Gene encoding a deubiquitinating enzyme is mutated in artesunate‐ and chloroquine‐resistant rodent malaria parasites<sup>§</sup>

Hunt, Paul; Afonso, Ana; Creasey, Alison M.; Culleton, Richard; Sidhu, Amar Bir Singh; Logan, John G.; Valderramos, Stephanie G.; McNae, I.W.; Cheesman, Sandra; Rosário, Virgı́lio do; Carter, Richard; Fidock, David A.; Cravo, Pedro Vitor Lemos

doi:10.1111/j.1365-2958.2007.05753.x

Cited by 162 publications

(189 citation statements)

References 50 publications

Supporting

Mentioning

183

Contrasting

Unclassified

Order By: Relevance

“…The AS-ART clone was then crossed with AJ and the progeny subjected to LGS. Ongoing studies associate resistance with a locus on chromosome 2 [27]. (b) Simulated results of a LGS analysis.…”

Section: Discussionmentioning

confidence: 99%

“…Culleton et al validated this technique as a method for identifying loci of resistance by crossing pyrimethamine resistant and sensitive lines of P. chabaudi and using LGS to identify a resistance locus including dhfr [26]. Applying LGS to the artemisinin pressured P. chabaudi line, Hunt et al [27] identified a locus on chromosome 2 harboring a de-ubiquitinating enzyme that is currently a candidate.…”

Section: Identifying Emerging Resistance Locimentioning

confidence: 99%

See 1 more Smart Citation

Advances in understanding the genetic basis of antimalarial drug resistance

Ekland

Fidock

2007

Current Opinion in Microbiology

View full text Add to dashboard Cite

SummaryThe acquisition of drug resistance by Plasmodium falciparum has severely curtailed global efforts to control malaria. Our ability to define resistance has been greatly enhanced by recent advances in Plasmodium genetics and genomics. Sequencing and microarray studies have identified thousands of polymorphisms in the P. falciparum genome, and linkage disequilibrium analyses have exploited these to rapidly identify known and novel loci that influence parasite susceptibility to antimalarials such as chloroquine, quinine, and sulfadoxine-pyrimethamine. Genetic approaches have also been designed to predict determinants of in vivo resistance to new antimalarials such as the artemisinins. Transfection methodologies have defined the role of determinants including pfcrt, pfmdr1 and dhfr. This knowledge can be leveraged to develop more efficient methods of surveillance and treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Identifying Emerging Resistance Locimentioning

confidence: 99%

Advances in understanding the genetic basis of antimalarial drug resistance

Ekland

Fidock

2007

Current Opinion in Microbiology

View full text Add to dashboard Cite

show abstract

“…RAD5 is thought to polyubiquitinate proliferating cell nuclear antigen (a DNA clamp that assists in processivity of DNA polymerase delta) in conjunction with two ubiquitin-conjugating enzymes, prompting activation of error-free DNA repair via template switching (21). Also involved in this pathway are several deubiquitinating enzymes, including ubp1, which has been linked to artemisinin resistance in the rodent malaria Plasmodium chabaudi (22). This pathway may be activated by DNA damage caused by oxidative stress from toxic by-products of hemoglobin degradation following artemisinin treatment (23).…”

Section: Discussionmentioning

confidence: 99%

Genetic loci associated with delayed clearance of Plasmodium falciparum following artemisinin treatment in Southeast Asia

Takala-Harrison

Clark

Jacob

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

253

243

View full text Add to dashboard Cite

The recent emergence of artemisinin-resistant Plasmodium falciparum malaria in western Cambodia could threaten prospects for malaria elimination. Identification of the genetic basis of resistance would provide tools for molecular surveillance, aiding efforts to contain resistance. Clinical trials of artesunate efficacy were conducted in Bangladesh, in northwestern Thailand near the Myanmar border, and at two sites in western Cambodia. Parasites collected from trial participants were genotyped at 8,079 single nucleotide polymorphisms (SNPs) using a P. falciparum-specific SNP array. Parasite genotypes were examined for signatures of recent positive selection and association with parasite clearance phenotypes to identify regions of the genome associated with artemisinin resistance. Four SNPs on chromosomes 10 (one), 13 (two), and 14 (one) were significantly associated with delayed parasite clearance. The two SNPs on chromosome 13 are in a region of the genome that appears to be under strong recent positive selection in Cambodia. The SNPs on chromosomes 10 and 13 lie in or near genes involved in postreplication repair, a DNA damage-tolerance pathway. Replication and validation studies are needed to refine the location of loci responsible for artemisinin resistance and to understand the mechanism behind it; however, two SNPs on chromosomes 10 and 13 may be useful markers of delayed parasite clearance in surveillance for artemisinin resistance in Southeast Asia.drug resistance | genome-wide association | molecular markers

show abstract

“…Components of the Ub cascade have been successfully targeted in the treatment of cancer (4); although these components have orthologs in parasitic pathogens, they show only moderate identity to their host counterparts, which makes them potential drug targets for apicomplexan-caused diseases such as malaria and toxoplasmosis. Indeed, the susceptibility of Plasmodium to the antimalarial drugs chloroquine and artesunate has been linked to mutations mapping to a DUB locus in the mouse malaria model Plasmodium chabaudi (5). Furthermore, Ubconjugating enzymes are up-regulated in the death response of Plasmodium parasites as induced by treatment with antifolates (6).…”

mentioning

confidence: 99%

Characterization and Structural Studies of the Plasmodium falciparum Ubiquitin and Nedd8 Hydrolase UCHL3

Artavanis‐Tsakonas

Weihofen

Antos

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Like their human hosts, Plasmodium falciparum parasites rely on the ubiquitin-proteasome system for survival. We previously identified PfUCHL3, a deubiquitinating enzyme, and here we characterize its activity and changes in active site architecture upon binding to ubiquitin. We find strong evidence that PfUCHL3 is essential to parasite survival. The crystal structures of both PfUCHL3 alone and in complex with the ubiquitinbased suicide substrate UbVME suggest a rather rigid active site crossover loop that likely plays a role in restricting the size of ubiquitin adduct substrates. Molecular dynamics simulations of the structures and a model of the PfUCHL3-PfNedd8 complex allowed the identification of shared key interactions of ubiquitin and PfNedd8 with PfUCHL3, explaining the dual specificity of this enzyme. Distinct differences observed in ubiquitin binding between PfUCHL3 and its human counterpart make it likely that the parasitic DUB can be selectively targeted while leaving the human enzyme unaffected.

show abstract

Gene encoding a deubiquitinating enzyme is mutated in artesunate‐ and chloroquine‐resistant rodent malaria parasites^§

Cited by 162 publications

References 50 publications

Advances in understanding the genetic basis of antimalarial drug resistance

Advances in understanding the genetic basis of antimalarial drug resistance

Genetic loci associated with delayed clearance of Plasmodium falciparum following artemisinin treatment in Southeast Asia

Characterization and Structural Studies of the Plasmodium falciparum Ubiquitin and Nedd8 Hydrolase UCHL3

Contact Info

Product

Resources

About

Gene encoding a deubiquitinating enzyme is mutated in artesunate‐ and chloroquine‐resistant rodent malaria parasites§

Cited by 162 publications

References 50 publications

Advances in understanding the genetic basis of antimalarial drug resistance

Advances in understanding the genetic basis of antimalarial drug resistance

Genetic loci associated with delayed clearance of Plasmodium falciparum following artemisinin treatment in Southeast Asia

Characterization and Structural Studies of the Plasmodium falciparum Ubiquitin and Nedd8 Hydrolase UCHL3

Contact Info

Product

Resources

About

Gene encoding a deubiquitinating enzyme is mutated in artesunate‐ and chloroquine‐resistant rodent malaria parasites^§