title: Effects of a squalene epoxidase inhibitor, terbinafine, on ether lipid biosyntheses in a thermoacidophilic archaeon, Thermoplasma acidophilum.
abstract: The archaeal plasma membrane consists mainly of diether lipids and tetraether lipids instead of the usual ester lipids found in other organisms. Although a molecule of tetraether lipid is thought to be synthesized from two molecules of diether lipids, there is no direct information about the biosynthetic pathway(s) or intermediates of tetraether lipid biosynthesis. In this study, we examined the effects of the fungal squalene epoxidase inhibitor terbinafine on the growth and ether lipid biosyntheses in the thermoacidophilic archaeon Thermoplasma acidophilum. Terbinafine was found to inhibit the growth of T. acidophilum in a concentration-dependent manner. When growing T. acidophilum cells were pulse-labeled with [2-(14)C]mevalonic acid in the presence of terbinafine, incorporation of radioactivity into the tetraether lipid fraction was strongly suppressed, while accumulation of radioactivity was noted at the position corresponding to diether lipids, depending on the concentration of terbinafine. After the cells were washed with fresh medium and incubated further without the radiolabeled substrate and the inhibitor, the accumulated radioactivity in the diether lipid fraction decreased quickly while that in the tetraether lipids increased simultaneously, without significant changes in the total radioactivity of ether lipids. These results strongly suggest that terbinafine inhibits the biosynthesis of tetraether lipids from a diether-type precursor lipid(s). The terbinafine treatment will be a tool for dissecting tetraether lipid biosynthesis in T. acidophilum.
authors.affiliation: Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Komaba, Tokyo 153-8902.
authors.forename: Takahide
authors.initials: T
authors.lastname: Kon
authors.forename: Naoki
authors.initials: N
authors.lastname: Nemoto
authors.forename: Tairo
authors.initials: T
authors.lastname: Oshima
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yamagishi
mesh_terms: D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008563:Membrane Lipids / Q000096:biosynthesis*; D009281:Naphthalenes / Q000494:pharmacology*; D010105:Oxygenases / Q000037:antagonists & inhibitors*; D010742:Phospholipid Ethers / Q000378:metabolism; D050603:Squalene Monooxygenase; D000077291:Terbinafine; D013822:Thermoplasma / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development*
chemical_list: D004791:Enzyme Inhibitors; D008563:Membrane Lipids; D009281:Naphthalenes; D010742:Phospholipid Ethers; D010105:Oxygenases; D050603:Squalene Monooxygenase; D000077291:Terbinafine