Figures & data
Figure 1. Location of geranylgeranyl diphosphate synthase (GGDPS) within the human isoprenoid biosynthetic pathway. 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.
Figure 2. Key feedback mechanisms that control isoprenoid biosynthetic gene expression at the transcriptional level. (A) Sterol regulatory element-binding proteins (SREBPs) regulate transcription of HMG-CoA reductase and other enzymes of isoprenoid biosynthesis in response to cellular sterol levels, which indirectly affects synthesis of geranylgeranyl diphosphate. (B) Egr-1 regulates transcription of isoprenoid biosynthesis in response to activation of the ERK pathway, which directly regulates GGPDS expression at the transcriptional level.
Figure 3. Structural evolution of GGDPS inhibitors. Small nitrogen-containing bisphosphonates are inhibitors of farnesyl diphosphate synthase (FDPS). Lipophilic bisphosphonates can inhibit the enzymes of farnesyl diphosphate metabolism, including GGDPS and squalene synthase. Branched bisalkyl bisphosphonates retain specificity for GGDPS. Non-bisphosphonate inhibitors of GGDPS have also been identified.
Figure 4. Geranylgeranylation of small GTPases including Rac, Rho, Rab, and Cdc42 promotes localization to the membrane domain, affecting proliferation. Geranylgeranyl transferase I catalyzes the addition of geranylgeranyl diphosphate to the C-terminus of Rho, Rac, or Cdc42 while geranylgeranyl transferase II catalyzes the addition of one or two geranylgeranyl moieties to Rab GTPases. Rab GTPases are primarily involved in vesicle trafficking, though disruption of Rab geranylgeranylation can affect cell viability and proliferation. Rho, Rac, and Cdc42 are involved in proliferation in addition to adhesion and migration regulation.
