Prenylation
Encyclopedia
Prenylation, or isoprenylation, or lipidation is the addition of hydrophobic molecules to a protein
. It is usually assumed that prenyl groups (3-methyl-2-buten-1-yl) facilitate attachment to cell membrane
s, similar to lipid anchor
like the GPI anchor, though direct evidence is missing. Prenyl groups have been shown to be important for protein
-protein binding through specialized prenyl-binding domains.
and Geranylgeranyltransferase I
are very similar proteins. They consist of two subunits, the α-subunit, which is common to both enzymes, and the β-subunit, whose sequence identity is just 25%. These enzymes recognise the CaaX box at the C-terminus of the target protein. C is the cysteine that is prenylated, a is any aliphatic amino acid, and the identity of X determines which enzyme acts on the protein. Work reported in the journal Genome Biology
in 2005 reports refinement of computational detection methods for identification of protein prenylation motifs and establishment of an on-line analysis facility entitled "PrePS".
. The C-terminus of Rab proteins varies in length and sequence and is referred to as hypervariable. Thus Rab proteins do not have a consensus sequence, such as the CAAX box, which the Rab geranylgeranyl transferase can recognize. Instead, Rab proteins are bound by the Rab escort protein
(REP) over a more conserved region of the Rab protein and then presented to the Rab geranylgeranyltransferase. Once Rab proteins are prenylated, the lipid anchor(s) ensure that Rabs are no longer soluble. REP, therefore, plays an important role in binding and solubilising the geranylgeranyl groups and delivers the Rab protein to the relevant cell membrane.
Both isoprenoid chains, geranylgeranyl pyrophosphate
(GGpp) and farnesyl pyrophosphate
are products of the HMG-CoA reductase pathway
. The product of HMG CoA reductase is mevalonate. By combining precursors with 5 carbons, the pathway subsequently produces geranyl pyrophosphate (10 carbons), farnesyl pyrophosphate (15 carbons) and geranylgeranyl pyrophosphate (20 carbons). Two farnesyl pyrophosphate groups can also be combined to form squalene, the precursor for cholesterol
. This means that statins, which inhibit HMG CoA reductase, inhibit the production of both cholesterol and isoprenoids.
Note that, in the HMG-CoA reductase/mevalonate pathway, the precursors already contain a pyrophosphate group, and isoprenoids are produced with a pyrophosphate group. There is no known enzyme activity that can carry out the prenylation reaction with the isoprenoid alcohol. However, enzymatic activity for isoprenoid kinases capable converting isoprenoid alcohols to isoprenoid diphosphates have been shown . In accordance with this, farnesol
and geranylgeraniol
have been shown to be able to rescue effects caused by statins or nitrogenous bisphosphonates, further supporting that alcohols can be involved in prenylation, likely via phosphorylation to the corresponding isoprenoid diphosphate.
Proteins that undergo prenylation include Ras, which plays a central role in the development of cancer
. This suggests that inhibitors of prenylation enzymes (e.g., farnesyltransferase
) may influence tumor growth. In the case of the K- and N-Ras forms of Ras, when cells are treated with FTIs
, these forms of Ras can undergo alternate prenylation in the form of geranylgeranylation . Recent work has shown that farnesyltransferase inhibitor
s (FTIs) also inhibit Rab geranylgeranyltransferase and that the success of such inhibitors in clinical trials may be as much due to effects on Rab
prenylation as on Ras
prenylation. It should be noted that inhibitors of prenyltransferase enzymes display different specificity for the prenyltransferases, dependent upon the specific compound being utilized.
FTIs
can also be used to inhibit farnesylation in parasites
such as trypansoma brucii and malaria
. Parasites seem to be more vulnerable to inhibition of Farnesyl transferase than humans are. In some cases, this may be because they lack Geranylgeranyltransferase I. Thus, it may be possible for the development of antiparastic drugs to 'piggyback' on the development of FTIs for cancer research.
In addition, FTIs have shown some promise in treating a mouse model of progeria
, and in May 2007 a phase II clinical trial using the FTI Lonafarnib
was started for children with progeria.
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...
. It is usually assumed that prenyl groups (3-methyl-2-buten-1-yl) facilitate attachment to cell 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...
s, similar to lipid anchor
Lipid anchored protein
In lipid-anchored proteins, a covalently attached fatty acid such as palmitate or myristate serves to anchor them to either face of the cell membrane. Examples include G proteins and certain kinases. It is believed that the fatty acid chain inserts and assumes a place in the bilayer structure of...
like the GPI anchor, though direct evidence is missing. Prenyl groups have been shown to be important for 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...
-protein binding through specialized prenyl-binding domains.
Protein prenylation
Protein prenylation involves the transfer of either a farnesyl or a geranyl-geranyl moiety to C-terminal cysteine(s) of the target protein. There are three enzymes that carry out prenylation in the cell, farnesyl transferase, Caax protease and methyl transferase.Farnesyltransferase and geranylgeranyltransferase I
FarnesyltransferaseFarnesyltransferase
Farnesyltransferase is one of the three enzymes in the prenyltransferase group. Farnesyltransferase adds a 15-carbon isoprenoid called a farnesyl group to proteins bearing a CaaX motif: a four-amino acid sequence at the carboxyl terminus of a protein...
and Geranylgeranyltransferase I
Geranylgeranyltransferase type 1
Geranylgeranyltransferase 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...
are very similar proteins. They consist of two subunits, the α-subunit, which is common to both enzymes, and the β-subunit, whose sequence identity is just 25%. These enzymes recognise the CaaX box at the C-terminus of the target protein. C is the cysteine that is prenylated, a is any aliphatic amino acid, and the identity of X determines which enzyme acts on the protein. Work reported in the journal Genome Biology
Genome Biology
Genome Biology is an online partially open access scientific journal that publishes original, peer-reviewed research in genomics. It is published by BioMed Central , and is currently the BMC journal with the highest impact factor...
in 2005 reports refinement of computational detection methods for identification of protein prenylation motifs and establishment of an on-line analysis facility entitled "PrePS".
Rab geranylgeranyl transferase
Rab geranylgeranyltransferase, or Geranylgeranyl transferase II, transfers (usually) two geranylgeranyl groups to the cystein(s) at the C-terminus of Rab proteinsRab (G-protein)
The Rab family of proteins is a member of the Ras superfamily of monomeric G proteins. Approximately 70 types of Rabs have now been identified in humans. Rab GTPases regulate many steps of membrane traffic, including vesicle formation, vesicle movement along actin and tubulin networks, and membrane...
. The C-terminus of Rab proteins varies in length and sequence and is referred to as hypervariable. Thus Rab proteins do not have a consensus sequence, such as the CAAX box, which the Rab geranylgeranyl transferase can recognize. Instead, Rab proteins are bound by the Rab escort protein
Rab escort protein
Rab escort protein 1 also known as rab proteins geranylgeranyltransferase component A 1 is an enzyme that in humans is encoded by the CHM gene.- Function :This gene encodes component A of the RAB geranylgeranyl transferase holoenzyme...
(REP) over a more conserved region of the Rab protein and then presented to the Rab geranylgeranyltransferase. Once Rab proteins are prenylated, the lipid anchor(s) ensure that Rabs are no longer soluble. REP, therefore, plays an important role in binding and solubilising the geranylgeranyl groups and delivers the Rab protein to the relevant cell membrane.
Both isoprenoid chains, geranylgeranyl pyrophosphate
Geranylgeranyl pyrophosphate
Geranylgeranyl pyrophosphate is an intermediate in the HMG-CoA reductase pathway used by organisms in the biosynthesis of terpenes and terpenoids. In plants it is also the precursor to carotenoids, gibberellins, tocopherols, and chlorophylls....
(GGpp) and farnesyl pyrophosphate
Farnesyl pyrophosphate
Farnesyl pyrophosphate is an intermediate in the HMG-CoA reductase pathway used by organisms in the biosynthesis of terpenes, terpenoids, and sterols...
are products of the HMG-CoA reductase pathway
HMG-CoA reductase pathway
The mevalonate pathway or HMG-CoA reductase pathway or mevalonate-dependent route or isoprenoid pathway, is an important cellular metabolic pathway present in all higher eukaryotes and many bacteria...
. The product of HMG CoA reductase is mevalonate. By combining precursors with 5 carbons, the pathway subsequently produces geranyl pyrophosphate (10 carbons), farnesyl pyrophosphate (15 carbons) and geranylgeranyl pyrophosphate (20 carbons). Two farnesyl pyrophosphate groups can also be combined to form squalene, the precursor for 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...
. This means that statins, which inhibit HMG CoA reductase, inhibit the production of both cholesterol and isoprenoids.
Note that, in the HMG-CoA reductase/mevalonate pathway, the precursors already contain a pyrophosphate group, and isoprenoids are produced with a pyrophosphate group. There is no known enzyme activity that can carry out the prenylation reaction with the isoprenoid alcohol. However, enzymatic activity for isoprenoid kinases capable converting isoprenoid alcohols to isoprenoid diphosphates have been shown . In accordance with this, farnesol
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...
and geranylgeraniol
Geranylgeraniol
Geranylgeraniol is a diterpene alcohol which plays a role a several important biological processes. It is an intermediate in the biosynthesis of other diterpenes and of vitamins E and K. It also used in the post-translational modification known as geranylgeranylation...
have been shown to be able to rescue effects caused by statins or nitrogenous bisphosphonates, further supporting that alcohols can be involved in prenylation, likely via phosphorylation to the corresponding isoprenoid diphosphate.
Proteins that undergo prenylation include Ras, which plays a central role in the development 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...
. This suggests that inhibitors of prenylation enzymes (e.g., farnesyltransferase
Farnesyltransferase
Farnesyltransferase is one of the three enzymes in the prenyltransferase group. Farnesyltransferase adds a 15-carbon isoprenoid called a farnesyl group to proteins bearing a CaaX motif: a four-amino acid sequence at the carboxyl terminus of a protein...
) may influence tumor growth. In the case of the K- and N-Ras forms of Ras, when cells are treated with FTIs
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....
, these forms of Ras can undergo alternate prenylation in the form of geranylgeranylation . Recent work has shown that farnesyltransferase inhibitor
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....
s (FTIs) also inhibit Rab geranylgeranyltransferase and that the success of such inhibitors in clinical trials may be as much due to effects on Rab
Rab (G-protein)
The Rab family of proteins is a member of the Ras superfamily of monomeric G proteins. Approximately 70 types of Rabs have now been identified in humans. Rab GTPases regulate many steps of membrane traffic, including vesicle formation, vesicle movement along actin and tubulin networks, and membrane...
prenylation as on Ras
Ras
Ras is the name given to a family of related proteins found inside cells, including human cells. All Ras protein family members belong to a class of protein called small GTPase, and are involved in transmitting signals within cells...
prenylation. It should be noted that inhibitors of prenyltransferase enzymes display different specificity for the prenyltransferases, dependent upon the specific compound being utilized.
FTIs
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....
can also be used to inhibit farnesylation in parasites
Parasitism
Parasitism is a type of symbiotic relationship between organisms of different species where one organism, the parasite, benefits at the expense of the other, the host. Traditionally parasite referred to organisms with lifestages that needed more than one host . These are now called macroparasites...
such as trypansoma brucii and malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
. Parasites seem to be more vulnerable to inhibition of Farnesyl transferase than humans are. In some cases, this may be because they lack Geranylgeranyltransferase I. Thus, it may be possible for the development of antiparastic drugs to 'piggyback' on the development of FTIs for cancer research.
In addition, FTIs have shown some promise in treating a mouse model 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 in May 2007 a phase II clinical trial using the FTI Lonafarnib
Lonafarnib
Lonafarnib is a farnesyl-OH-transferase inhibitor that is being investigated in a human clinical trial as a potential treatment for progeria....
was started for children with progeria.
See also
- MyristoylationMyristoylationMyristoylation is an irreversible, co-translational protein modification found in animals, plants, fungi, protozoans and viruses. In this protein modification, a myristoyl group is covalently attached via an amide bond to the alpha-amino group of an N-terminal amino acid of a nascent polypeptide...
- PalmitoylationPalmitoylationS-Palmitoylation is the covalent attachment of fatty acids, such as palmitic acid, to cysteine residues of membrane proteins. The precise function of palmitoylation depends on the particular protein being considered. Palmitoylation enhances the hydrophobicity of proteins and contributes to their...
- ChoroideremiaChoroideremiaChoroideremia is an X-linked recessive retinal degenerative disease that leads to the degeneration of the choriocapillaris, the retinal pigment epithelium, and the photoreceptor of the eye....
, a genetic disease caused by the loss of REP1, REP2 almost conmpensates, but cannot rescue the slow onset of blindness