title: Isopentenyl diphosphate isomerase. Mechanism-based inhibition by diene analogues of isopentenyl diphosphate and dimethylallyl diphosphate.
abstract: Isopentenyl diphosphate isomerase (IDI) catalyzes the interconversion of isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). This is an essential step in the mevalonate entry into the isoprenoid biosynthetic pathway. The isomerization catalyzed by type I IDI involves protonation of the carbon-carbon double bond in IPP or DMAPP to form a tertiary carbocation, followed by deprotonation. Diene analogues for DMAPP (E-2-OPP and Z-2-OPP) and IPP (4-OPP) were synthesized and found to be potent active-site-directed irreversible inhibitors of the enzyme. X-ray analysis of the E.I complex between Escherichia coli IDI and 4-OPP reveals the presence of two isomers that differ in the stereochemistry of the newly formed C3-C4 double bond in the hydrocarbon chain of the inhibitor. In both adducts C5 of the inhibitor is joined to the sulfur of C67. In these structures the methyl group formed upon protonation of the diene moiety in 4-OPP is located near E116, implicating that residue in the protonation step.
authors.affiliation: Department of Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wu
authors.forename: Johan
authors.initials: J
authors.lastname: Wouters
authors.forename: C Dale
authors.initials: CD
authors.lastname: Poulter
mesh_terms: D019748:Carbon-Carbon Double Bond Isomerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004926:Escherichia coli / Q000201:enzymology; D045782:Hemiterpenes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D015394:Molecular Structure; D009943:Organophosphorus Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D012568:Schizosaccharomyces / Q000201:enzymology
chemical_list: D045782:Hemiterpenes; D009943:Organophosphorus Compounds; C004809:isopentenyl pyrophosphate; C043060:3,3-dimethylallyl pyrophosphate; D019748:Carbon-Carbon Double Bond Isomerases; C021453:isopentenyldiphosphate delta-isomerase