1.5 Drugs targeting the Rab prenylation pathway
1.5.1 Prenylation pathway
Prenylation of Rab proteins is the essential lipid modification step that begins the membrane trafficking cycle. It is a crucial post-translational modification that allows the stable attachment of Rab proteins to the membrane by increasing hydrophobicity to be able to insert into the lipid bilayer (Maltese, Wilson and Erdman, 1996).
As depicted in Figure 7, the Rab cycle starts with a Rab protein that is GDP bound, in its inactive state. It binds to Rab escort protein (REP), which directs it to the RGGT, where the Rab protein is isoprenylated by addition of geranylgeranyl pyrophosphate (GPP) group or farnesyl pyrophosphate (FPP) onto the cysteine. The REP then transports …show more content…
However, they are also of interest in cancer as they have been shown to affect its many aspects (Pich et al., 2013). The mechanism that underpins the effectiveness of statins for hypercholesterolemia is the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, an enzyme that catalyses the formation of mevalonic acid from HMG-CoA. Mevalonic acid is a precursor of cholesterol, and therefore inhibiting HMG-CoA reductase is very effective for inhibiting cholesterol synthesis. Mevalonic acid is also of particular interest in relation to Rab GTPases because it is also the precursor to isoprenyl groups FPP and GPP, which are essential for prenylation (Hindler, 2006). Once activated with attachment of these groups, intracellular transport and downstream signal transduction can occur, leading to transcription of genes that are favourable to differentiation and proliferation (Gazzerro et al., 2011). This highlights the pleiotropic effects of statins. Figure 8 shows the importance of HMG-CoA reductase in the mevalonate pathway, influencing both cholesterol synthesis and prenylation of Rab proteins. The use of statins depletes cells of mevalonate as well as
1.5.1 Prenylation pathway
Prenylation of Rab proteins is the essential lipid modification step that begins the membrane trafficking cycle. It is a crucial post-translational modification that allows the stable attachment of Rab proteins to the membrane by increasing hydrophobicity to be able to insert into the lipid bilayer (Maltese, Wilson and Erdman, 1996).
As depicted in Figure 7, the Rab cycle starts with a Rab protein that is GDP bound, in its inactive state. It binds to Rab escort protein (REP), which directs it to the RGGT, where the Rab protein is isoprenylated by addition of geranylgeranyl pyrophosphate (GPP) group or farnesyl pyrophosphate (FPP) onto the cysteine. The REP then transports …show more content…
However, they are also of interest in cancer as they have been shown to affect its many aspects (Pich et al., 2013). The mechanism that underpins the effectiveness of statins for hypercholesterolemia is the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, an enzyme that catalyses the formation of mevalonic acid from HMG-CoA. Mevalonic acid is a precursor of cholesterol, and therefore inhibiting HMG-CoA reductase is very effective for inhibiting cholesterol synthesis. Mevalonic acid is also of particular interest in relation to Rab GTPases because it is also the precursor to isoprenyl groups FPP and GPP, which are essential for prenylation (Hindler, 2006). Once activated with attachment of these groups, intracellular transport and downstream signal transduction can occur, leading to transcription of genes that are favourable to differentiation and proliferation (Gazzerro et al., 2011). This highlights the pleiotropic effects of statins. Figure 8 shows the importance of HMG-CoA reductase in the mevalonate pathway, influencing both cholesterol synthesis and prenylation of Rab proteins. The use of statins depletes cells of mevalonate as well as