Linked Life Data

8357989

Source:http://linkedlifedata.com/resource/pubmed/id/8357989

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1-3
pubmed:dateCreated
1993-9-24
pubmed:abstractText
5-Lipoxygenase-activating protein (FLAP) plays an essential role in cellular leukotriene (LT) synthesis and represents the target of three classes of LT biosynthesis inhibitors. We have taken three approaches to localize regions of FLAP involved in the binding of these inhibitors. A comparison of the amino acid sequences of FLAP from eight mammalian species identifies regions of the protein which are highly conserved and consequently may be involved in functional and inhibitor binding properties of the protein. Conversely, amino acids not conserved amongst these species are unlikely to play an essential role in inhibitor binding. Immunoprecipitation of peptide fragments of FLAP cross-linked to photoaffinity analogues of LT biosynthesis inhibitors following site-specific peptide cleavage indicates that the inhibitor attachment site is amino-terminal to 72Trp. Taken together, the cross-species analysis and photoaffinity labelling studies suggest a region within the first hydrophilic loop of FLAP which may be important for inhibitor binding. Site-directed mutagenesis of human FLAP followed by the analysis of FLAP mutants in a radioligand binding assay was used to more accurately define critical amino acid residues within this region. Mutagenesis studies reveal that mutants containing deletions of amino acids in regions of FLAP not conserved between species retain the ability to specifically bind inhibitors. Furthermore, mutants containing deletions in a highly conserved region of the protein (residues 42-61) do not bind inhibitors. These studies have therefore localized specific amino acids of FLAP which are essential for inhibitor binding. The roles that these amino acids play in inhibitor binding and may play in 5-LO activation is under investigation.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:issn
0921-8319
pubmed:author
pubmed:issnType
Print
pubmed:volume
6
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
31-42
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:8357989-5-Lipoxygenase-Activating Proteins, pubmed-meshheading:8357989-Affinity Labels, pubmed-meshheading:8357989-Amino Acid Sequence, pubmed-meshheading:8357989-Animals, pubmed-meshheading:8357989-Binding Sites, pubmed-meshheading:8357989-Carrier Proteins, pubmed-meshheading:8357989-Cattle, pubmed-meshheading:8357989-Dogs, pubmed-meshheading:8357989-Horses, pubmed-meshheading:8357989-Humans, pubmed-meshheading:8357989-Leukotrienes, pubmed-meshheading:8357989-Macaca mulatta, pubmed-meshheading:8357989-Membrane Proteins, pubmed-meshheading:8357989-Mice, pubmed-meshheading:8357989-Molecular Sequence Data, pubmed-meshheading:8357989-Mutagenesis, Site-Directed, pubmed-meshheading:8357989-Rabbits, pubmed-meshheading:8357989-Rats, pubmed-meshheading:8357989-Sequence Homology, Amino Acid, pubmed-meshheading:8357989-Sheep, pubmed-meshheading:8357989-Species Specificity, pubmed-meshheading:8357989-Swine
pubmed:articleTitle
Amino acid residues of 5-lipoxygenase-activating protein critical for the binding of leukotriene biosynthesis inhibitors.
pubmed:affiliation
Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Pointe Claire-Dorva, Quebec, Canada.
pubmed:publicationType
Journal Article, Comparative Study