Linked Life Data

12820798

Source:http://linkedlifedata.com/resource/pubmed/id/12820798

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2003-6-24
pubmed:abstractText
In the folate biosynthetic pathway, sulfa drugs (sulfonamides and sulfones) compete with the natural substrate, para-aminobenzoate (pABA) causing depletion of dihydrofolate (DHF) and subsequent growth inhibition. The sulfa drugs condense with 2-amino-4-hydroxy-6-hydroxymethyl-7,8 dihydropteridine pyrophosphate (DHPPP) forming sulfa-dihydropteroate (sulfa-DHP). Here evidence is presented using yeast that such dihydropteroate (DHP) analogs are inhibitory through competition with DHF. Two folate synthesis mutants, with respective dihydrofolate synthase (DHFS) and dihydropteroate synthase (DHPS) deletions and requiring DHF for growth were exposed to sulfa drugs. The DHFS knockout mutant was inhibited, but the DHPS knockout mutant that was incapable of forming sulfa-DHP was insensitive. Such sulfa-DHP compounds were chemically synthesized and shown to be inhibitory in vivo by competing with DHF, but in vitro assays with double the concentration of the sulfa-DHP to DHF showed no inhibition of dihydrofolate reductase (DHFR). Sequence analysis of resistant mutants obtained in the presence of sulfa drugs showed no changes in DHFR, or DHPS, unlike previously found antifolate-resistant mutants. The diamino derivatives, which are precursors of the sulfa-DHP, were found to be DHFR inhibitors. These results suggest that a new class of drugs, based on DHP analogs, could be investigated.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:issn
1076-6294
pubmed:author
pubmed:issnType
Print
pubmed:volume
9
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
139-46
pubmed:dateRevised
2009-11-3
pubmed:meshHeading
pubmed:year
2003
pubmed:articleTitle
Inhibition studies of sulfonamide-containing folate analogs in yeast.
pubmed:affiliation
CSIRO Health Sciences and Nutrition & Biomolecular Research Institute, Parkville, Victoria, Australia.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.