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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
3
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pubmed:dateCreated |
2002-2-6
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pubmed:abstractText |
Nonribosomal peptide synthetases responsible for the production of macrocyclic compounds often use their C-terminal thioesterase (TE) domain for enzymatic cyclization of a linear precursor. The excised TE domain from the nonribosomal peptide synthetase responsible for the production of the cyclic decapeptide tyrocidine A, TycC TE, retains autonomous ability to catalyze head-to-tail macrocyclization of a linear peptide thioester with the native sequence of tyrocidine A and can additionally cyclize peptide analogs that incorporate limited alterations in the peptide sequence. Here we show that TycC TE can catalyze macrocyclization of peptide substrates that are dramatically different from the native tyrocidine linear precursor. Several peptide thioesters that retain a limited number of elements of the native peptide sequence are shown to be substrates for TycC TE. These peptides were designed to integrate an Arg-Gly-Asp sequence that confers potential activity in the inhibition of ligand binding by integrin receptors. Although enzymatic hydrolysis of the peptide thioester substrates is preferred over cyclization, TycC TE can be used on a preparative scale to generate both linear and cyclic peptide products for functional characterization. The products are shown to be inhibitors of ligand binding by integrin receptors, with cyclization and N(alpha)-methylation being important contributors to the nanomolar potency of the best inhibitors of fibrinogen binding to alpha IIb beta 3 integrin. This study provides evidence for TycC TE as a versatile macrocyclization catalyst and raises the prospect of using TE catalysis for the generation of diverse macrocyclic peptide libraries that can be probed for novel biological function.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/11805307-10051557,
http://linkedlifedata.com/resource/pubmed/commentcorrection/11805307-10447947,
http://linkedlifedata.com/resource/pubmed/commentcorrection/11805307-10631508,
http://linkedlifedata.com/resource/pubmed/commentcorrection/11805307-10764747,
http://linkedlifedata.com/resource/pubmed/commentcorrection/11805307-11001063,
http://linkedlifedata.com/resource/pubmed/commentcorrection/11805307-11196652,
http://linkedlifedata.com/resource/pubmed/commentcorrection/11805307-11323715,
http://linkedlifedata.com/resource/pubmed/commentcorrection/11805307-11401554,
http://linkedlifedata.com/resource/pubmed/commentcorrection/11805307-11401555,
http://linkedlifedata.com/resource/pubmed/commentcorrection/11805307-11828432,
http://linkedlifedata.com/resource/pubmed/commentcorrection/11805307-1438188,
http://linkedlifedata.com/resource/pubmed/commentcorrection/11805307-1497316,
http://linkedlifedata.com/resource/pubmed/commentcorrection/11805307-15335856,
http://linkedlifedata.com/resource/pubmed/commentcorrection/11805307-1555235,
http://linkedlifedata.com/resource/pubmed/commentcorrection/11805307-2521482,
http://linkedlifedata.com/resource/pubmed/commentcorrection/11805307-7507411,
http://linkedlifedata.com/resource/pubmed/commentcorrection/11805307-7528107,
http://linkedlifedata.com/resource/pubmed/commentcorrection/11805307-7604280,
http://linkedlifedata.com/resource/pubmed/commentcorrection/11805307-7690752,
http://linkedlifedata.com/resource/pubmed/commentcorrection/11805307-7770773,
http://linkedlifedata.com/resource/pubmed/commentcorrection/11805307-8068614,
http://linkedlifedata.com/resource/pubmed/commentcorrection/11805307-8694841,
http://linkedlifedata.com/resource/pubmed/commentcorrection/11805307-8756458,
http://linkedlifedata.com/resource/pubmed/commentcorrection/11805307-8970741,
http://linkedlifedata.com/resource/pubmed/commentcorrection/11805307-9151803,
http://linkedlifedata.com/resource/pubmed/commentcorrection/11805307-9756477,
http://linkedlifedata.com/resource/pubmed/commentcorrection/11805307-9923894
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
0027-8424
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
5
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pubmed:volume |
99
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1247-52
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pubmed:dateRevised |
2010-9-14
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pubmed:meshHeading |
pubmed-meshheading:11805307-Amino Acid Sequence,
pubmed-meshheading:11805307-Anti-Bacterial Agents,
pubmed-meshheading:11805307-Catalysis,
pubmed-meshheading:11805307-Integrins,
pubmed-meshheading:11805307-Ligands,
pubmed-meshheading:11805307-Oligopeptides,
pubmed-meshheading:11805307-Palmitoyl-CoA Hydrolase,
pubmed-meshheading:11805307-Peptide Synthases,
pubmed-meshheading:11805307-Peptides, Cyclic,
pubmed-meshheading:11805307-Tyrocidine
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pubmed:year |
2002
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pubmed:articleTitle |
The thioesterase domain from a nonribosomal peptide synthetase as a cyclization catalyst for integrin binding peptides.
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pubmed:affiliation |
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.
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