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Prenylation or isoprenylation or lipidation is the addition of hydrophobic molecules to a protein. It is usually assumed that prenyl groups facilitate attachment to cell membranes, similar to lipid anchor like the GPI anchor, though direct evidence is missing. Prenyl groups have been shown to be important for protein-protein binding through specialized prenyl-binding domains.
Protein prenylation involves the transfer of either a farnesyl or a geranyl-geranyl moiety to C-terminal cysteine(s) of the target protein. There are three enzymes that carry out prenylation in the cell.
Farnesyltransferase and geranylgeranyltransferase I
Farnesyltransferase and Geranylgeranyltransferase I are very similar proteins. They consist of two subunits, the α-subunit which is common to both enzymes, and the β-subunit whose sequence identity is just 25%. These enzymes recognise the CaaX box at the C-terminus of the target protein. C is the cystein that is prenylated, a is any aliphatic amino acid, and the identity of X determines which enzyme acts on the protein. Work reported in the journal Genome Biology in 2005 reports refinement of computational detection methods for identification of protein prenylation motifs and establishment of an on-line analysis facility entitled "PrePS".
Rab geranylgeranyl transferase
Rab geranylgeranyltransferase, or Geranylgeranyl transferase II, transfers (usually) two geranylgeranyl groups to the cystein(s) at the C-terminus of Rab proteins. The C-terminus of Rab proteins varies in length and sequence and is referred to as hypervariable. Thus Rab proteins do not have a consensus sequence, such as the CAAX box, which the Rab geranylgeranyl transferase can recognise. Instead Rab proteins are bound by the Rab escort protein (REP) over a more conserved region of the Rab protein and then presented to the Rab geranylgeranyltransferase. Once Rab proteins are prenylated the lipid anchor(s) ensure that Rabs are no longer soluble. REP therefore plays an important role in binding and solubilising the geranylgeranyl groups and delivers the Rab protein to the relevant cell membrane.
Both isoprenoid chains geranylgeranyl pyrophosphate (GGpp) and farnesyl pyrophosphate are products of the HMG-CoA reductase pathway. The product of HMG CoA reductase is mevalonate. By combining precursors with 5 carbons, the pathway subsequently produces geranyl pyrophosphate (10 carbons), farnesyl pyrophosphate (15 carbons) and geranylgeranyl pyrophosphate (20 carbons). Two farnesyl pyrophosphate groups can also be combined to form squalene, the precursor for cholesterol This means that statins, which inhibit HMG CoA reductase, inhibit the production of both cholesterol and isoprenoids.
Note that in the HMG-CoA reductase/mevalonate pathway the precursors already contain a pyrophosphate group and isoprenoids are produced with a pyrophosphate group. There is no known mechanism for adding a pyrophosphate group to the alcohol form of the isoprenoids (farnesol and geranylgeraniol), and there is no known enzyme activity that can carry out the prenylation reaction with the isprenoid alcohol. Nevertheless farnesol has been shown to be able to rescue effects caused by statins, suggesting that alcohols can be involved in prenylation.
Proteins that undergo prenylation include Ras, which plays a central role in the development of cancer. This suggests that inhibitors of prenylation enzymes (e.g. farnesyltransferase) may influence tumor growth. Recent work has show that farnesyltransferase inhibitors (FTIs) also inhibit Rab geranylgeranyltransferase and that the success of such inhibitors in clinical trials may be as much due to effects on Rab prenylation as on Ras prenylation.
FTIs can also be used to inhibit farnesylation in parasites such as trypansoma brucii and malaria. Parasites seem to be more vulnerable to inhibition of Farnesyl transferase than humans are. In some cases this may be because they lack Geranylgeranyltransferase I. Thus it may be possible for the development of antiparastic drugs to 'piggyback' on the development of FTIs for cancer research. In addition FTIs have shown some promise in treating a mouse model of progeria.
- ^ Sebastian Maurer-Stroh and Frank Eisenhaber (2005). "Refinement and prediction of protein prenylation motifs". Genome Biology. 6:R55.
- Magee A, Seabra M (2003). "Are prenyl groups on proteins sticky fingers or greasy handles?". Biochem J. 376 (Pt 2): e3–4. PMID 14627432.
- Taylor J, Reid T, Terry K, Casey P, Beese L (2003). "Structure of mammalian protein geranylgeranyltransferase type-I". EMBO J. 22 (22): 5963–74. PMID 14609943.