Linked Life Data

12832630

Source:http://linkedlifedata.com/resource/pubmed/id/12832630

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
11
pubmed:dateCreated
2003-11-7
pubmed:abstractText
The activation peptide of mammalian trypsinogens contains a highly conserved tetra-aspartate sequence (D19-D20-D21-D22) preceding the K23-I24 scissile peptide bond, which is hydrolyzed as the first step in the activation process. Here, we examined the evolution and function of trypsinogen activation peptides through integrating functional characterization of disease-associated mutations with comparative genomic analysis. Activation properties of three chronic pancreatitis-associated activation peptide mutants (the novel D19A and the previously reported D22G and K23R) were simultaneously analyzed, for the first time, in the context of recombinant human cationic trypsinogen. A dramatic increase in autoactivation of cationic trypsinogen was observed in all three mutants, with D22G and K23R exhibiting the most marked increases. The physiological activator enteropeptidase activated the D19A mutant normally, activated the D22G mutant very poorly, and stimulated activation of the K23R mutant. The biochemical and structural data, taken together with a comprehensive sequence comparison, indicates that the tetra-aspartate sequence in mammalian trypsinogen activation peptides has evolved not only for optimal enteropeptidase recognition in the duodenum but also for efficient inhibition of trypsinogen autoactivation within the pancreas. Moreover, the use of lysine instead of arginine at the P1 position of activation peptides also has an advantageous effect against trypsinogen autoactivation. Finally, fixed substitutions in the key residues of the trypsinogen activation peptide may suggest the evolution of new functions unrelated to digestion, as found in the group III trypsinogens of cold-adapted fishes.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0737-4038
pubmed:author
pubmed:issnType
Print
pubmed:volume
20
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1767-77
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:12832630-Amino Acid Sequence, pubmed-meshheading:12832630-Animals, pubmed-meshheading:12832630-Arginine, pubmed-meshheading:12832630-Cations, pubmed-meshheading:12832630-Enteropeptidase, pubmed-meshheading:12832630-Enzyme Activation, pubmed-meshheading:12832630-Evolution, Molecular, pubmed-meshheading:12832630-Fishes, pubmed-meshheading:12832630-Hydrolysis, pubmed-meshheading:12832630-Lysine, pubmed-meshheading:12832630-Molecular Sequence Data, pubmed-meshheading:12832630-Mutagenesis, Site-Directed, pubmed-meshheading:12832630-Mutation, pubmed-meshheading:12832630-Oligopeptides, pubmed-meshheading:12832630-Peptides, pubmed-meshheading:12832630-Plasmids, pubmed-meshheading:12832630-Recombinant Proteins, pubmed-meshheading:12832630-Time Factors, pubmed-meshheading:12832630-Trypsinogen
pubmed:year
2003
pubmed:articleTitle
Evolution of trypsinogen activation peptides.
pubmed:affiliation
Institut National de la Santé et de la Recherche Médicale, Génétique Moléculaire et Génétique Epidémiologique, Université de Bretagne Occidentale, Etablissement Français du Sang-Bretagne, Brest, France.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't