Document Detail

Inhibition of Plasmodium falciparum choline kinase by hexadecyltrimethylammonium bromide: a possible antimalarial mechanism.
MedLine Citation:
PMID:  17145794     Owner:  NLM     Status:  MEDLINE    
Choline kinase is the first enzyme in the Kennedy pathway (CDP-choline pathway) for the biosynthesis of the most essential phospholipid, phosphatidylcholine, in Plasmodium falciparum. In addition, choline kinase also plays a pivotal role in trapping essential polar head group choline inside the malaria parasite. Recently, Plasmodium falciparum choline kinase (PfCK) has been cloned, overexpressed, and purified. However, the function of this enzyme in parasite growth and survival has not been evaluated owing to the lack of a suitable inhibitor. Purified recombinant PfCK enabled us to identify an inhibitor of PfCK, hexadecyltrimethylammonium bromide (HDTAB), which has a very close structural resemblance to hexadecylphosphocholine (miltefosin), the well-known antiproliferative and antileishmanial drug. HDTAB inhibited PfCK in a dose-dependent manner and offered very potent antimalarial activity in vitro against Plasmodium falciparum. Moreover, HDTAB exhibited profound antimalarial activity in vivo against the rodent malaria parasite Plasmodium yoelii (N-67 strain). Interestingly, parasites at the trophozoite and schizont stages were found to be particularly sensitive to HDTAB. The stage-specific antimalarial effect of HDTAB correlated well with the expression pattern of PfCK in P. falciparum, which was observed by reverse transcription-PCR and immunofluorescence microscopy. Furthermore, the antimalarial activity of HDTAB paralleled the decrease in phosphatidylcholine content, which was found to correlate with the decreased phosphocholine generation. These results suggest that inhibition of choline kinase by HDTAB leads to decreased phosphocholine, which in turn causes a decrease in phosphatidylcholine biosynthesis, resulting in death of the parasite.
Vinay Choubey; Pallab Maity; Mithu Guha; Sanjay Kumar; Kumkum Srivastava; Sunil Kumar Puri; Uday Bandyopadhyay
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-12-04
Journal Detail:
Title:  Antimicrobial agents and chemotherapy     Volume:  51     ISSN:  0066-4804     ISO Abbreviation:  Antimicrob. Agents Chemother.     Publication Date:  2007 Feb 
Date Detail:
Created Date:  2007-01-22     Completed Date:  2007-06-04     Revised Date:  2013-06-06    
Medline Journal Info:
Nlm Unique ID:  0315061     Medline TA:  Antimicrob Agents Chemother     Country:  United States    
Other Details:
Languages:  eng     Pagination:  696-706     Citation Subset:  IM    
Division of Drug Target Discovery and Development, Central Drug Research Institute, Chatter Manzil Palace, Lucknow, Uttar Pradesh, India.
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MeSH Terms
Antiprotozoal Agents / pharmacology
Cetrimonium Compounds / chemistry,  pharmacology*
Choline Kinase / antagonists & inhibitors*,  genetics
Dose-Response Relationship, Drug
Malaria, Falciparum / drug therapy*,  parasitology
Phosphorylcholine / analogs & derivatives,  chemistry,  metabolism
Plasmodium falciparum / drug effects*,  enzymology
Protozoan Proteins / antagonists & inhibitors,  genetics
Recombinant Proteins / antagonists & inhibitors,  genetics
Reg. No./Substance:
0/Antiprotozoal Agents; 0/Cetrimonium Compounds; 0/Protozoan Proteins; 0/Recombinant Proteins; 107-73-3/Phosphorylcholine; 58066-85-6/miltefosine; EC Kinase; Z7FF1XKL7A/cetrimonium

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