Document Detail


Inhibition of Plasmodium falciparum choline kinase by hexadecyltrimethylammonium bromide: a possible antimalarial mechanism.
MedLine Citation:
PMID:  17145794     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Vinay Choubey; Pallab Maity; Mithu Guha; Sanjay Kumar; Kumkum Srivastava; Sunil Kumar Puri; Uday Bandyopadhyay
Related Documents :
2250564 - Effect of spermine on association of protein kinase c with phospholipid vesicles.
3100654 - L-serine potentiates the mitogenic effects of growth factors on cultured human keratino...
6324764 - Human hepatic 3-hydroxy-3-methylglutaryl coenzyme a reductase: evidence for the regulat...
3689494 - Allosteric activation of rat liver microsomal [hydroxymethylglutaryl-coa reductase (nad...
3345204 - Inhibition of protein kinase c by defensins, antibiotic peptides from human neutrophils.
16085714 - Caenorhabditis elegans cnk-1 promotes raf activation but is not essential for ras/raf s...
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    
Affiliation:
Division of Drug Target Discovery and Development, Central Drug Research Institute, Chatter Manzil Palace, Lucknow, Uttar Pradesh, India.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Animals
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
Chemical
Reg. No./Substance:
0/Antiprotozoal Agents; 0/Cetrimonium Compounds; 0/Protozoan Proteins; 0/Recombinant Proteins; 107-73-3/Phosphorylcholine; 58066-85-6/miltefosine; EC 2.7.1.32/Choline Kinase; Z7FF1XKL7A/cetrimonium
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Emergence and dissemination of Enterobacteriaceae isolates producing CTX-M-1-like enzymes in Spain a...
Next Document:  IS21-558 insertion sequences are involved in the mobility of the multiresistance gene cfr.