Human Squalene synthase in complex with inhibitor. PDB 
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / EGO|
|farnesyl-diphosphate farnesyltransferase 1|
|Locus||Chr. 8 p23.1-p22|
Squalene synthase (SQS) or farnesyl-diphosphate:farnesyl-diphosphate farnesyl transferase is an enzyme localized to the membrane of the endoplasmic reticulum. SQS participates in the isoprenoid biosynthetic pathway, catalyzing a two-step reaction in which two identical molecules of farnesyl pyrophosphate (FPP) are converted into squalene, with the consumption of NADPH. Catalysis by SQS is the first committed step in sterol synthesis, since the squalene produced is converted exclusively into various sterols, such as cholesterol, via a complex, multi-step pathway. SQS belongs to squalene/phytoene synthase family of proteins.
Squalene synthase has been characterized in animals, plants, and yeast. In terms of structure and mechanics, squalene synthase closely resembles phytoene synthase (PHS), another prenyltransferase. PHS serves a similar role to SQS in plants and bacteria, catalyzing the synthesis of phytoene, a precursor of carotenoid compounds.
Squalene synthase (SQS) is localized exclusively to the membrane of the endoplasmic reticulum (ER). SQS is anchored to the membrane by a short C-terminal membrane-spanning domain. The N-terminal catalytic domain of the enzyme protrudes into the cytosol, where the soluble substrates are bound. Mammalian forms of SQS are approximately 47kDa and consist of ~416 amino acids. The crystal structure of human SQS was determined in 2000, and revealed that the protein was composed entirely of α-helices. The enzyme is folded into a single domain, characterized by a large central channel. The active sites of both of the two half-reactions catalyzed by SQS are located within this channel. One end of the channel is open to the cytosol, whereas the other end forms a hydrophobic pocket. SQS contains two conserved aspartate-rich sequences, which are believed to participate directly in the catalytic mechanism. These aspartate-rich motifs are one of several conserved structural features in class I isoprenoid biosynthetic enzymes, although these enzymes do not share sequence homology.
Squalene synthase (SQS) catalyzes the reductive dimerization of farnesyl pyrophosphate (FPP), in which two identical molecules of FPP are converted into one molecule of squalene, via a two-step mechanism. FPP is a soluble allylic compound containing 15 carbon atoms (C15), whereas squalene is an insoluble, C30 isoprenoid. This reaction is a head-to-head terpene synthesis, because the two FPP molecules are both joined at the C1 position and form a 1'-1 linkage. 1'-4 linkages are much more common in isoprene biosynthesis than 1'-1  The reaction mechanism of SQS requires a divalent cation, often Mg2+, to facilitate binding of the pyrophosphate groups on FPP.
In the first half-reaction, two identical molecules of farnesyl pyrophosphate (FPP) are bound to squalene synthase (SQS) in a sequential manner. The FPP molecules bind to distinct regions of the enzyme, and with different binding affinities  The pyrophosphate group is cleaved from one molecule of FPP, designated as the donor FPP. The resulting allylic carbocation reacts with the C2,3 double bond of the acceptor FPP in a 1',2,3 prenyl transferase reaction. The product of this condensation is presqualene pyrophosphate (PSPP), a stable cyclopropylcarbinyl pyrophosphate intermediate. The condensation of the two FPP molecules releases a pyrophosphate and a proton (H+). The PSPP created remains associated with SQS for the second reaction.
PSPP rearrangement and reduction
In the second half-reaction of SQS, presqualene pyrophosphate (PSPP) moves to a second reaction site within SQS. Keeping PSPP in the central channel of SQS is thought to protect the reactive intermediate from reacting with water. The cyclopropyl group is opened, and PSPP is rearranged and reduced using NADPH to produce a linear final product, squalene. SQS releases squalene into the membrane of the endoplasmic reticulum. This reaction also produces pyrophosphate, H+, and NADP+.
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".
Squalene synthase (SQS) is an enzyme participating in the isoprenoid biosynthetic pathway. SQS synthase catalyzes the branching point between sterol and nonsterol biosynthesis, and commits farnesyl pyrophosphate (FPP) exclusively to production of sterols. An important sterol produced by this pathway is cholesterol, which is used in cell membranes and for the synthesis of hormones. SQS competes with several other enzymes for use of FPP, since it is a precursor for a variety of terpenoids. Decreases in SQS activity limit flux of FPP to the sterol pathway, and increase the production of nonsterol products. Important nonsterol products include ubiquinone, dolichols, heme A, and farnesylated proteins 
Squalene synthase is a target for the regulation of cholesterol levels. Increased expression of SQS has been shown to elevate cholesterol levels in mice. Therefore, inhibitors of SQS are of great interest in the treatment of hypercholesterolemia and prevention of coronary heart disease (CHD). It has also been suggested that variants in this enzyme may be part of a genetic association with hypercholesterolemia.
Squalene synthase inhibitors
Squalene synthase inhibitors have been shown to decrease cholesterol synthesis, as well as to decrease plasma triglyceride levels. SQS inhibitors may provide an alternative to HMG-CoA reductase inhibitors (statins), which have problematic side effects for some patients. Squalene synthase inhibitors that have been investigated for use in the prevention of cardiovascular disease include TAK-475, zaragozic acid, and RPR 107393. Despite reaching phase 2 clinical trials, TAK-475 was discontinued and is no longer being investigated for clinical use.
Model organisms have been used in the study of FDFT1 function. A conditional knockout mouse line called Fdft1tm1a(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping
|All data available at.|
|Haematology 6 Weeks||Normal|
|Homozygous viability at P14||Abnormal|
|Recessive lethal study||Abnormal|
|Glucose tolerance test||Normal|
|Auditory brainstem response||Normal|
|Haematology 16 Weeks||Normal|
|Peripheral blood leukocytes 16 Weeks||Normal|
|Cytotoxic T Cell Function||Normal|
|Mesenteric Lymph Node Immunophenotyping||Normal|
|Bone Marrow Immunophenotyping||Normal|
|Epidermal Immune Composition||Normal|
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- "Infection and Immunity Immunophenotyping (3i) Consortium".
- Farnesyl-Diphosphate Farnesyltransferase at the US National Library of Medicine Medical Subject Headings (MeSH)