Inhibition of Plasmodium falciparum Choline Kinase by Hexadecyltrimethylammonium Bromide: a Possible Antimalarial Mechanism
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
View Archive Info| Field | Value | |
| Title |
Inhibition of Plasmodium falciparum Choline Kinase by
Hexadecyltrimethylammonium Bromide: a Possible
Antimalarial Mechanism
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| Creator |
Choubey, Vinay
Maity, Pallab Guha, Mithu Kumar, Sanjay Srivastava, Kumkum Puri, Sunil Kumar Bandyopadhyay, Uday |
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| Subject |
Infectious Diseases and Immunology
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| Description |
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.
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| Date |
2007
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| Type |
Article
PeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/314/1/ANTIMICROBIAL_AGENTS_AND_CHEMOTHERAPY%2C_51(_2)%2C_696%2D706%2C2007_[116].pdf
Choubey, Vinay and Maity, Pallab and Guha, Mithu and Kumar, Sanjay and Srivastava, Kumkum and Puri, Sunil Kumar and Bandyopadhyay, Uday (2007) Inhibition of Plasmodium falciparum Choline Kinase by Hexadecyltrimethylammonium Bromide: a Possible Antimalarial Mechanism. Antimicrobial Agents and Chemotherapy, 51 (2). pp. 696-706. |
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| Relation |
http://dx.doi.org/10.1128/AAC.00919-06
http://www.eprints.iicb.res.in/314/ |
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