Abstract
The enzyme geranylgeranyl diphosphate synthase (GGDPS) catalyzes the synthesis of the 20-carbon isoprenoid geranylgeranyl diphosphate (GGPP). GGPP is the isoprenoid donor for protein geranylgeranylation reactions catalyzed by the enzymes geranylgeranyl transferase (GGTase) I and II. Inhibitors of GGDPS result in diminution of protein geranylgeranylation through depletion of cellular GGPP levels, and there has been interest in GGDPS inhibitors as potential anti-cancer agents. Here we discuss recent advances in the development of GGDPS inhibitors, including insights gained by structure-function relationships, and review the preclinical data that support the continued development of this novel class of drugs.
Highlights
The isoprenoid biosynthetic pathway (IBP) is one of the most heavily targeted biochemical pathways in medicine, with millions of individuals currently taking statins to lower cholesterol levels or nitrogenous bisphosphonates to address bone disease
Mevalonate is phosphorylated and decarboxylated to yield isopentenyl pyrophosphate (IPP), which can reversibly isomerize to dimethylallyl pyrophosphate (DMAPP)
Both DMAPP and IPP serve as substrates for farnesyl diphosphate synthase (FDPS) which generates first the 10-carbon geranyl pyrophosphate (GPP) and the 15-carbon farnesyl pyrophosphate (FPP)
Summary
Mevalonate is phosphorylated and decarboxylated to yield isopentenyl pyrophosphate (IPP), which can reversibly isomerize to dimethylallyl pyrophosphate (DMAPP) Both DMAPP and IPP serve as substrates for farnesyl diphosphate synthase (FDPS) which generates first the 10-carbon geranyl pyrophosphate (GPP) and the 15-carbon farnesyl pyrophosphate (FPP). Two key products of the IBP, FPP and GGPP (1 and 2, Figure 2), serve as substrates for farnesyl transferase (FTase) and geranylgeranyl transferases (GGTase I and II), respectively. These enzymes play a critical role in the posttranslational modification of the Ras small GTPase superfamily of proteins (e.g., Ras, Rab, and Rho families). We discuss IBP inhibitors with particular focus on GGDPS inhibitor development
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