Farnesyltransferase
Encyclopedia
Farnesyltransferase is one of the three enzyme
s in the prenyltransferase
group. Farnesyltransferase (FTase) adds a 15-carbon isoprenoid called a farnesyl group
to protein
s bearing a CaaX motif
: a four-amino acid
sequence at the carboxyl terminus of a protein. Farnesyltransferase's targets include members of the Ras superfamily of small GTP-binding proteins
critical to cell cycle
progression. For this reason, several FTase inhibitors
are undergoing testing as anti-cancer agents. FTase inhibitors have shown efficacy as anti-parasitic agents, as well. FTase is also believed to play an important role in development of progeria
and various forms of cancer
s.
proteins by adding an isoprenoid lipid
called a farnesyl group
to the -SH of the cysteine near the end of target proteins to form a thioether
linkage. This process, called farnesylation (which is a type of prenylation
), causes farnesylated proteins to become membrane
-associated due to the hydrophobic nature of the farnesyl group. Most farnesylated proteins are involved in cellular signaling
wherein membrane association is critical for function.
s: a 48kDa alpha subunit and a 46kDa beta subunit
. Both subunits are primarily composed of alpha helices
. The α subunit is made of a double layer of paired alpha helices stacked in parallel, which wraps partly around the beta subunit like a blanket. The alpha helices of the β subunit form a barrel. The active site is formed by the center of the β subunit flanked by part of the α subunit. Farnesyltransferase coordinates a zinc
cation on its β subunit at the lip of the active site. Farnesyltransferase has a hydrophobic binding pocket for farnesyl diphosphate, the lipid donor molecule. All farnesyltransferase substrates have a cysteine
as their fourth-to-last residue. This cysteine engages in an SN2 type attack, coordinated by the zinc and a transient stabilizing magnesium
ion on the farnesyl diphosphate, displacing the diphosphate. The product remains bound to farnesyltransferase until displaced by new substrates. The last three amino acids of the CaaX motif are removed later.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s in the prenyltransferase
Prenyltransferase
Prenyltransferases are a class of enzymes that transfer allylic prenyl groups to acceptor molecules. Prenyl transferases commonly refer to prenyl diphosphate synthases....
group. Farnesyltransferase (FTase) adds a 15-carbon isoprenoid called a farnesyl group
Farnesol
Farnesol is a natural organic compound which is an acyclic sesquiterpene alcohol found as a colorless liquid. It is insoluble in water, but miscible with oils...
to protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s bearing a CaaX motif
Sequence motif
In genetics, a sequence motif is a nucleotide or amino-acid sequence pattern that is widespread and has, or is conjectured to have, a biological significance...
: a four-amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
sequence at the carboxyl terminus of a protein. Farnesyltransferase's targets include members of the Ras superfamily of small GTP-binding proteins
GTPase
GTPases are a large family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate . The GTP binding and hydrolysis takes place in the highly conserved G domain common to all GTPases.-Functions:...
critical to cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
progression. For this reason, several FTase inhibitors
Farnesyltransferase inhibitor
The farnesyltransferase inhibitors are a class of experimental cancer drugs that target protein farnesyltransferase with the downstream effect of preventing the proper functioning of the Ras , which is commonly abnormally active in cancer....
are undergoing testing as anti-cancer agents. FTase inhibitors have shown efficacy as anti-parasitic agents, as well. FTase is also believed to play an important role in development of progeria
Progeria
Progeria is an extremely rare genetic condition wherein symptoms resembling aspects of aging are manifested at an early age. The word progeria comes from the Greek words "pro" , meaning "before", and "géras" , meaning "old age"...
and various forms of cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
s.
Overview
Farnesyltransferase posttranslationally-modifiesPosttranslational modification
Posttranslational modification is the chemical modification of a protein after its translation. It is one of the later steps in protein biosynthesis, and thus gene expression, for many proteins....
proteins by adding an isoprenoid lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
called a farnesyl group
Farnesol
Farnesol is a natural organic compound which is an acyclic sesquiterpene alcohol found as a colorless liquid. It is insoluble in water, but miscible with oils...
to the -SH of the cysteine near the end of target proteins to form a thioether
Thioether
A thioether is a functional group in organosulfur chemistry with the connectivity C-S-C as shown on right. Like many other sulfur-containing compounds, volatile thioethers have foul odors. A thioether is similar to an ether except that it contains a sulfur atom in place of the oxygen...
linkage. This process, called farnesylation (which is a type of prenylation
Prenylation
Prenylation, or isoprenylation, or lipidation is the addition of hydrophobic molecules to a protein. It is usually assumed that prenyl groups facilitate attachment to cell membranes, similar to lipid anchor like the GPI anchor, though direct evidence is missing...
), causes farnesylated proteins to become membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
-associated due to the hydrophobic nature of the farnesyl group. Most farnesylated proteins are involved in cellular signaling
Cell signaling
Cell signaling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue...
wherein membrane association is critical for function.
Farnesyltransferase structure and function
Farnesyltransferase has two subunitProtein subunit
In structural biology, a protein subunit or subunit protein is a single protein molecule that assembles with other protein molecules to form a protein complex: a multimeric or oligomeric protein. Many naturally occurring proteins and enzymes are multimeric...
s: a 48kDa alpha subunit and a 46kDa beta subunit
FNTB
Protein farnesyltransferase subunit beta is an enzyme that in humans is encoded by the FNTB gene.-Further reading:...
. Both subunits are primarily composed of alpha helices
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
. The α subunit is made of a double layer of paired alpha helices stacked in parallel, which wraps partly around the beta subunit like a blanket. The alpha helices of the β subunit form a barrel. The active site is formed by the center of the β subunit flanked by part of the α subunit. Farnesyltransferase coordinates a zinc
Zinc
Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...
cation on its β subunit at the lip of the active site. Farnesyltransferase has a hydrophobic binding pocket for farnesyl diphosphate, the lipid donor molecule. All farnesyltransferase substrates have a cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
as their fourth-to-last residue. This cysteine engages in an SN2 type attack, coordinated by the zinc and a transient stabilizing magnesium
Magnesium
Magnesium is a chemical element with the symbol Mg, atomic number 12, and common oxidation number +2. It is an alkaline earth metal and the eighth most abundant element in the Earth's crust and ninth in the known universe as a whole...
ion on the farnesyl diphosphate, displacing the diphosphate. The product remains bound to farnesyltransferase until displaced by new substrates. The last three amino acids of the CaaX motif are removed later.
Specificity
There are four binding pockets in FTase, which accommodate the last four amino acids on the carboxyl-terminus of a protein. Only those with a suitable CaaX motif can bind ('C' is Cysteine, 'a' is an aliphatic amino acid, and 'X' is variable). The carboxyl-terminal amino acid (X) discriminates FTase’s targets from those of the other prenyltransferases, allowing only six different amino acids to bind with any affinity. It has been shown that geranylgeranyltransferase can prenylate some of the substrates of Farnesyltransferase and vice versa.External links
See also
- PrenylationPrenylationPrenylation, or isoprenylation, or lipidation is the addition of hydrophobic molecules to a protein. It is usually assumed that prenyl groups facilitate attachment to cell membranes, similar to lipid anchor like the GPI anchor, though direct evidence is missing...
- Farnesyltransferase inhibitorFarnesyltransferase inhibitorThe farnesyltransferase inhibitors are a class of experimental cancer drugs that target protein farnesyltransferase with the downstream effect of preventing the proper functioning of the Ras , which is commonly abnormally active in cancer....
- Geranylgeranyltransferase type 1Geranylgeranyltransferase type 1Geranylgeranyltransferase type 1 or simply geranylgeranyltransferase is one of the three enzymes in the prenyltransferase group. In specific terms, Geranylgeranyltransferase adds a 20-carbon isoprenoid called a geranylgeranyl group to proteins bearing a CaaX motif: a four-amino acid sequence at...
- also referred to as Geranylgeranyltranferase 1 or just Geranylgeranyltranferase - Rab geranylgeranyltransferaseRab geranylgeranyltransferaseRab geranylgeranyltransferase also known as geranylgeranyltransferase II is one of the three prenyltransferases. It transfers two geranylgeranyl groups to the cystein at the C-terminus of Rab proteins....
- Geranylgeranyltransferase type 2