FTase

Farnesyltransferase (FTase) is an isoprenyltransferase that catalyzes the covalent attachment of a farnesyl group from farnesyl pyrophosphate (FPP) to a cysteine residue within a CaaX motif at the C-terminus of target proteins. This modification typically marks a subset of signaling and structural proteins for membrane association and proper function, including members of the Ras superfamily and various kinases and nuclear lamins.

In humans, FTase is a heterodimer composed of an alpha subunit (FNTA) and a beta subunit (FNTB). The enzyme is localized to cytosolic membranes, including the surface of the endoplasmic reticulum, and recognizes CaaX-containing substrates, where the cysteine is the farnesylation-site, two aliphatic residues follow, and X influences substrate selectivity.

After farnesylation, the CaaX motif undergoes further processing: the AAX residues are proteolytically removed by RCE1, exposing the farnesylated cysteine, which is then methylated by isoprenylcysteine carboxyl methyltransferase (ICMT). Some substrates may also undergo additional lipid modifications such as palmitoylation, aiding membrane targeting and function.

Biological and medical relevance centers on the role of FTase in necessary membrane localization of many signaling proteins. Inhibitors of FTase (FTIs) were developed as anticancer agents to block Ras-driven signaling; however, Ras proteins can sometimes be geranylgeranylated when FTase is inhibited, limiting efficacy. Examples of FTIs include tipifarnib and lonafarnib. Ongoing research explores combination therapies and alternative strategies to overcome resistance and broaden therapeutic applicability.