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J. Biol. Chem., Vol. 279, Issue 53, 55042-55050, December 31, 2004

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Dissection of Antibacterial and Toxic Activity of Melittin

A LEUCINE ZIPPER MOTIF PLAYS A CRUCIAL ROLE IN DETERMINING ITS HEMOLYTIC ACTIVITY BUT NOT ANTIBACTERIAL ACTIVITY^*

Neeta Asthana, Sharada Prasad Yadav¶, and Jimut Kanti Ghosh||

From the Molecular and Structural Biology Division, Central Drug Research Institute, Lucknow 226 001, India

Melittin, a naturally occurring antimicrobial peptide, exhibits strong lytic activity against both eukaryotic and prokaryotic cells. Despite a tremendous amount of work done, very little is known about the amino acid sequence, which regulates its toxic activity. With the goal of understanding the basis of toxic activity and poor cell selectivity in melittin, a leucine zipper motif has been identified. To evaluate the possible structural and functional roles of this motif, melittin and its two analogs, after substituting the heptadic leucine by alanine, were synthesized and characterized. Functional studies indicated that alanine substitution in the leucine zipper motif resulted in a drastic reduction of the hemolytic activity of melittin. However, interestingly, both the designed analogs exhibited antibacterial activity comparable to melittin. Mutations caused a significant decrease in the membrane permeability of melittin in zwitterionic but not in negatively charged lipid vesicles. Although both the analogs exhibited similar secondary structures in the presence of negatively charged lipid vesicles as melittin, they failed to adopt a significant helical structure in the presence of zwitterionic lipid vesicles. Results suggest that the substitution of heptadic leucine by alanine impaired the assembly of melittin in an aqueous environment and its localization only in zwitterionic but not in negatively charged membrane. Altogether, the results suggest the identification of a structural element in melittin, which probably plays a prominent role in regulating its toxicity but not antibacterial activity. The results indicate that cell selectivity in some antimicrobial peptides can probably be introduced by modulating their assembly in an aqueous environment.

Received for publication, August 4, 2004 , and in revised form, September 29, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

J. K. G. dedicates this article to his mentor Prof. Yechiel Shai of Dept. of Biological Chemistry, Weiznmann Institute of Science, Israel, with deep respect. This is Central Drug Research Institute Communication 6622.

Both authors contributed equally to this work.

Recipient of a Junior Research Fellowship from the Council of Scientific and Industrial Research, India.

^¶ Recipient of a Senior Research Fellowship from the Council of Scientific and Industrial Research, India.

^|| To whom correspondence should be addressed. Tel.: 091-522-2212412 (ext. 4282); Fax: 091-522-223405/223938; E-mail: jighosh{at}yahoo.com.

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