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Functional conservation of the active sites of human and Drosophila angiotensin I-converting enzyme.

Coates, David and Isaac, R. Elwyn and Cotton, Joel and Siviter, Richard J. and Williams, Tracy A. and Shirras, Alan D. and Corvol, Pierre and Dive, Vincent (2000) Functional conservation of the active sites of human and Drosophila angiotensin I-converting enzyme. Biochemistry, 39 (30). pp. 8963-8969. ISSN 0006-2960

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Abstract

Human somatic angiotensin I-converting enzyme (sACE) has two active sites present in two homologous protein domains, resulting from a tandem gene duplication. It has been proposed that the N- and C-terminal active sites can have specific in vivo roles. In Drosophila melanogaster, Ance and Acer code for two ACE-like single-domain proteins, also predicted to have distinct physiological roles. We have investigated the relationship of Ance and Acer to the N- and C-domains of human sACE by genomic sequence analysis and by using domain-selective inhibitors, including RXP 407, a selective inhibitor of the human N-domain. These phosphinic peptides were potent inhibitors of Acer, but not of Ance. We conclude that the active sites of the N-domain and of Acer share structural features that permit the binding of the unusual RXP407 inhibitor and the hydrolysis of a broader range of peptide structures. In comparison, Ance, like the human C-domain of ACE, displays greater inhibitor selectivity. From the analysis of the published sequence of the Adh region of Drosophila chromosome 2, which carries Ance, Acer, and four additional ACE-like genes, we also suggest that this functional conservation is reflected in an ancestral gene structure identifiable in both protostome and deuterostome lineages and that the duplication seen in vertebrate genomes predates the divergence of these lineages. The conservation of ACE enzymes with distinct active sites in the evolution of both vertebrate and invertebrate species provides further evidence that these two kinds of active sites have different physiological functions.

Item Type: Article
Journal or Publication Title: Biochemistry
Subjects: Q Science > QH Natural history > QH301 Biology
Departments: Faculty of Science and Technology > Lancaster Environment Centre
Faculty of Health and Medicine > Biomedical & Life Sciences
ID Code: 9346
Deposited By: Dr Alan Shirras
Deposited On: 05 Jun 2008 11:29
Refereed?: Yes
Published?: Published
Last Modified: 26 Jul 2012 18:35
Identification Number:
URI: http://eprints.lancs.ac.uk/id/eprint/9346

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