACE by TPTQQS further, DS2.1 (a suitable a program for performing automated docking simulations of ligands to their macromolecular receptors) was used to carry out the docking simulation. Because tACE can completely perform the blood pressure regulation function of sACE, the three-dimensional structure of tACE (1O8A) was used as the macromolecular receptor in the docking simulation to investigate the inhibition mechanism of ACE by TPTQQS [14]. Fig. 3A showed the docking mode of TPTQQS, with the highest LibDock Score (188.439), onto the binding site of ACE. It was observed that this peptide had an expanded conformation and was deeply inserted into the binding pocket. The active cleft divides tACE into two structural subdomains: subdomain I and subdomain II. The peptide was adjacent to subdomain I, far from the active site, which includes the important positions S1′ and S2′, especially [16].

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