Studies on the mechanism of inhibition of bacterial ribonuclease P by aminoglycoside derivatives
| Autor: | Venkat Gopalan, Edward J. Behrman, Christopher G. Sudhahar, Cynthia L. Hatfield, Steven A. Kawamoto, Jing Sun |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2007 |
| Předmět: |
RNase P
Protein subunit Endoribonuclease Molecular Sequence Data Biology Arginine 01 natural sciences RNase PH Guanidines Ribonuclease P 03 medical and health sciences Structure-Activity Relationship Species Specificity Genetics Structure–activity relationship Magnesium 030304 developmental biology 0303 health sciences Base Sequence 010405 organic chemistry Escherichia coli Proteins Lysine Aminoglycoside RNA Molecular biology Archaea 0104 chemical sciences Anti-Bacterial Agents RNase MRP Aminoglycosides Biochemistry Framycetin |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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