FPTase

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Introductions

FT, also known as FTase, or Farnesyltransferase, is a class of molecularly targeted antitumor drugs in trials that target Ras proteins in cellular signal transduction pathways, which require post-translational farnesylation modification to bind to cell membranes and perform their signaling functions. Farnesylation modification is the addition of farnesyl groups to protein molecules by the action of farnesyltransferases.

Structure and functions

Farnesyltransferase has two subunits: a 48kDa α subunit and a 46kDa β subunit. These two subunits are mainly composed of α-helices. α-subunit consists of a double layer of paired α-helices stacked in parallel, which partially wraps around β-subunit like a blanket. α-helices of β-subunit form a barrel. The active site is formed by the center of the β subunit, flanked by part of the α subunit. Farnesyltransferase coordinates zinc cations on the β-subunit at the edge of its active site. Farnesyltransferases have a hydrophobic binding pocket for farnesyl diphosphate (lipid donor molecule). All farnesyltransferase substrates contain a cysteine as their penultimate residue. This cysteine is involved in SN2-type attack, coordinated by zinc and transiently stabilized magnesium ions on the farnesyl diphosphate, replacing the diphosphate. The product remains bound to farnesyltransferase until replaced by a new substrate. the last three amino acids of the CaaX motif are removed later.

Inhibitors

Farnesyltransferase Inhibitors (FTIs) are a class of molecularly targeted antitumor drugs that target Ras proteins in cellular signal transduction pathways, which require post-translational farnesylation to bind to cell membranes and perform their signaling functions. Farnesylation modification is the addition of farnesyl groups to protein molecules by the action of farnesyltransferases.

Ras protein relations

Ras protein is a key molecule involved in cell signaling, regulating cell proliferation and differentiation, and after mutation of Ras gene, Ras protein will be continuously activated and signal transduction will be disrupted, resulting in continuous cell proliferation and tumor development. Farnesyltransferase inhibitors inhibit farnesyltransferase, so that Ras protein cannot be farnesylated and modified to bind to the cell membrane and function, and therefore have anti-tumor effects. Farnesyltransferase inhibitors are the focus of global antitumor drug development.