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Squalene synthase (SQS) or farnesyl-diphosphate:farnesyl-diphosphate farnesyl transferase is an enzyme in the isoprenoid biosynthetic pathway. Squalene synthase catalyzes a two-step reaction in which two identical molecules of farnesyl diphosphate (FPP) are converted into squalene.



It has been described as the first dedicated enzyme of sterol (i.e., cholesterol, etc.) synthesis, since the squalene formed by it is exclusively routed into various sterols via a complex, multi-step pathway.

Diversity
Squalene synthase is considered to be an enzyme of eukaryotes or advanced organisms, although at least one prokaryote has been shown to possess a functionally similar enzyme.

In terms of structure and mechanics, squalene synthase most closely resembles phytoene synthase, which serves a similar role in many plants in the elaboration of phytoene, a precursor of many carotenoid compounds. (Carotenoids are the colorful pigments present in most vegetables.)

Structure
Squalene synthase (SQS) is a 47-kDa enzyme localized to the membrane of the endoplasmic reticulum. SQS is anchored to the membrane by a C-terminal membrane-spanning domain. The N-terminal catalytic domain of the enzyme protrudes into the cytosol. The crystal structure of human SQS was determined in 2000, and revealed that the protein was comprised of thirteen alpha-helices. The enzyme is folded into a single domain, characterized by a large central channel. The active sites of the two half-reactions catalyzed by SQS are located within the channel. One end of the channel is open to the cytosol, whereas the other end forms an enclosed hydrophobic pocket. Squalene synthase contains two conserved aspartate-rich sequences, which are believed to participate in the catalytic mechanism.

Mechanism
Squalene synthase (SQS) converts two molecules of farnesyl pyrophosphate (FPP) into squalene via a two-step mechanism. FPP is a soluble C15 allylic compound, 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. The reaction mechanism requires a divalent cation, often Mg2+, to facilitate pyrophosphate release.

FPP 1'-1 condensation
In the first half-reaction, two identical molecules of farnesyl pyrophosphate (FPP) are bound to squalene synthase (SQS) in a sequential manner. The pyrophosphate group is cleaved from one molecule of FPP, designated as the donor prenyl. The resulting allylic carbocation reacts with the C2,3 double bond of the acceptor FPP in a 1',2,3 prenyl transferase reaction, forming the stable intermediate presqualene pyrophosphate (PSPP). The 1'-1 condensation of the two FPP molecules releases a pyrophosphate and a proton (H+). The PSPP created remains associated with squalene synthase for the second reaction.

PSPP rearrangement and reduction
In the second half-reaction of SQS, the intermediate 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. PSPP is rearranged and reduced using NADPH to produce the final product, squalene. SQS released squalene into the membrane of the endoplasmic reticulum. This reaction also produces pyrophosphate, H+, and NADP+.

Biological Function
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 other enzymes for use of FPP, since it is a precursor for a variety of terpenoids. Decreases in SQS activity limit the flux of FPP to the sterol pathway, and increase the production of nonsterol products.

Development of squalene synthase knockout mice has demonstrated that loss of squalene synthase is lethal, and that the enzyme is essential for development of the central nervous system.

Disease Relevance
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).

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.

Other squalene synthase inhibitors that have been investigated for use in the prevention of cardiovascular diseases include lapaquistat, Zaragozic acid, and RPR 107393. Lapaquistat is no longer being investigated for clinical use.

It has also been suggested that variants in this enzyme may be part of a genetic association with hypercholesterolemia.

Squalene synthase homolog inhibition in Staphylococcus aureus is currently being investigated as a virulence factor-based antibacterial therapy.