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Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/4902

Title: Investigation of the molecular mechanism of drug resistance with specific reference to the pfcrt gene in plasmodium falciparum
Authors: Chung, Yik-to
Subjects: Plasmodium falciparum.
Chloroquine.
Drug resistance.
Hong Kong Polytechnic University -- Dissertations
Malaria.
Issue Date: 2011
Publisher: The Hong Kong Polytechnic University
Abstract: Malaria is a serious disease threatening the tropical area. The parasites developed resistance to the first line drug chloroquine (CQ), causing more than 250 million cases and 1 million deaths every year. The Plasmodium falciparum chloroquine resistance transporter (PfCRT) was identified as the determinant that mediates CQ efflux. The protein consists of 10 putative transmembrane domains (TMD) and point mutations at different positions were reported in field isolates. In this thesis, the S163R mutation discovered by drug selection experiments in vivo was further studied by [{195}H]-CQ accumulation assay in vitro using heterologous expression system developed in our research group. PfCRT mutants were generated by site-directed mutagenesis and expressed in Pichia pastoris. Substituted cysteine accessibility analysis (SCAM) and cross-linking analysis was performed on TMD4 which harbors the residue 163. Our data confirms that positive charge on residue 163 is capable of restoring CQ sensitivity to PfCRT mutants. An aqueous-facing surface of TMD4 is revealed with S163, I166 and F170 lining a potential CQ binding crevice. Positive charge on the lumen-facing residues significantly reduces the drug transport. Residue 163 is also spatially close to TMD1 which harbors the well-known CQ resistance modulating residue K76T. The two TMDs are believed to function in chorus to form the drug translocation path.
Degree: Ph.D., Dept. of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, 2011
Description: xi, 113 leaves : ill. (some col.) ; 30 cm.
PolyU Library Call No.: [THS] LG51 .H577P ABCT 2011 Chung
Rights: All rights reserved.
Type: Thesis
URI: http://hdl.handle.net/10397/4902
Appears in Collections:ABCT Theses
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