title: Growth defects resulting from inhibiting ERG20 and RAM2 in Candida glabrata.
abstract: Farnesyl pyrophosphate (FPP) is utilized for many cellular processes, including the production of dolichols, ubiquinone (CoQ), sterols, farnesylated heme A and prenylated proteins. This lipid synthesized by FPP synthetase (ERG20) becomes attached to target proteins by the prenyltransferases, CDC43/RAM2 and RAM1/RAM2 complexes after the formation of the C15 and C20 units, respectively. Defects in protein prenylation as a result of inhibiting these enzyme complexes lead to pleiotropic effects in all eukaryotes. In this study, using Candida glabrata conditional mutants, the importance of the ERG20 and RAM2 genes for growth using both in vivo and in vitro assays was assessed by placing the RAM2 and ERG20 genes under the control of a regulatable promoter. Repression of RAM2 gene expression revealed growth defects under both conditions. However, repression of ERG20 gene expression did not impair fungal growth in a mouse host, but did result in growth defects on laboratory media. Thus, FPP synthase is not required for survival in an infected mouse, but the RAM2-encoded prenyltransferase was critical for growth under both conditions. This study strongly suggests that inhibitors of prenyltransferase may be promising antifungals.
authors.affiliation: Faculty of Pharmaceutical Science, Suzuka University of Medical Science, Suzuka, Mie, Japan. nakayamh@suzuka-u.ac.jp
authors.forename: Hironobu
authors.initials: H
authors.lastname: Nakayama
authors.forename: Keigo
authors.initials: K
authors.lastname: Ueno
authors.forename: Jun
authors.initials: J
authors.lastname: Uno
authors.forename: Minoru
authors.initials: M
authors.lastname: Nagi
authors.forename: Koichi
authors.initials: K
authors.lastname: Tanabe
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Aoyama
authors.forename: Hiroji
authors.initials: H
authors.lastname: Chibana
authors.forename: Martin
authors.initials: M
authors.lastname: Bard
mesh_terms: D000818:Animals; D041221:Candida glabrata / Q000235:genetics* / Q000254:growth & development*; D002177:Candidiasis / Q000382:microbiology; D004122:Dimethylallyltranstransferase / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D005656:Fungal Proteins / Q000378:metabolism*; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors*; D051379:Mice; D011499:Protein Processing, Post-Translational; D014774:Virulence
chemical_list: D005656:Fungal Proteins; D004122:Dimethylallyltranstransferase; D051228:Geranyltranstransferase