PMC

Schematic representation of IPP and DMAPP coupling reactions catalyzed by typical trans- and cis-PDPS family members. The newly identified enzyme and the reaction it catalyzed are circled (adapted from Thulasiram et al. ()). CPP, chrysanthemyl diphosphate; CPPS, chrysanthemyl diphosphate synthase; DMAPP, dimethylallyl diphosphate; IPP, isopentenyl diphosphate; GPP, geranyl diphosphate; GPPS, geranyl diphosphate synthase; LPP, lavandulyl diphosphate; LiLPPS, L. x intermedia lavandulyl diphosphate synthase; LinS, linalool synthase; NPP, neryl diphosphate; and NPPS, neryl diphosphate synthase.

Stereochemical scheme for the enzymatic conversion of geranyl diphosphate to (−)-limonene and (+)-bornyl diphosphate. Formation of these cyclic products requires preliminary isomerization of geranyl diphosphate to either (3R)- or (3S)-linalyl diphosphate. OPP denotes the diphosphate moiety. Note that the numbering for the linalyl diphosphate skeleton is the same as for geranyl diphosphate.

The first and rate-limiting step of human isoprenoid synthesis is the conversion of HMG-CoA to mevalonate by HMG-CoA reductase (HMGCR). This enzyme is the molecular target of the statin drugs. Several steps downstream, farnesyl diphosphate synthase (FDPS) catalyzes the production of farnesyl diphosphate (FPP) from dimethylallyl diphosphate DMAPP and two equivalents of isopentenyl diphosphate (IPP). This enzyme is the molecular target of the nitrogenous bisphosphonates. Farnesyl diphosphate is a key branch point of isoprenoid metabolism, giving rise to squalene in a reaction catalyzed by squalene synthase (SQS) and geranylgeranyl diphosphate (GGPP) in the GGDPS reaction.

Isoprenoid coupling reactions. (A) (top) Binding conformations of the unreactive DMAPP analogue dimethylallyl-S-thiolodiphosphate coordinated to three Mg²⁺ ions (gray) and isopentenyl diphosphate (IPP) in the active site of farnesyl diphosphate synthase from E. coli (beige) [] superimposed on the binding conformation of geranylgeranyl diphosphate in the active site of geranylgeranyl diphosphate synthase from S. alba (blue) []. (bottom) Stereochemistry of the isoprenoid chain elongation reaction inferred from the superposition above (for clarity, enzyme residues are not shown). The observed binding conformations of DMAPP and IPP suggest that the pyrophosphate product mediates the stereospecific elimination of the C2-H_R proton of the isopentenyl moiety []. Reprinted with permission from reference 13. Copyright 2006 American Chemical Society. (B) Isoprenoid coupling reactions catalyzed by terpenoid synthases. Farnesyl diphosphate synthase (FPPase) catalyzes chain elongation reactions leading to the formation of geranyl diphosphate (GPP) and longer isoprenoid diphosphates. Chrysanthemyl diphosphate synthase catalyzes a cyclopropanation reaction leading to chrysanthemyl diphosphate (CPP). Chimeric synthases constructed from FPPase and CPPase generate the branching product lavandulyl diphosphate (LPP) as well as cyclobutanation products maconellyl diphosphate (MPP) and planococcyl diphosphate (PPP). From Thulasiram HV, Erickson HK, Poulter, CD: Science 316:73–76 (6 April 2007). Reprinted with permission from AAAS. (C) Products generated by CPPase-FPPase chimeras when incubated with DMAPP and IPP as indicated: farnesyl diphosphate, blue; geranyl diphosphate, gold; lavadulyl diphosphate, green; chrysanthemyl diphosphate, red; maconellyl diphosphate, pink; planococcyl diphosphate, orange. Synthase abbreviations are as follows: FPPase-M is G69E/E210Q FPPase and CPPase-M is M98I/E177D/D243A CPPase, constructs prepared to facilitate the preparation of chimeric enzymes; these modified synthases exhibit kinetic parameters comparable to those of the wild-type synthases. Chimeric synthases are indicated by their splice junctions, e.g., the c69f synthase contains the first 69 residues of CPPase-M and the remaining residues of FPPase-M (see also ). From Thulasiram HV, Erickson HK, Poulter, CD: Science 316:73–76 (6 April 2007). Reprinted with permission from AAAS.