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Nucleic Acids Research Advance Access originally published online on October 11, 2007
Nucleic Acids Research 2007 35(20):6895-6903; doi:10.1093/nar/gkm817
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Nucleic Acids Research, 2007, Vol. 35, No. 20 6895-6903
© 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.

Molecular Biology

Sinefungin resistance of Saccharomyces cerevisiae arising from sam3 mutations that inactivate the AdoMet transporter or from increased expression of AdoMet synthase plus mRNA cap guanine-N7 methyltransferase

Sushuang Zheng1, Stewart Shuman1,* and Beate Schwer2

1Molecular Biology Program, Sloan-Kettering Institute and 2Microbiology and Immunology Department, Weill Cornell Medical College, New York, NY 10065, USA

* To whom correspondence should be addressed. Tel: 212 639 7145; Fax: 212 717 3623; Email: s-shuman{at}ski.mskcc.org

Received August 22, 2007. Revised September 18, 2007. Accepted September 18, 2007.

The S-adenosylmethionine (AdoMet) analog sinefungin is a natural product antibiotic that inhibits nucleic acid methyltransferases and arrests the growth of unicellular eukarya and eukaryal viruses. The basis for the particular sensitivity of fungi and protozoa to sinefungin is not known. Here we report the isolation and characterization of spontaneous sinefungin-resistant mutants of the budding yeast Saccharomyces cerevisiae. In all cases, sinefungin resistance was attributable to a loss-of-function mutation in Sam3, the yeast high-affinity AdoMet transporter. Overexpression of wild-type Sam3 increased the sensitivity of yeast to growth inhibition by sinefungin. Thus, Sam3 is a tunable determinant of sinefungin potency. The shared ability of protozoan parasites to import AdoMet might determine sinefungin's anti-infective spectrum. Insights to the intracellular action of sinefungin stem from the finding that increased gene dosage of yeast AdoMet synthase plus cap guanine-N7 methyltransferase afforded greater resistance to sinefungin than either enzyme alone. These results are consistent with the proposal that mRNA cap methylation is a principal target of sinefungin's bioactivity.


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S. Zheng and S. Shuman
Structure-function analysis of vaccinia virus mRNA cap (guanine-N7) methyltransferase
RNA, April 1, 2008; 14(4): 696 - 705.
[Abstract] [Full Text] [PDF]


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