title: A small molecule inhibitor of fungal histone acetyltransferase Rtt109.
abstract: The histone acetyltransferase Rtt109 is the sole enzyme responsible for acetylation of histone H3 lysine 56 (H3K56) in fungal organisms. Loss of Rtt109 renders fungal cells extremely sensitive to genotoxic agents, and prevents pathogenesis in several clinically important species. Here, via a high throughput chemical screen of >300,000 compounds, we discovered a chemical inhibitor of Rtt109 that does not inhibit other acetyltransferase enzymes. This compound inhibits Rtt109 regardless of which histone chaperone cofactor protein (Asf1 or Vps75) is present, and appears to inhibit Rtt109 via a tight-binding, uncompetitive mechanism.
authors.affiliation: Program in Gene Function and Expression, Program in Molecular Medicine, University of Massachusetts Medical School, 364 Plantation St., LRB506, Worcester, MA 01605, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Lopes da Rosa
authors.forename: Vineeta
authors.initials: V
authors.lastname: Bajaj
authors.forename: James
authors.initials: J
authors.lastname: Spoonamore
authors.forename: Paul D
authors.initials: PD
authors.lastname: Kaufman
mesh_terms: D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D012440:Saccharomyces / Q000201:enzymology*; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D029701:Saccharomyces cerevisiae Proteins; D054852:Small Molecule Libraries; D051548:Histone Acetyltransferases; C517120:Rtt109 protein, S cerevisiae