Farnesyltransferase

Farnesyltransferase is an enzyme that catalyzes the transfer of a farnesyl group from farnesyl pyrophosphate to a cysteine within the C-terminal CAAX motif of target proteins. This prenylation reaction promotes membrane association and proper function of many signaling proteins.

In humans, farnesyltransferase is a heterodimer composed of an alpha subunit (FNTA) and a beta subunit (FNTB). The enzyme recognizes CaaX motif–containing substrates and attaches a 15-carbon farnesyl group to the cysteine residue. After farnesylation, the protein commonly undergoes further processing: the AAX residues are cleaved by RCE1, and the free carboxyl group is methylated by isoprenylcysteine carboxyl methyltransferase (ICMT).

Substrate proteins include a variety of small GTPases and other signaling proteins that end in a CaaX motif, notably members of the RAS and RHO families. Farnesylation is essential for their proper localization to cellular membranes and their activity. Some proteins can also be processed by alternative prenylation pathways if FTase activity is inhibited, which has implications for therapeutic strategies targeting farnesylation.

Biological significance is broad, as farnesylation regulates numerous pathways involved in cell growth, differentiation, and cytoskeletal organization. Disruption of FTase function can alter signaling and trafficking of its substrates.

Clinical relevance centers on the development of farnesyltransferase inhibitors (FTIs) as anticancer agents. Inhibitors such as lonafarnib and tipifarnib have been evaluated in clinical trials. A major consideration is that KRAS and NRAS proteins can sometimes undergo alternative geranylgeranylation when FTase is inhibited, reducing efficacy, whereas HRAS is more susceptible to FTIs.