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Nucleic Acids Research Advance Access originally published online on December 15, 2007
Nucleic Acids Research 2008 36(2):697-704; doi:10.1093/nar/gkm1088
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Nucleic Acids Research, 2008, Vol. 36, No. 2 697-704
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

RNA

Studies on the mechanism of inhibition of bacterial ribonuclease P by aminoglycoside derivatives

Steven A. Kawamoto, Christopher G. Sudhahar, Cynthia L. Hatfield, Jing Sun, Edward J. Behrman and Venkat Gopalan*

Department of Biochemistry, The Ohio State University, Columbus, OH 43210, USA

*To whom correspondence should be addressed. Tel: +1 614 292 1332; Fax: +1 614 292 6773; Email: gopalan.5{at}osu.edu

Received October 10, 2007. Revised November 19, 2007. Accepted November 20, 2007.

Ribonuclease P (RNase P) is a Mg2+-dependent endoribonuclease responsible for the 5'-maturation of transfer RNAs. It is a ribonucleoprotein complex containing an essential RNA and a varying number of protein subunits depending on the source: at least one, four and nine in Bacteria, Archaea and Eukarya, respectively. Since bacterial RNase P is required for viability and differs in structure/subunit composition from its eukaryal counterpart, it is a potential antibacterial target. To elucidate the basis for our previous finding that the hexa-arginine derivative of neomycin B is 500-fold more potent than neomycin B in inhibiting bacterial RNase P, we synthesized hexa-guanidinium and -lysyl conjugates of neomycin B and compared their inhibitory potential. Our studies indicate that side-chain length, flexibility and composition cumulatively account for the inhibitory potency of the aminoglycoside-arginine conjugates (AACs). We also demonstrate that AACs interfere with RNase P function by displacing Mg2+ ions. Moreover, our finding that an AAC can discriminate between a bacterial and archaeal (an experimental surrogate for eukaryal) RNase P holoenzyme lends promise to the design of aminoglycoside conjugates as selective inhibitors of bacterial RNase P, especially once the structural differences in RNase P from the three domains of life have been established.

The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.


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