Linked Life Data

11223131

Source:http://linkedlifedata.com/resource/pubmed/id/11223131

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2001-3-6
pubmed:databankReference
pubmed:abstractText
Folate metabolism in the human malaria parasite Plasmodium falciparum is an essential activity for cell growth and replication, and the target of an important class of therapeutic agents in widespread use. However, resistance to antifolate drugs is a major health problem in the developing world. To date, only two activities in this complex pathway have been targeted by antimalarials. To more fully understand the mechanisms of antifolate resistance and to identify promising targets for new chemotherapies, we have cloned genes encoding as yet uncharacterised enzymes in this pathway. By means of complementation experiments using 1-carbon metabolism mutants of both Escherichia coli and Saccharomyces cerevisiae, we demonstrate here that one of these parasite genes encodes both dihydrofolate synthetase (DHFS) and folylpolyglutamate synthetase (FPGS) activities, which catalyse the synthesis and polyglutamation of folate derivatives, respectively. The malaria parasite is the first known example of a eukaryote encoding both DHFS and FPGS activities in a single gene. DNA sequencing of this gene in antifolate-resistant strains of P. falciparum, as well as drug-inhibition assays performed on yeast and bacteria expressing PfDHFS--FPGS, indicate that current antifolate regimes do not target this enzyme. As PfDHFS--FPGS harbours two activities critical to folate metabolism, one of which has no human counterpart, this gene product offers a novel chemotherapeutic target with the potential to deliver a powerful blockage to parasite growth.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0166-6851
pubmed:author
pubmed:issnType
Print
pubmed:volume
112
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
239-52
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:11223131-Amino Acid Sequence, pubmed-meshheading:11223131-Animals, pubmed-meshheading:11223131-Base Sequence, pubmed-meshheading:11223131-Cloning, Molecular, pubmed-meshheading:11223131-Escherichia coli, pubmed-meshheading:11223131-Folic Acid Antagonists, pubmed-meshheading:11223131-Gene Deletion, pubmed-meshheading:11223131-Genes, Protozoan, pubmed-meshheading:11223131-Genetic Complementation Test, pubmed-meshheading:11223131-Glycine, pubmed-meshheading:11223131-Methionine, pubmed-meshheading:11223131-Molecular Sequence Data, pubmed-meshheading:11223131-Multienzyme Complexes, pubmed-meshheading:11223131-Peptide Synthases, pubmed-meshheading:11223131-Plasmodium falciparum, pubmed-meshheading:11223131-RNA, Fungal, pubmed-meshheading:11223131-Saccharomyces cerevisiae, pubmed-meshheading:11223131-Sequence Alignment, pubmed-meshheading:11223131-Transformation, Genetic
pubmed:year
2001
pubmed:articleTitle
A bifunctional dihydrofolate synthetase--folylpolyglutamate synthetase in Plasmodium falciparum identified by functional complementation in yeast and bacteria.
pubmed:affiliation
Department of Biomolecular Sciences, University of Manchester Institute of Science and Technology, PO Box 88, Manchester M60 1QD, UK.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't