Farnesyl-diphosphate farnesyltransferase
Encyclopedia
Farnesyl-diphosphate farnesyltransferase (FDFT1) (or squalene synthase (SQS)) is an enzyme that converts two units of farnesyl pyrophosphate
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.
s 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 syntase, 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.)
, is under investigation as a method of lowering cholesterol levels in the prevention of cardiovascular disease. It has also been suggested that variants in this enzyme may be part of a genetic association with hypercholesterolemia
.
(Lapaquistat is no longer being investigated for clinical use.)
Other squalene synthase inhibitors include Zaragozic acid
, and RPR 107393.
Squalene synthase homolog inhibition in Staphylococcus aureus
is currently being investigated as a virulence factor-based antibacterial therapy.
Farnesyl pyrophosphate
Farnesyl pyrophosphate is an intermediate in the HMG-CoA reductase pathway used by organisms in the biosynthesis of terpenes, terpenoids, and sterols...
into squalene
Squalene
Squalene is a natural organic compound originally obtained for commercial purposes primarily from shark liver oil, though plant sources are used as well, including amaranth seed, rice bran, wheat germ, and olives. All plants and animals produce squalene, including humans...
.
Sterol
Sterols, also known as steroid alcohols, are a subgroup of the steroids and an important class of organic molecules. They occur naturally in plants, animals, and fungi, with the most familiar type of animal sterol being cholesterol...
(i.e., cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
, etc.) synthesis, since the squalene
Squalene
Squalene is a natural organic compound originally obtained for commercial purposes primarily from shark liver oil, though plant sources are used as well, including amaranth seed, rice bran, wheat germ, and olives. All plants and animals produce squalene, including humans...
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 eukaryoteEukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...
s or advanced organisms, although at least one prokaryote
Prokaryote
The prokaryotes are a group of organisms that lack a cell nucleus , or any other membrane-bound organelles. The organisms that have a cell nucleus are called eukaryotes. Most prokaryotes are unicellular, but a few such as myxobacteria have multicellular stages in their life cycles...
has been shown to possess a functionally similar enzyme.
In terms of structure and mechanics, squalene synthase most closely resembles phytoene syntase, which serves a similar role in many plants in the elaboration of phytoene
Phytoene
Phytoene is a 40-carbon intermediate in the biosynthesis of carotenoids. The synthesis of phytoene is the committed step in the synthesis of carotenoids in plants. Phytoene is produced from two molecules of geranylgeranyl pyrophosphate by the action of the enzyme phytoene synthase...
, a precursor of many carotenoid
Carotenoid
Carotenoids are tetraterpenoid organic pigments that are naturally occurring in the chloroplasts and chromoplasts of plants and some other photosynthetic organisms like algae, some bacteria, and some types of fungus. Carotenoids can be synthesized fats and other basic organic metabolic building...
compounds. (Carotenoids are the colorful pigments present in most vegetables.)
Clinical significance
Inhibition of squalene synthase, e.g., by lapaquistatLapaquistat
Lapaquistat is a cholesterol-lowering drug. Unlike statins, which inhibit HMG-CoA reductase, lapaquistat metabolites inhibit squalene synthase, which is further downstream in the synthesis of cholesterol...
, is under investigation as a method of lowering cholesterol levels in the prevention of cardiovascular disease. It has also been suggested that variants in this enzyme may be part of a genetic association with hypercholesterolemia
Hypercholesterolemia
Hypercholesterolemia is the presence of high levels of cholesterol in the blood. It is not a disease but a metabolic derangement that can be caused by many diseases, notably cardiovascular disease...
.
(Lapaquistat is no longer being investigated for clinical use.)
Other squalene synthase inhibitors include Zaragozic acid
Zaragozic acid
Zaragozic acids are a family of natural products produced by fungi. The first characterized zaragozic acids, A, B, and C were isolated from an unidentified sterile fungal culture, S. intermedia, and L. elatius, respectively. just outside of the European city Zaragoza, Spain on the Jalón river...
, and RPR 107393.
Squalene synthase homolog inhibition in Staphylococcus aureus
Staphylococcus aureus
Staphylococcus aureus is a facultative anaerobic Gram-positive coccal bacterium. It is frequently found as part of the normal skin flora on the skin and nasal passages. It is estimated that 20% of the human population are long-term carriers of S. aureus. S. aureus is the most common species of...
is currently being investigated as a virulence factor-based antibacterial therapy.