Farnesyl-diphosphate farnesyltransferase 1 (FDFT1) (FDFT1)

Farnesyl-diphosphate farnesyltransferase 1 (FDFT1), commonly known as squalene synthase, is a membrane-associated enzyme located in the endoplasmic reticulum that catalyzes the first committed step in the sterol biosynthesis branch of the mevalonate pathway [3, 10, 11]. It facilitates the head-to-head condensation of two molecules of farnesyl pyrophosphate (FPP) to form squalene, a precursor to cholesterol and other sterols [3, 18, 20]. In the rat liver, FDFT1 is a key regulatory enzyme whose activity is modulated by sterol levels via the SREBP2 transcription factor [16, 30]. Pharmacological inhibition of this enzyme is a therapeutic strategy for treating hypercholesterolemia and cardiovascular disease, as it lowers cholesterol production without depleting essential non-sterol isoprenoids like ubiquinone and dolichol [1, 22, 24]. Beyond its role in lipid metabolism, FDFT1 has been implicated in cancer progression, where it supports cell proliferation and invasion, and in the regulation of ferroptosis by modulating lipid peroxidation [10, 11, 17]. Several classes of inhibitors, including zaragozic acids and lapaquistat, have been developed to target this enzyme, though challenges such as hepatotoxicity have impacted their clinical progression [2, 26].

Other names

Squalene synthaseSqualene synthetaseSQSSSFPP:FPP farnesyltransferasePresqualene-di-diphosphate synthase

Inhibits the reductive dimerization of two farnesyl pyrophosphate (FPP) molecules into squalene, the first committed step in cholesterol biosynthesis [3, 9, 20]. This leads to reduced hepatic cholesterol synthesis and compensatory upregulation of LDL receptors, lowering plasma LDL-cholesterol levels [1, 22, 23].