Gene encoding a deubiquitinating enzyme is mutated in artesunate- and chloroquine-resistant rodent malaria parasites
Language: 
English
Abstract: 

Artemisinin- and artesunate-resistant Plasmodium chabaudi mutants, AS-ART and AS-ATN, were previously selected from chloroquine-resistant clones AS-30CQ and AS-15CQ respectively. Now, a genetic cross between AS-ART and the artemisinin-sensitive clone AJ has been analysed by Linkage Group Selection. A genetic linkage group on chromosome 2 was selected under artemisinin treatment. Within this locus, we identified two different mutations in a gene encoding a deubiquitinating enzyme. A distinct mutation occurred in each of the clones AS-30CQ and AS-ATN, relative to their respective progenitors in the AS lineage. The mutations occurred independently in different clones under drug selection with chloroquine (high concentration) or artesunate. Each mutation maps to a critical residue in a homologous human deubiquitinating protein structure. Although one mutation could theoretically account for the resistance of AS-ATN to artemisinin derivates, the other cannot account solely for the resistance of AS-ART, relative to the responses of its sensitive progenitor AS-30CQ. Two lines of Plasmodium falciparum with decreased susceptibility to artemisinin were also selected. Their drug-response phenotype was not genetically stable. No mutations in the UBP-1 gene encoding the P. falciparum orthologue of the deubiquitinating enzyme were observed. The possible significance of these mutations in parasite responses to chloroquine or artemisinin is discussed.

Author(s): 
Hunt, Paul
Afonso, Ana
Creasey, Alison
Culleton, Richard
Sidhu, Amar Bir Singh
Logan, John
Valderramos, Stephanie G.
McNae, Iain
Cheesman, Sandra
do Rosário, Virgílio
Carter, Richard
Fidock, David A.
Cravo, Pedro
Item Type: 
Journal Article
Publication Title: 
Molecular Microbiology
Journal Abbreviation: 
Mol. Microbiol.
Publication Date: 
7/7/2015
Publication Year: 
2007
Pages: 
27-40
Volume: 
65
Issue: 
1
ISSN: 
0950-382X
DOI: 
10.1111/j.1365-2958.2007.05753.x
Library Catalog: 
PubMed
Extra: 
PMID: 17581118 PMCID: PMC1974797

Turabian/Chicago Citation

Paul Hunt, Ana Afonso, Alison Creasey, Richard Culleton, Amar Bir Singh Sidhu, John Logan, Stephanie G. Valderramos, Iain McNae, Sandra Cheesman, Virgílio do Rosário, Richard Carter, David A. Fidock and Pedro Cravo. 7/7/2015. "Gene encoding a deubiquitinating enzyme is mutated in artesunate- and chloroquine-resistant rodent malaria parasites." Molecular Microbiology 65: 1: 27-40. 10.1111/j.1365-2958.2007.05753.x.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1111/j.1365-2958.2007.05753.x | issn = 0950-382X | volume = 65 | pages = 27-40 | last = Hunt | first = Paul | coauthors = Afonso, Ana, Creasey, Alison, Culleton, Richard, Sidhu, Amar Bir Singh, Logan, John, Valderramos, Stephanie G., McNae, Iain, Cheesman, Sandra, do Rosário, Virgílio, Carter, Richard, Fidock, David A., Cravo, Pedro | title = Gene encoding a deubiquitinating enzyme is mutated in artesunate- and chloroquine-resistant rodent malaria parasites | journal = Molecular Microbiology | date = 7/7/2015 | pmid = | pmc = }} </ref>