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 Journal Article

   

Authors:	Zheng, S.; Shuman, S.; Schwer, B.
Article Title:	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
Abstract:	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. © 2007 The Author(s).
Keywords:	controlled study; protein expression; carrier protein; unclassified drug; gene mutation; mutation; nonhuman; gene overexpression; drug potency; enzyme activity; wild type; methyltransferase; antibiotic resistance; methyltransferases; drug mechanism; messenger rna; saccharomyces cerevisiae; adenosine; eukaryota; saccharomyces cerevisiae proteins; saccharomycetales; gene dosage; protozoa; fungi; fungus growth; growth inhibition; antifungal activity; s-adenosylmethionine; rna capping; rna methylation; fungus mutant; fungus isolation; guanine n7 methyltransferase; methionine adenosyltransferase; methionine adenosyltransferase 3; s adenosylmethionine transporter; sinefungin; fungal metabolism; amino acid transport systems; antibiotics, antifungal; drug resistance, fungal
Journal Title:	Nucleic Acids Research
Volume:	35
Issue:	20
ISSN:	0305-1048
Publisher:	Oxford University Press
Date Published:	2007-11-01
Start Page:	6895
End Page:	6903
Language:	English
DOI:	10.1093/nar/gkm817
PUBMED:	17932050
PROVIDER:	scopus
PMCID:	PMC2175321
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-36749061282&partnerID=40&md5=3780f8df53e1487ba5273ff66f31cf62
Notes:	--- - "Cited By (since 1996): 3" - "Export Date: 17 November 2011" - "CODEN: NARHA" - "Source: Scopus"

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