Functional Conservation of the Active Sites of Human andDrosophilaAngiotensin I-Converting Enzyme
| Autor: | R. Elwyn Isaac, Alan D. Shirras, Tracy Ann Williams, Richard J. Siviter, Vincent Dive, Joël Cotton, Pierre Corvol, David Coates |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Sequence analysis
Molecular Sequence Data Angiotensin-Converting Enzyme Inhibitors Peptidyl-Dipeptidase A Biochemistry Genome Peptide Library Gene duplication Animals Drosophila Proteins Humans Amino Acid Sequence Gene Conserved Sequence Genetics Binding Sites Deuterostome biology Metalloendopeptidases Acetylation Protein superfamily biology.organism_classification Phosphinic Acids Protein Structure Tertiary Drosophila melanogaster Insect Proteins Protostome Peptides |
| Zdroj: | Biochemistry. 39:8963-8969 |
| ISSN: | 1520-4995 0006-2960 |
| DOI: | 10.1021/bi000593q |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|