title: Synthesis and Enzymatic Studies of Isoprenoid Thiolo Bisubstrate Analogues.
abstract: Chain elongation prenyltransferases catalyze the addition of the hydrocarbon moiety of allylic isoprenoid diphosphates to the carbon-carbon double bond in isopentenyl diphosphate (IPP) in the primary building reactions in the isoprenoid biosynthetic pathway. Bis-O-diphosphate analogues 3-OPP/OPP, 4-OPP/OPP, and 5-OPP/OPP and bis-thiolodiphosphate bisubstrate analogues 3-SPP/SPP, 4-SPP/SPP, and 5-SPP/SPP were synthesized. The analogues 4-OPP/OPP, 5-OPP/OPP, 4-SPP/SPP, and 5-SPP/SPP were excellent competitive inhibitors of avian farnesyl diphosphate synthase with KI = 1.0 ± 0.12 μM, KI = 0.5 ± 0.2 μM, KI = 0.7 ± 0.3 μM, and KI = 2.9 ± 0.27 μM, respectively, whereas, analogues 3-OPP/OPP and 3-SPP/SPP displayed mixed type inhibition with KI = 1.4 μM and KI = 5.5 μM, respectively.
authors.affiliation: Department of Chemistry, University of Utah , Salt Lake City, Utah 84112, United States.
authors.forename: Gurusankar
authors.initials: G
authors.lastname: Ramamoorthy
authors.affiliation: Department of Chemistry, University of Utah , Salt Lake City, Utah 84112, United States.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Phan
authors.affiliation: Department of Chemistry, University of Utah , Salt Lake City, Utah 84112, United States.
authors.forename: C Dale
authors.initials: CD
authors.lastname: Poulter
mesh_terms: D002384:Catalysis; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors; D045782:Hemiterpenes; D007700:Kinetics; D009943:Organophosphorus Compounds; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013729:Terpenes / Q000138:chemical synthesis* / Q000494:pharmacology; D014961:X-Ray Diffraction
chemical_list: D004791:Enzyme Inhibitors; D045782:Hemiterpenes; D009943:Organophosphorus Compounds; D013729:Terpenes; C004809:isopentenyl pyrophosphate; D051228:Geranyltranstransferase