Linked Life Data

7925353

Source:http://linkedlifedata.com/resource/pubmed/id/7925353

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
1994-10-27
pubmed:databankReference
pubmed:abstractText
Dihydropteroate synthase (H2Pte synthase) is the target of the sulfur-based antimalarial drugs, which are frequently used in synergistic combination with inhibitors of dihydrofolate reductase (H2folate reductase) to combat chloroquine-resistant malaria. We have isolated the H2Pte synthase coding sequence of the most pathogenic human parasite Plasmodium falciparum. It forms part of a longer coding sequence, located on chromosome 8, that also specifies 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (CH2OH-H2pterinPP kinase) at its 5' proximal end. This domain is unusually large, with two long insertions relative to other CH2OH-H2pterinPP kinase molecules. To investigate a possible genetic basis for clinical resistance to sulfa drugs, we sequenced the complete H2Pte synthase domains from eleven isolates of P. falciparum with diverse geographical origins and levels of sulfadoxine resistance. Overall, point mutations in five positions were observed, affecting four codons. Parasite lines exhibiting high-level resistance were found to carry either a double mutation, altering both Ser436 and Ala613, or a single mutation affecting Ala581. The mutations at positions 436 and 581 have the same location relative to each of two degenerate repeated amino acid motifs that are conserved across all other known H2Pte synthase molecules. The amino acid alteration at residue 613 is identically positioned relative to a different conserved motif. The fourth amino acid residue (437) affected by mutation, though adjacent to the apparently crucial residue 436, shows no obvious correlation with resistance. Although these mutations have no exact counterparts in any other organism, that at position 581 falls within a region of three amino acids where H2Pte synthase is modified in various ways in a number of sulfonamide-resistant pathogenic bacteria. Copy-number analysis indicated that there was no amplification of the H2Pte synthase domain in resistant parasite lines of P. falciparum, compared to sensitive lines.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
0014-2956
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
224
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
397-405
pubmed:dateRevised
2009-9-29
pubmed:meshHeading
pubmed-meshheading:7925353-Amino Acid Sequence, pubmed-meshheading:7925353-Animals, pubmed-meshheading:7925353-Base Sequence, pubmed-meshheading:7925353-Chromosome Mapping, pubmed-meshheading:7925353-Consensus Sequence, pubmed-meshheading:7925353-DNA, Protozoan, pubmed-meshheading:7925353-DNA Primers, pubmed-meshheading:7925353-Dihydropteroate Synthase, pubmed-meshheading:7925353-Diphosphotransferases, pubmed-meshheading:7925353-Drug Resistance, pubmed-meshheading:7925353-Genetic Variation, pubmed-meshheading:7925353-Humans, pubmed-meshheading:7925353-Malaria, Falciparum, pubmed-meshheading:7925353-Molecular Sequence Data, pubmed-meshheading:7925353-Mutation, pubmed-meshheading:7925353-Plasmodium falciparum, pubmed-meshheading:7925353-Sequence Homology, Amino Acid, pubmed-meshheading:7925353-Sulfadoxine
pubmed:year
1994
pubmed:articleTitle
Sequence variation of the hydroxymethyldihydropterin pyrophosphokinase: dihydropteroate synthase gene in lines of the human malaria parasite, Plasmodium falciparum, with differing resistance to sulfadoxine.
pubmed:affiliation
Department of Biochemistry and Applied Molecular Biology, University of Manchester Institute of Science and Technology, England.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, Non-U.S. Gov't