enzymology Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

, a geranyltranstransferase () is an

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

that

catalyzes Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...

the

chemical reaction A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the pos ...

:geranyl diphosphate + isopentenyl diphosphate

\rightleftharpoons

diphosphate + trans,trans-farnesyl diphosphate Thus, the two substrates of this enzyme are

geranyl diphosphate Geranyl pyrophosphate (GPP), also known as geranyl diphosphate (GDP), is the pyrophosphate ester of the terpenoid geraniol. Its salts are colorless. It is a precursor to many natural products. Occurrence GPP is an intermediate in the isoprenoid ...

(a 10 carbon precursor) and

isopentenyl diphosphate Isopentenyl pyrophosphate (IPP, isopentenyl diphosphate, or IDP) is an isoprenoid precursor. IPP is an intermediate in the classical, HMG-CoA reductase pathway (commonly called the mevalonate pathway) and in the ''non-mevalonate'' MEP pathway of ...

(a 5 carbon precursor) whereas its two

products Product may refer to: Business * Product (business), an item that serves as a solution to a specific consumer problem. * Product (project management), a deliverable or set of deliverables that contribute to a business solution Mathematics * Produ ...

are

diphosphate In chemistry, pyrophosphates are phosphorus oxyanions that contain two phosphorus atoms in a P–O–P linkage. A number of pyrophosphate salts exist, such as disodium pyrophosphate (Na2H2P2O7) and tetrasodium pyrophosphate (Na4P2O7), among othe ...

and trans,trans-farnesyl diphosphate (a 15 carbon product). This enzyme belongs to the family of

transferase A transferase is any one of a class of enzymes that catalyse the transfer of specific functional groups (e.g. a methyl or glycosyl group) from one molecule (called the donor) to another (called the acceptor). They are involved in hundreds of di ...

s, specifically those transferring aryl or alkyl groups other than methyl groups.

Nomenclature

The

systematic name A systematic name is a name given in a systematic way to one unique group, organism, object or chemical substance, out of a specific population or collection. Systematic names are usually part of a nomenclature. A semisystematic name or semitrivial ...

of this enzyme class is geranyl-diphosphate:isopentenyl-diphosphate geranyltranstransferase. Other names in common use include: * farnesyl-diphosphate synthase * geranyl transferase I * prenyltransferase * farnesyl pyrophosphate synthetase * farnesylpyrophosphate synthetase Common abbreviations include: FPS, FDS, FPPS, and FDPS.

Structure

The structure and mechanism of farnesyl pyrophosphate synthase (FPPS), a type of geranyltranstransferase, is well characterized. FPPS is a ~30 kDa Mg²⁺ dependent homodimeric enzyme that synthesizes (E, E)-farnesyl pyrophosphate in a successive manner from two equivalents of

isopentenyl pyrophosphate Isopentenyl pyrophosphate (IPP, isopentenyl diphosphate, or IDP) is an isoprenoid precursor. IPP is an intermediate in the classical, HMG-CoA reductase pathway (commonly called the mevalonate pathway) and in the ''non-mevalonate'' MEP pathway of ...

(IPP) and

dimethylallyl pyrophosphate Dimethylallyl pyrophosphate (DMAPP; or alternatively, dimethylallyl diphosphate (DMADP); also isoprenyl pyrophosphate) is an isoprenoid precursor. It is a product of both the mevalonate pathway and the MEP pathway of isoprenoid precursor biosynt ...

(DMAPP).

FPPS adopts a 3-layered α-helical fold characteristic of many prenyltransferases with 11 helices and flexible loops in between. The centrally located helices (α4 and α8) contain conserved aspartate motifs (DDXXD) that participate in substrate binding and catalysis. Motif aspartate residues, water oxygens, and pyrophosphate coordinate three Mg²⁺in an octahedral manner. The trinuclear Mg²⁺ complex is critical for binding DMAPP and stabilizing the pyrophosphate leaving group while the growing hydrocarbon tail wedges into a deep hydrophobic pocket. Site-directed mutagenesis studies have shown that the ultimate length of the isoprenoid product is determined by bulky residues (often phenyalanine) at the hydrophobic pocket's base.

Mechanism

From crystal structures and kinetic assays, it is believed that FPPS catalyzes the condensation reaction in three concerted steps: (1) Ionization, (2) Condensation, and (3) Elimination. In the first step, three Mg²⁺stabilize the anionic leaving group, pyrophosphate, on

(DMAPP). The loss of pyrophosphate forms dimethylallyl cation. In the second step, the reactive C3-C5 double bond in isopentyl pyrophosphate (IPP) performs a nucleophilic attack on the previously formed dimethylallyl cation. The final step involves pyrophosphate held in the trinuclear Mg²⁺ center acting as a catalytic base in an elimination reaction to form geranyl pyrophosphate. A second consecutive round of geranyl pyrophosphate ionization, condensation with IPP, and elimination forms farnesyl pyrophosphate.

Function

Geranyltranstransferases are an evolutionarily conserved class of enzymes in Archaea, Bacteria, and Eukarya that participate in a broad range of biosynthetic pathways including those of

cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...

porphyrin Porphyrins ( ) are a group of heterocyclic macrocycle organic compounds, composed of four modified pyrrole subunits interconnected at their α carbon atoms via methine bridges (=CH−). The parent of porphyrin is porphine, a rare chemical com ...

carotenoids Carotenoids (), also called tetraterpenoids, are yellow, orange, and red organic pigments that are produced by plants and algae, as well as several bacteria, and fungi. Carotenoids give the characteristic color to pumpkins, carrots, parsnips, ...

ubiquinone Coenzyme Q, also known as ubiquinone and marketed as CoQ10, is a coenzyme family that is ubiquitous in animals and most bacteria (hence the name ubiquinone). In humans, the most common form is coenzyme Q10 or ubiquinone-10. It is a 1,4-benzoq ...

, and isoprenoids. Various studies have located FPPS in chloroplasts, mitochondria, cytosol, and peroxisomes. FPPS Biosynthetic Pathways Version 2

In cholesterol synthesis, the product, farnesyl pyrophosphate, is consumed in a reductive tail-to-tail condensation with another farnesyl pyrophosphate to form a 30-carbon compound called

squalene Squalene is an organic compound. It is a triterpenoid with the formula C30H50. It is a colourless oil, although impure samples appear yellow. It was originally obtained from shark liver oil (hence its name, as ''Squalus'' is a genus of sharks). A ...

squalene synthase 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 react ...

. Through several more biosynthetic steps, squalene is transformed into

lanosterol Lanosterol is a tetracyclic triterpenoid and is the compound from which all animal and fungal steroids are derived. By contrast plant steroids are produced via cycloartenol. Role in biosynthesis of other steroids Elaboration of lanosterol under e ...

, a direct precursor for cholesterol. Notably,

sterols Sterol is an organic compound with formula , whose molecule is derived from that of gonane by replacement of a hydrogen atom in position 3 by a hydroxyl group. It is therefore an alcohol of gonane. More generally, any compounds that contain the gon ...

control FPPS expression through two cis regulatory factors (an inverted CAAT box and SRE-3) in the proximal FPPS promoter. In plants, porphyrin and carotenoids constitute accessory pigments that help capture light in the

photosystems Photosystems are functional and structural units of protein complexes involved in photosynthesis. Together they carry out the primary photochemistry of photosynthesis: the absorption of light and the transfer of energy and electrons. Photosystems ...

Ubiquinone Coenzyme Q, also known as ubiquinone and marketed as CoQ10, is a coenzyme family that is ubiquitous in animals and most bacteria (hence the name ubiquinone). In humans, the most common form is coenzyme Q10 or ubiquinone-10. It is a 1,4-benzoq ...

is a key electron carrier in the

electron transport chain An electron transport chain (ETC) is a series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...

cellular respiration Cellular respiration is the process by which biological fuels are oxidised in the presence of an inorganic electron acceptor such as oxygen to produce large amounts of energy, to drive the bulk production of ATP. Cellular respiration may be des ...

. Isoprenoids are a large group of compounds that serve as biosynthetic precursors for lipids and

hormones A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and beh ...

. Farnesyl and geranyl pyrophosphate also serve as precursors for prenylated proteins. Prenylation is a common type of covalent

post-translational modification Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribosome ...

at C-terminal CaaX motifs that allows proteins to localize to membranes or bind to one another. A notable example of the former is the farnesylation of small G-proteins including

Ras Ras or RAS may refer to: Arts and media * RAS Records Real Authentic Sound, a reggae record label * Rundfunk Anstalt Südtirol, a south Tyrolese public broadcasting service * Rás 1, an Icelandic radio station * Rás 2, an Icelandic radio stati ...

, CDC42, Rho, and Rac. The attachment of a hydrophobic aliphatic chain as those present in farnesyl or geranylgeranyl groups allows small G-proteins to tether from membranes and carry out effector functions.

Drug targeting

FPPS is the target of bisphosphonate drugs such as Fosamax (

alendronate Alendronic acid, sold under the brand name Fosamax among others, is a bisphosphonate medication used to treat osteoporosis and Paget's disease of bone. It is taken by mouth. Use is often recommended together with vitamin D, calcium supplementatio ...

) and Actonel (

risedronate Risedronic acid, often used as its sodium salt risedronate sodium, is a bisphosphonate. It slows down the cells which break down bone. It's used to treat or prevent osteoporosis, and treat Paget's disease of bone. It is taken by mouth. It was pa ...

). Bisphosphonate drugs are commonly prescribed for bone diseases including Paget’s disease, osteolytic metastases, and post-menopausal

osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone ...

. Bisphosphonate drugs help maintain bone tissue in osteoporotic patients and reduce blood calcium levels in hypercalcemic patients by inhibiting FPPS in bone-reabsorbing

osteoclasts An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and remodeling of bones of the vertebral skeleton. The osteoclast disassembles and digests the composite of hydrated prote ...

. An FPPS-IPP-risendronate ternary complex demonstrated that risendronate binds to the trinuclear Mg²⁺ complex and interacts with the hydrophobic pocket in a manner similar to DMAPP.

References

{{Portal bar, Biology, border=no EC 2.5.1 Enzymes of known structure