2. What is prenylation?
Prenylation, or isoprenylation, or lipidation is the addition of
hydrophobic molecules to a protein or chemical compound.
Protein prenylation
involves the transfer of
either a farnesyl or a
geranyl-geranyl moiety
to C-terminal cysteine(s)
of the target protein.
3. Protein prenylation
• The joining of the 15-carbon farnesyl group (C15
H25) to the protein cysteines at or near their
carboxy-termini is called fernesylation (FTase).
While, addition of 20 carbon (C20 H33)
geranylgeranyl is catalyzed to protein–cysteines at
or near their carboxy-termini by protein
geranylgeranyltransferase-I and II (GGTase-I and
GGTase-II)
4. Protein prenylation
• The prenyltransferases are heterodimers of
alpha and beta subunits with combined
molecular masses ranging from 91- 98kDa.
• Prenyltransferases participate in signal
transduction pathways related to cell growth,
differentiation, cytoskeletal function, and
vesicle trafficking.
5. Role of prenylation
• FTase acts upon Ras proteins. It prevents cancer if
prenylation site is modified.
• FTase inhibitors are used to treat cancer.
• FTase inhibitors may be effective in tumor cells
containing non-mutant Ras proteins that are
activated by upstream oncoproteins.
• Signaling pathways are interfered.
6. Ras proteins
• The name 'Ras' is an abbreviation of 'Rat sarcoma',
reflecting the way the first members of the protein
family were discovered. The name ras is also used to
refer to the family of genes encoding those proteins.
• When Ras is 'switched on' by incoming signals, it
subsequently switches on other proteins, which
ultimately turn on genes involved in cell growth,
differentiation and survival. As a result, mutations in
ras genes can lead to the production of permanently
activated Ras proteins. This can cause unintended and
overactive signalling inside the cell, even in the
absence of incoming signals
7. Substrate for FTase and GGTase-I are same
• Farnesyltransferase 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 recognize 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.
Farnesyltransferase recognizes CaaX boxes where X =
M, S, Q, A, or C, whereas Geranylgeranyltransferase I
recognizes CaaX boxes with X = L or E
• aaX is later removed by an endoprotease.
• FTase and GGTase-I can catalyze the prenylation of
tetrapeptides, polypeptides, and proteins containing
appropriate CaaX box sequences.
8. Few exceptions are there!
• In some exceptional cases, if FTase is inhibited, its
typical substrate may be geranylgeranylated by
GGTase-I (e.g K-Ras)
• RhoB, which contains a GGTase-I CaaX box (CKVL) is
found both in fernesylated and geranylgeranylated
• RhoB is GTP binding proteins.
9. Substrate for GGTase-II differs
• Protein geranylgeranyltransferase- II (GGTase-II), or
Rab geranylgeranyltransferase, catalyzes the
geranylgeranylation of Rab proteins that terminate
in CC or CXC sequences. Rab proteins ending with
CXC residues are methyl esterified; those ending
with CC are not.
10. The role of metals in prenylation
• All three prenyltransferases require Zn+2
• Zn+2 greatly enhances the productive binding of
protein or peptide substrates to FTase and GGTase-I,
but it is not required for the binding of prenyl
diphosphate.
• FTase and GGTase-II require Mg+2 for activity
• Mg is not required for catalysis, however its
presence increase the catalysis by 700 folds.
• FTase or GGTase require acidic pH
• Activity of FTase or GGTase-I can be restored by
reconstitution with Co+2 or Cd+2
