Faiza A Siddiqui1, Mynthia Cabrera1, Meilian Wang2, Awtum Brashear1, Karen Kemirembe1, Zenglei Wang1, Jun Miao1, Thanat Chookajorn3, Zhaoqing Yang4, Yaming Cao2, Gang Dong5, Philip J Rosenthal6, Liwang Cui1. 1. Department of Entomology, Pennsylvania State University, University Park. 2. College of Basic Medical Sciences, China Medical University, Shenyang. 3. Genomics and Evolutionary Medicine Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. 4. Department of Pathogen Biology and Immunology, Kunming Medical University, China. 5. Max F. Perutz Laboratories, Medical University of Vienna, Austria. 6. Department of Medicine, University of California, San Francisco.
Abstract
Background: Falcipain-2a ([FP2a] PF3D7_1115700) is a Plasmodium falciparum cysteine protease and hemoglobinase. Functional FP2a is required for potent activity of artemisinin, and in vitro selection for artemisinin resistance selected for an FP2a nonsense mutation. Methods: To investigate associations between FP2a polymorphisms and artemisinin resistance and to characterize the diversity of the enzyme in parasites from the China-Myanmar border, we sequenced the full-length FP2a gene in 140 P falciparum isolates collected during 2004-2011. Results: The isolates were grouped into 8 different haplotype groups. Haplotype group I appeared in samples obtained after 2008, coinciding with implementation of artemisinin-based combination therapy in this region. In functional studies, compared with wild-type parasites, the FP2a haplotypes demonstrated increased ring survival, and all haplotype groups exhibited significantly reduced FP2a activity, with group I showing the slowest protease kinetics and reduced parasite fitness. Conclusions: These results suggest that altered hemoglobin digestion due to FP2a mutations may contribute to artemisinin resistance.
Background: Falcipain-2a ([FP2a] PF3D7_1115700) is a Plasmodium falciparum cysteine protease and hemoglobinase. Functional FP2a is required for potent activity of artemisinin, and in vitro selection for artemisinin resistance selected for an FP2a nonsense mutation. Methods: To investigate associations between FP2a polymorphisms and artemisinin resistance and to characterize the diversity of the enzyme in parasites from the China-Myanmar border, we sequenced the full-length FP2a gene in 140 P falciparum isolates collected during 2004-2011. Results: The isolates were grouped into 8 different haplotype groups. Haplotype group I appeared in samples obtained after 2008, coinciding with implementation of artemisinin-based combination therapy in this region. In functional studies, compared with wild-type parasites, the FP2a haplotypes demonstrated increased ring survival, and all haplotype groups exhibited significantly reduced FP2a activity, with group I showing the slowest protease kinetics and reduced parasite fitness. Conclusions: These results suggest that altered hemoglobin digestion due to FP2a mutations may contribute to artemisinin resistance.
Authors: Stephanie X Wang; Kailash C Pandey; John R Somoza; Puran S Sijwali; Tanja Kortemme; Linda S Brinen; Robert J Fletterick; Philip J Rosenthal; James H McKerrow Journal: Proc Natl Acad Sci U S A Date: 2006-07-24 Impact factor: 11.205
Authors: Jun Liu; Eva S Istvan; Ilya Y Gluzman; Julia Gross; Daniel E Goldberg Journal: Proc Natl Acad Sci U S A Date: 2006-05-26 Impact factor: 11.205
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