Definition: Prenylation is a post-translational modification initiated by the addition of an isoprenoid lipid. Prenylation or isoprenylation or lipidation is the addition of hydrophobic molecules to a protein in order to facilitate its attachment to the cell membrane.
The result is similar to that of all lipid anchored proteins (e.g. the GPI anchor). 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.
All isoprenylation chains (geranylgeraniol, farnesol and dolichol) are products of the HMG-CoA reductase pathway.
RAS 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.
RABs prenylation
RABs are involved in vesicular transport regulation. Although intrinsically soluble, post-translational addition of isoprenoid moieties (isoprenylation) allows RABs to associate with the cytoplasmic face of membrane-bound intracellular organelles and vesicles.
Prenylation and cancer
RAS and many other oncogenic proteins undergo a complex series of post-translational modifications that are initiated by the addition of an isoprenoid lipid through a process known as prenylation.
Following prenylation, these proteins usually undergo endoproteolytic processing by the RCE1 protease and then carboxyl methylation by a unique methyltransferase known as isoprenylcysteine carboxyl methyltransferase (ICMT).
Although inhibitors that have been designed to target the prenylation step are now in advanced-stage clinical trials, their utility and efficacy seem to be limited.
Inhibition of these post-prenylation-processing steps, particularly that of ICMT-catalysed methylation, might provide a better approach to the control of cancer-cell proliferation.
References
Winter-Vann AM, Casey PJ. Post-prenylation-processing enzymes as new targets in oncogenesis. Nat Rev Cancer. 2005 May;5(5):405-12. PMID: 15864282
Magee T, Seabra MC. Fatty acylation and prenylation of proteins: what’s hot in fat. Curr Opin Cell Biol. 2005 Apr;17(2):190-6. PMID: 15780596