Farnesyltransferase () is one of the three
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
s in the
prenyltransferase group. Farnesyltransferase (FTase) adds a 15-carbon
isoprenoid called a
farnesyl group to
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...
s bearing a CaaX
motif
Motif may refer to:
General concepts
* Motif (chess composition), an element of a move in the consideration of its purpose
* Motif (folkloristics), a recurring element that creates recognizable patterns in folklore and folk-art traditions
* Moti ...
: a four-
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
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
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA ( DNA replication) and some of its organelles, and sub ...
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
Progeria is a specific type of progeroid syndrome, also known as Hutchinson–Gilford syndrome. A single gene mutation is responsible for progeria. The gene, known as lamin A (LMNA), makes a protein necessary for holding the Nucleus of the cell ...
and various forms of
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...
s.
Farnesyltransferase
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 chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the positions of electrons in the forming and break ...
:farnesyl diphosphate + protein-cysteine
S-farnesyl protein +
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 o ...
Thus, the two
substrates of this enzyme are
farnesyl diphosphate and
protein-cysteine, whereas its two
products are
S-farnesyl protein and
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 o ...
.
Overview
Farnesyltransferase
posttranslationally-modifies proteins by adding an isoprenoid
lipid
Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids incl ...
called a
farnesyl group to the -SH of the cysteine near the end of target proteins to form a
thioether
In organic chemistry, an organic sulfide (British English sulphide) or thioether is an organosulfur functional group with the connectivity as shown on right. Like many other sulfur-containing compounds, volatile sulfides have foul odors. A sul ...
linkage. This process, called farnesylation (which is a type of
prenylation
Prenylation (also known as isoprenylation or lipidation) is the addition of hydrophobic molecules to a protein or a biomolecule. It is usually assumed that prenyl groups (3-methylbut-2-en-1-yl) facilitate attachment to cell membranes, similar t ...
), causes farnesylated proteins to become
membrane
A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. ...
-associated due to the
hydrophobic
In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water.
Hydrophobic molecules tend to be nonpolar and, ...
nature of the farnesyl group. Most farnesylated proteins are involved in
cellular signaling wherein membrane association is critical for function.
Farnesyltransferase structure and function
Farnesyltransferase has two
subunit
Subunit may refer to:
*Subunit HIV vaccine, a class of HIV vaccine
*Protein subunit, a protein molecule that assembles with other protein molecules
*Monomer, a molecule that may bind chemically to other molecules to form a polymer
*Sub-subunit, a ...
s: a 48kDa alpha subunit and a 46kDa
beta subunit
Beta (, ; uppercase , lowercase , or cursive ; grc, βῆτα, bē̂ta or ell, βήτα, víta) is the second letter of the Greek alphabet. In the system of Greek numerals, it has a value of 2. In Modern Greek, it represents the voiced lab ...
. Both subunits are primarily composed of
alpha helices
The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues earli ...
. 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 is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodic t ...
cation
An ion () is an atom or molecule with a net electrical charge.
The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...
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 (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile.
When present as a deprotonated catalytic residue, s ...
as their fourth-to-last residue. This cysteine engages in an
SN2 type attack, coordinated by the zinc and a transient stabilizing
magnesium
Magnesium is a chemical element with the symbol Mg and atomic number 12. It is a shiny gray metal having a low density, low melting point and high chemical reactivity. Like the other alkaline earth metals (group 2 of the periodic ...
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
In organic chemistry, hydrocarbons ( compounds composed solely of carbon and hydrogen) are divided into two classes: aromatic compounds and aliphatic compounds (; G. ''aleiphar'', fat, oil). Aliphatic compounds can be saturated, like hexane, ...
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.
Structural studies
As of late 2007, 15
structures have been solved for this class of enzymes, with
PDB accession codes , , , , , , , , , , , , , , and .
See also
*
Farnesyltransferase inhibitor
*
Geranylgeranyltransferase type 1 – also referred to as geranylgeranyltranferase 1 or just geranylgeranyltranferase
*
Prenylation
Prenylation (also known as isoprenylation or lipidation) is the addition of hydrophobic molecules to a protein or a biomolecule. It is usually assumed that prenyl groups (3-methylbut-2-en-1-yl) facilitate attachment to cell membranes, similar t ...
*
Rab geranylgeranyltransferase – Geranylgeranyltransferase type 2
References
*
*
*
*
*
*
*
*
* Sinnott, M. (Ed.), Comprehensive Biological Catalysis. A Mechanistic Reference, vol. 1, Academic Press, San Diego, CA, 1998, p. 31-118.
External links
EurekAlert: NIH, UNC scientists find anti-cancer drugs might work in treating deadly aging disease*
*
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