178
is known to associate with the protein FKBP12 thereby forming a complex that binds
to mTOR complex (Choi et al. 1996). An activated mTORC1 will activate its two
downstream effectors that evoke a signal leading to translational initiation. In the
mammalian system, translation is regulated via the ribosomal S6 kinases (S6K1 and
S6K2) and the eukaryotic initiation factor 4E (eIF-4E)-binding protein 1 (4EBP1)
which are under the direct phosphorylation control of mTORC1 (Hay and Sonenberg
2004). In the protein synthesis machinery, the assembly of small ribosomal units to
mRNA requires the presence of eukaryotic translational initiation factor 4F (eIF4F)
complex at the 5′ end of mRNA. The eIF4F complex constitutes three components,
namely eIF4E, eIF4G, and eIF4A (Pestova et al. 2001; Gebauer and Hentze 2004).
The binding of eIF4E to 5′cap of mRNA leads to further binding of other components of the eIF4F complex. The association of eIF4E to other component of eIF4F
will be inhibited by binding of 4E-BP1to eIF4E, thus causing blockage in translation
initiation. Signal transduction-mediated activation of mTORC1 will lead to phosphorylation of 4E-BP1 that leads to its dissociation from eIF4E (Gingras et al. 1999).
The phosphorylation of 4E-BP1 is regulated by a complex mechanism of events.
4E-BP1 requires phosphorylation at four sites for its dissociation from eIF4E,
namely, Thr-37, Thr-46, Ser-65, and Thr-70. Phosphorylation of Thr-37 and Thr-46
is the initiating event that causes conformation change in the protein leading to exposure of the other two sites for phosphorylation (Thoreen, et al. 2009). The phosphorylation sites Thr-37 and Thr-46 are rapamycin insensitive while the sites Ser-65
and Thr-70 are rapamycin sensitive (Fingar et al. 2004). Rapamycin, at the same
time, leads to complete inhibition of p70s6k. Rapamycin has no effect on the action
of mTORC2, so the functions of this protein remains stable while the functions of
mTORC1 are partially inhibited (Fig. 7.1).
Pentostatin is produced by S. antibioticus and is widely used in treatment of
hairy cell leukemia (HCL). It was used as purine analogue in treatment for HCL in
the early 1980s. The compound is an effective inhibitor of adenosine deaminase
(Grever and Lozanski 2011). In case of HCL, it was observed that on inhibition of
adenosine deaminase by pentostatin leads to accumulation of deoxyadenosine triphosphate at the intracellular level, thus causing cytotoxicity. This accumulation
further causes blockage of the repair system that repairs DNA breaks. All these
events lead to the activation of p53 and further cyctochome c release from mitochondria, thus driving the cell to apoptosis (Johnston 2011).
Manumycin is a compound of marine origin from the bacteria S. parvulus. The
compound is known to inhibit Ras farnesyltransferase inhibitor from the initial
microbial screening. Ras proteins are major molecules within cells that play vital
role in many signal transduction pathways. The protein is involved in controlling
pathways that are linked with proliferation, cytoskeletal integrity, and differentiation. Farnesyltransferase (FTase) inhibitors are potential anticancer drugs that works
by inhibiting the farnesylation required for function of several cellular proteins.
Manumycin functions as a competitive inhibitor of protein FTase competing with
farnesylpyrophosphate and at the same time play as a noncompetitive inhibitor in
relation to Ras protein (Hara et al. 1993; Yang et al. 1997). FTase is involved in the
enzymatic reaction that is important for posttranslational modification of Ras and
V.M. Dan and R. Sanawar
is known to associate with the protein FKBP12 thereby forming a complex that binds
to mTOR complex (Choi et al. 1996). An activated mTORC1 will activate its two
downstream effectors that evoke a signal leading to translational initiation. In the
mammalian system, translation is regulated via the ribosomal S6 kinases (S6K1 and
S6K2) and the eukaryotic initiation factor 4E (eIF-4E)-binding protein 1 (4EBP1)
which are under the direct phosphorylation control of mTORC1 (Hay and Sonenberg
2004). In the protein synthesis machinery, the assembly of small ribosomal units to
mRNA requires the presence of eukaryotic translational initiation factor 4F (eIF4F)
complex at the 5′ end of mRNA. The eIF4F complex constitutes three components,
namely eIF4E, eIF4G, and eIF4A (Pestova et al. 2001; Gebauer and Hentze 2004).
The binding of eIF4E to 5′cap of mRNA leads to further binding of other components of the eIF4F complex. The association of eIF4E to other component of eIF4F
will be inhibited by binding of 4E-BP1to eIF4E, thus causing blockage in translation
initiation. Signal transduction-mediated activation of mTORC1 will lead to phosphorylation of 4E-BP1 that leads to its dissociation from eIF4E (Gingras et al. 1999).
The phosphorylation of 4E-BP1 is regulated by a complex mechanism of events.
4E-BP1 requires phosphorylation at four sites for its dissociation from eIF4E,
namely, Thr-37, Thr-46, Ser-65, and Thr-70. Phosphorylation of Thr-37 and Thr-46
is the initiating event that causes conformation change in the protein leading to exposure of the other two sites for phosphorylation (Thoreen, et al. 2009). The phosphorylation sites Thr-37 and Thr-46 are rapamycin insensitive while the sites Ser-65
and Thr-70 are rapamycin sensitive (Fingar et al. 2004). Rapamycin, at the same
time, leads to complete inhibition of p70s6k. Rapamycin has no effect on the action
of mTORC2, so the functions of this protein remains stable while the functions of
mTORC1 are partially inhibited (Fig. 7.1).
Pentostatin is produced by S. antibioticus and is widely used in treatment of
hairy cell leukemia (HCL). It was used as purine analogue in treatment for HCL in
the early 1980s. The compound is an effective inhibitor of adenosine deaminase
(Grever and Lozanski 2011). In case of HCL, it was observed that on inhibition of
adenosine deaminase by pentostatin leads to accumulation of deoxyadenosine triphosphate at the intracellular level, thus causing cytotoxicity. This accumulation
further causes blockage of the repair system that repairs DNA breaks. All these
events lead to the activation of p53 and further cyctochome c release from mitochondria, thus driving the cell to apoptosis (Johnston 2011).
Manumycin is a compound of marine origin from the bacteria S. parvulus. The
compound is known to inhibit Ras farnesyltransferase inhibitor from the initial
microbial screening. Ras proteins are major molecules within cells that play vital
role in many signal transduction pathways. The protein is involved in controlling
pathways that are linked with proliferation, cytoskeletal integrity, and differentiation. Farnesyltransferase (FTase) inhibitors are potential anticancer drugs that works
by inhibiting the farnesylation required for function of several cellular proteins.
Manumycin functions as a competitive inhibitor of protein FTase competing with
farnesylpyrophosphate and at the same time play as a noncompetitive inhibitor in
relation to Ras protein (Hara et al. 1993; Yang et al. 1997). FTase is involved in the
enzymatic reaction that is important for posttranslational modification of Ras and
V.M. Dan and R. Sanawar