| pubmed-article:11432860 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:11432860 | lifeskim:mentions | umls-concept:C0086418 | lld:lifeskim |
| pubmed-article:11432860 | lifeskim:mentions | umls-concept:C0022709 | lld:lifeskim |
| pubmed-article:11432860 | lifeskim:mentions | umls-concept:C0003765 | lld:lifeskim |
| pubmed-article:11432860 | lifeskim:mentions | umls-concept:C0439857 | lld:lifeskim |
| pubmed-article:11432860 | lifeskim:mentions | umls-concept:C0596019 | lld:lifeskim |
| pubmed-article:11432860 | lifeskim:mentions | umls-concept:C1264638 | lld:lifeskim |
| pubmed-article:11432860 | lifeskim:mentions | umls-concept:C0243102 | lld:lifeskim |
| pubmed-article:11432860 | lifeskim:mentions | umls-concept:C1511545 | lld:lifeskim |
| pubmed-article:11432860 | pubmed:issue | 36 | lld:pubmed |
| pubmed-article:11432860 | pubmed:dateCreated | 2001-9-4 | lld:pubmed |
| pubmed-article:11432860 | pubmed:abstractText | Angiotensin (Ang) I-converting enzyme (ACE) is a Zn(2+) metalloprotease with two homologous catalytic domains. Both the N- and C-terminal domains are peptidyl dipeptidases. Hydrolysis by ACE of its decapeptide substrate Ang I is increased by Cl(-), but the molecular mechanism of this regulation is unclear. A search for single substitutions to Gln among all conserved basic residues (Lys/Arg) in human ACE C-domain identified R1098Q as the sole mutant that lacked Cl(-) dependence. Cl(-) dependence is also lost when the equivalent Arg in the N-domain, Arg(500), is substituted with Gln. The Arg(1098) to Lys substitution reduced Cl(-) binding affinity by approximately 100-fold. In the absence of Cl(-), substrate binding affinity (1/K(m)) of and catalytic efficiency (k(cat)/K(m)) for Ang I hydrolysis are increased 6.9- and 32-fold, respectively, by the Arg(1098) to Gln substitution, and are similar (<2-fold difference) to the respective wild-type C-domain catalytic constants in the presence of optimal [Cl(-)]. The Arg(1098) to Gln substitution also eliminates Cl(-) dependence for hydrolysis of tetrapeptide substrates, but activity toward these substrates is similar to that of the wild-type C-domain in the absence of Cl(-). These findings indicate that: 1) Arg(1098) is a critical residue of the C-domain Cl(-)-binding site and 2) a basic side chain is necessary for Cl(-) dependence. For tetrapeptide substrates, the inability of R1098Q to recreate the high affinity state generated by the Cl(-)-C-domain interaction suggests that substrate interactions with the enzyme-bound Cl(-) are much more important for the hydrolysis of short substrates than for Ang I. Since Cl(-) concentrations are saturating under physiological conditions and Arg(1098) is not critical for Ang I hydrolysis, we speculate that the evolutionary pressure for the maintenance of the Cl(-)-binding site is its ability to allow cleavage of short cognate peptide substrates at high catalytic efficiencies. | lld:pubmed |
| pubmed-article:11432860 | pubmed:language | eng | lld:pubmed |
| pubmed-article:11432860 | pubmed:journal | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:11432860 | pubmed:citationSubset | IM | lld:pubmed |
| pubmed-article:11432860 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:11432860 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:11432860 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:11432860 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:11432860 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:11432860 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:11432860 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:11432860 | pubmed:status | MEDLINE | lld:pubmed |
| pubmed-article:11432860 | pubmed:month | Sep | lld:pubmed |
| pubmed-article:11432860 | pubmed:issn | 0021-9258 | lld:pubmed |
| pubmed-article:11432860 | pubmed:author | pubmed-author:HusainAA | lld:pubmed |
| pubmed-article:11432860 | pubmed:author | pubmed-author:LimPP | lld:pubmed |
| pubmed-article:11432860 | pubmed:author | pubmed-author:FernandezMM | lld:pubmed |
| pubmed-article:11432860 | pubmed:author | pubmed-author:WoutersM AMA | lld:pubmed |
| pubmed-article:11432860 | pubmed:author | pubmed-author:HeybergerSS | lld:pubmed |
| pubmed-article:11432860 | pubmed:issnType | Print | lld:pubmed |
| pubmed-article:11432860 | pubmed:day | 7 | lld:pubmed |
| pubmed-article:11432860 | pubmed:volume | 276 | lld:pubmed |
| pubmed-article:11432860 | pubmed:owner | NLM | lld:pubmed |
| pubmed-article:11432860 | pubmed:authorsComplete | Y | lld:pubmed |
| pubmed-article:11432860 | pubmed:pagination | 33518-25 | lld:pubmed |
| pubmed-article:11432860 | pubmed:dateRevised | 2004-11-17 | lld:pubmed |
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| pubmed-article:11432860 | pubmed:year | 2001 | lld:pubmed |
| pubmed-article:11432860 | pubmed:articleTitle | Arg(1098) is critical for the chloride dependence of human angiotensin I-converting enzyme C-domain catalytic activity. | lld:pubmed |
| pubmed-article:11432860 | pubmed:affiliation | Enzyme Research Unit, Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia. | lld:pubmed |
| pubmed-article:11432860 | pubmed:publicationType | Journal Article | lld:pubmed |
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| http://linkedlifedata.com/r... | pubmed:referesTo | pubmed-article:11432860 | lld:pubmed |
