Abstract
Angiotensin-I Converting Enzyme (ACE) is a Zinc Metallopeptidase of which the three-dimensional stucture was unknown until recently, when the Xray structure of testis isoform (C-terminal domain of somatic) was determined. ACE plays an important role in the regulation of blood pressure due to its action in the frame of the Renin-Angiotensin System. Efforts for the specific inhibition of the catalytic function of this enzyme have been made on the basis of the Xray structures of other enzymes with analogous efficacy in the hydrolytic cleavage of peptide substrate terminal fragments. Angiotensin-I Converting Enzyme bears the sequence and topology characteristics of the well-known gluzincins, a sub-family of zincins metallopeptidases and these similarities are exploited in order to reveal common structural elements among these enzymes. 3D homology models are also built using the X-ray structure of Thermolysin as template and peptide models that represent the amino acid sequence of the ACEs two catalytic, zinc-containing sites are designed and synthesized. Conformational analysis of the zinc-free and zinc-bound peptides through high resolution 1H NMR Spectroscopy provides new insights into the solution structure of ACE catalytic centers. Structural properties of these peptides could provide valuable information towards the design and preparation of new potent ACE inhibitors.
Keywords: Angiotensin-I Converting Enzyme, Angiotensin-I, ACE inhibitors
Current Topics in Medicinal Chemistry
Title: Structural Features of Angiotensin-I Converting Enzyme Catalytic Sites: Conformational Studies in Solution, Homology Models and Comparison with Other Zinc Metallopeptidases
Volume: 4 Issue: 4
Author(s): Georgios A. Spyroulias, Athanassios S. Galanis, George Pairas, Evy Manessi-Zoupa and Paul Cordopatis
Affiliation:
Keywords: Angiotensin-I Converting Enzyme, Angiotensin-I, ACE inhibitors
Abstract: Angiotensin-I Converting Enzyme (ACE) is a Zinc Metallopeptidase of which the three-dimensional stucture was unknown until recently, when the Xray structure of testis isoform (C-terminal domain of somatic) was determined. ACE plays an important role in the regulation of blood pressure due to its action in the frame of the Renin-Angiotensin System. Efforts for the specific inhibition of the catalytic function of this enzyme have been made on the basis of the Xray structures of other enzymes with analogous efficacy in the hydrolytic cleavage of peptide substrate terminal fragments. Angiotensin-I Converting Enzyme bears the sequence and topology characteristics of the well-known gluzincins, a sub-family of zincins metallopeptidases and these similarities are exploited in order to reveal common structural elements among these enzymes. 3D homology models are also built using the X-ray structure of Thermolysin as template and peptide models that represent the amino acid sequence of the ACEs two catalytic, zinc-containing sites are designed and synthesized. Conformational analysis of the zinc-free and zinc-bound peptides through high resolution 1H NMR Spectroscopy provides new insights into the solution structure of ACE catalytic centers. Structural properties of these peptides could provide valuable information towards the design and preparation of new potent ACE inhibitors.
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Spyroulias A. Georgios, Galanis S. Athanassios, Pairas George, Manessi-Zoupa Evy and Cordopatis Paul, Structural Features of Angiotensin-I Converting Enzyme Catalytic Sites: Conformational Studies in Solution, Homology Models and Comparison with Other Zinc Metallopeptidases, Current Topics in Medicinal Chemistry 2004; 4 (4) . https://dx.doi.org/10.2174/1568026043451294
DOI https://dx.doi.org/10.2174/1568026043451294 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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