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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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Overlap of captopril (green) in the crystal structure of the captopril-ACE complex with TPTQQS (cyan) in the docking simulation for TPTQQS.The figures were prepared using PYMOL software.
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pone-0037077-g005: Overlap of captopril (green) in the crystal structure of the captopril-ACE complex with TPTQQS (cyan) in the docking simulation for TPTQQS.The figures were prepared using PYMOL software.

Mentions: The active site of ACE is composed of a zinc ion and a HEXXH…E motif, which includes His383, Glu384, His387 and Glu411. ACE accommodates two substrate residues that are C-terminal to the zinc ion (in the S1′ and S2′ subsites) and, thus, has dipeptidase activity. The S1′ and S2′ subsites are conserved and important subsites in ACE and are occupied by competitive inhibitors. According to the proposed mechanism of HHL hydrolysis catalyzed by ACE [28], [29] and the crystal structure of the captopril-ACE complex (PDB code 1UZF), as a competitive inhibitor of ACE, captopril forms H-bonds with key residues in the active site of ACE and occupies the key positions that would be occupied by HHL, such as the S1′ and S2′ subsites, consistent with the typical competitive inhibition model (Fig. 5). We found that TPTQQS does not occupy the S1′ and S2′ subsites and is not located in the active site of ACE, only Ser6 can interact with the zinc ion, and the other amino acids are not located near the active site of ACE. Therefore, we concluded that TPTQQS cannot compete with HHL for the active site of ACE, indicating that TPTQQS is a non-competitive inhibitor of ACE structurally.


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)

Overlap of captopril (green) in the crystal structure of the captopril-ACE complex with TPTQQS (cyan) in the docking simulation for TPTQQS.The figures were prepared using PYMOL software.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0037077-g005: Overlap of captopril (green) in the crystal structure of the captopril-ACE complex with TPTQQS (cyan) in the docking simulation for TPTQQS.The figures were prepared using PYMOL software.
Mentions: The active site of ACE is composed of a zinc ion and a HEXXH…E motif, which includes His383, Glu384, His387 and Glu411. ACE accommodates two substrate residues that are C-terminal to the zinc ion (in the S1′ and S2′ subsites) and, thus, has dipeptidase activity. The S1′ and S2′ subsites are conserved and important subsites in ACE and are occupied by competitive inhibitors. According to the proposed mechanism of HHL hydrolysis catalyzed by ACE [28], [29] and the crystal structure of the captopril-ACE complex (PDB code 1UZF), as a competitive inhibitor of ACE, captopril forms H-bonds with key residues in the active site of ACE and occupies the key positions that would be occupied by HHL, such as the S1′ and S2′ subsites, consistent with the typical competitive inhibition model (Fig. 5). We found that TPTQQS does not occupy the S1′ and S2′ subsites and is not located in the active site of ACE, only Ser6 can interact with the zinc ion, and the other amino acids are not located near the active site of ACE. Therefore, we concluded that TPTQQS cannot compete with HHL for the active site of ACE, indicating that TPTQQS is a non-competitive inhibitor of ACE structurally.

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