Angiotensin-converting enzyme - new insights into structure, biological significance and prospects for domain-selective inhibitors.

dc.contributor.authorWatermeyer, Jean M
dc.contributor.authorKröger, Wendy L
dc.contributor.authorSturrock, Edward D
dc.contributor.authorEhlers, Mario R W
dc.date.accessioned2016-07-28T13:41:13Z
dc.date.available2016-07-28T13:41:13Z
dc.date.issued2009
dc.date.updated2016-07-28T13:39:38Z
dc.description.abstractSomatic angiotensin-converting enzyme (ACE) - well known for its role in cardiovascular pathophysiology - has an unusual, two-domain, double active-site structure. The two domains (designated N and C) are 55% identical and each contains a similar active site with overlapping but distinct substrate preferences. While both convert angiotensin I to angiotensin II in vitro, current evidence suggests the C domain site predominates in this role in vivo. The N domain site inactivates a hemoregulatory and antifibrotic peptide, AcSDKP, in vivo, although the significance of this remains unclear. However, differences in the characteristics of the two domains may result in different context-dependent activities, as is the case with other enzymes containing tandem repeats. The N domain may also have a role in modulating C domain activity, through a combination of inter-domain cooperativity and structural stabilization. Comparison of ACE with its structural homologues reveals conservation of peptidase activity and a tendency to hinge about the active-site cleft. Recent work on ACE active-site mutants containing one or more key residues replaced by their cognate residues from the other domain, synthesis of domain-selective inhibitors, and co-crystal structures of each domain with such inhibitors, has led to a better resolution of the basis for domain selectivity and should enable the design of next-generation, domain-selective inhibitors with distinct pharmacological profiles.en_ZA
dc.identifier.apacitationWatermeyer, J. M., Kröger, W. L., Sturrock, E. D., & Ehlers, M. R. W. (2009). Angiotensin-converting enzyme - new insights into structure, biological significance and prospects for domain-selective inhibitors. <i>Current Enzyme Inhibition</i>, http://hdl.handle.net/11427/21003en_ZA
dc.identifier.chicagocitationWatermeyer, Jean M, Wendy L Kröger, Edward D Sturrock, and Mario R W Ehlers "Angiotensin-converting enzyme - new insights into structure, biological significance and prospects for domain-selective inhibitors." <i>Current Enzyme Inhibition</i> (2009) http://hdl.handle.net/11427/21003en_ZA
dc.identifier.citationWatermeyer, J. M., Kroger, W. L., Sturrock, E. D., & Ehlers, M. R. (2009). Angiotensin-converting enzyme-New insights into structure, biological significance and prospects for domain-selective inhibitors. Current Enzyme Inhibition, 5(3), 134-147.en_ZA
dc.identifier.issn1573-4080en_ZA
dc.identifier.ris TY - Journal Article AU - Watermeyer, Jean M AU - Kröger, Wendy L AU - Sturrock, Edward D AU - Ehlers, Mario R W AB - Somatic angiotensin-converting enzyme (ACE) - well known for its role in cardiovascular pathophysiology - has an unusual, two-domain, double active-site structure. The two domains (designated N and C) are 55% identical and each contains a similar active site with overlapping but distinct substrate preferences. While both convert angiotensin I to angiotensin II in vitro, current evidence suggests the C domain site predominates in this role in vivo. The N domain site inactivates a hemoregulatory and antifibrotic peptide, AcSDKP, in vivo, although the significance of this remains unclear. However, differences in the characteristics of the two domains may result in different context-dependent activities, as is the case with other enzymes containing tandem repeats. The N domain may also have a role in modulating C domain activity, through a combination of inter-domain cooperativity and structural stabilization. Comparison of ACE with its structural homologues reveals conservation of peptidase activity and a tendency to hinge about the active-site cleft. Recent work on ACE active-site mutants containing one or more key residues replaced by their cognate residues from the other domain, synthesis of domain-selective inhibitors, and co-crystal structures of each domain with such inhibitors, has led to a better resolution of the basis for domain selectivity and should enable the design of next-generation, domain-selective inhibitors with distinct pharmacological profiles. DA - 2009 DB - OpenUCT DP - University of Cape Town J1 - Current Enzyme Inhibition LK - https://open.uct.ac.za PB - University of Cape Town PY - 2009 SM - 1573-4080 T1 - Angiotensin-converting enzyme - new insights into structure, biological significance and prospects for domain-selective inhibitors TI - Angiotensin-converting enzyme - new insights into structure, biological significance and prospects for domain-selective inhibitors UR - http://hdl.handle.net/11427/21003 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/21003
dc.identifier.urihttp://www.ingentaconnect.com/content/ben/cei/2009/00000005/00000003/art00002
dc.identifier.vancouvercitationWatermeyer JM, Kröger WL, Sturrock ED, Ehlers MRW. Angiotensin-converting enzyme - new insights into structure, biological significance and prospects for domain-selective inhibitors. Current Enzyme Inhibition. 2009; http://hdl.handle.net/11427/21003.en_ZA
dc.languageengen_ZA
dc.publisherBentham Science Publishersen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.sourceCurrent Enzyme Inhibitionen_ZA
dc.source.urihttp://www.ingentaconnect.com/content/ben/cei/2009/00000005/00000003/art00002
dc.subject.otherAcSDKP
dc.subject.otherAngiotensin-converting enzyme (ACE)
dc.subject.othercrystal
dc.subject.otherdomain-selective inhibitors
dc.subject.othermetallopeptidase
dc.titleAngiotensin-converting enzyme - new insights into structure, biological significance and prospects for domain-selective inhibitors.en_ZA
dc.typeJournal Articleen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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