Post-translational famesylation

The most understandable and well-discussed inhibitory mechanism is the blockade of protein prenylation. Rho GTPase, such as Rho, Rac, and Cdc42, play a key role in the migration signal transduction pathway, and post-translational modification with isoprenoids is necessary for their full activation to anchor to the cell membrane. Famesyl pyrophosphate and geranylgeranyl pyrophosphate are well-known isoprenoids prodncts, and HMG-CoA reductase is also involved in the isoprenoid synthetic pathway. 

The chaetomellic acids A and B (43 and 44), isolated from Chaetomella acutiseta found in seeds of peas, are potent and highly specific famesyl-mimic inhibitors of ras farnesyl-protein transferase. Farnesylation by this enzyme is the first and obligatory step for the post-translational modification of ras. The modified ras protein appears to be involved in tumorigenesis (approximately 25% of tumours) and there is evidence that inhibitors of the transferase have the potential to be antitumorigenic agents. These metabolites can be considered to be assembled by condensation of a palmitoyl and oleic acid chain C2 with pyruvate or oxaloacetate (Scheme 2) [38, 39]. Two syntheses have been reported for chaetomallic acid A [39, 40], one of which is patterned on the probable biogenesis [39]. 

Scheme 1. Post-translational modification by famesylation. The cysteine as part of the consensus sequence CAAX (C, cysteine A, aliphatic amino acid residue X, serine or methionine) near the C-terminus in the Ras protein is famesylated by famesylpyrophosphate (FPP) catalyzed by famesyl protein transferase (FPTase). The famesylated protein can then attach itself to the plasma membrane. If mutated Ras proteins are famesylated and attached to the cell membrane this will lead to transformation.

NO (nM concentxation) has been reported to activate Ras post-translational modification via S-nitrosylation of critical cysllS residue which stimulates guanine nucleotide exchange (Gallo et al. 1998). We have reported that NO (60 nM) treatment of MDA-MB-231 cells led to Ras-mediated increase in PI-3 kinase/Akt and Raf/MEK/ERK signal transduction pathways which was independent of cGMP. It was shown that pre-treatment of the cells by famesyl transferase inhibitors (FTIs), which block the post-translational modification of Ras protein, decreased the basal levels of pERKl/2, pAKT, and cyclin D1 to induce cytostasis (Pervin et al. 2007). 

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