Linked Life Data

2146271

Source:http://linkedlifedata.com/resource/pubmed/id/2146271

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
31
pubmed:dateCreated
1990-12-10
pubmed:abstractText
We have investigated some unusual aspects of the inhibition of mammalian thymidylate synthase (TS) by the folate antimetabolite, 10-propargyl-5,8-dideaza-folic acid (CB 3717). From our results, we conclude that binding of CB 3717 metabolites to one subunit of L1210 TS modified the conformation of the second active site of this enzyme so that it retained the ability to bind 5-fluro-2'-deoxyuridine-5'-monophosphate (FdUMP) but not its catalytic activity. Exposure of intact mouse L1210 cells to CB 3717 resulted in inactivation of cellular TS activity, yet desalted cytosol preparations from these cells retained the ability to bind FdUMP. The same effect was found with several analogs of CB 3717. Complexes of FdUMP formed in vitro with TS from cells exposed to CB 3717 were covalent and co-migrated on sodium dodecyl sulfate-polyacrylamide gel electrophoresis with complexes of FdUMP, folate cofactor, and TS from cells not exposed to CB 3717. In the presence of dUMP, a tightly bound complex rapidly formed between isolated pure TS and the pentaglutamate of CB 3717 but not the monoglutamate form of this compound. Binding experiments using CB 3717 pentaglutamate-inhibited TS suggested a stoichiometry of 1 mol of FdUMP bound per mol of dimeric TS.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
5
pubmed:volume
265
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
19163-9
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
1990
pubmed:articleTitle
Quinazoline folate analogs inhibit the catalytic activity of thymidylate synthase but allow binding of 5-fluorodeoxyuridylate.
pubmed:affiliation
Department of Biochemistry, School of Medicine, University of Southern California, Los Angeles 90033.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't