Alendronate: Difference between revisions
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== Target Proteins and Bone == | == Target Proteins and Bone == | ||
Alendronate not only targets several proteins, but also directly binds to a bone mineral (hydroxyapatite), which causes the inhibition of bone resorption. The | Alendronate not only targets several proteins, but also directly binds to a bone mineral (hydroxyapatite), which causes the inhibition of bone resorption. The alendronate is bound to hydroxypatite and taken up into the osteoclsat during bone resorption.<ref>http://www.ncbi.nlm.nih.gov/pubmed/20209564</ref><ref>http://www.ncbi.nlm.nih.gov/pubmed/16046206</ref> | ||
=== Protein-Tyrosine-Phosphatases (PTP) === | === Protein-Tyrosine-Phosphatases (PTP) === | ||
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<Structure load='2f92' size='450' frame='true' align='right' caption='Shown: The asymmetric subunit of FPPS, not the assumed biological molecule.' scene='Insert optional scene name here' /> | <Structure load='2f92' size='450' frame='true' align='right' caption='Shown: The asymmetric subunit of FPPS, not the assumed biological molecule.' scene='Insert optional scene name here' /> | ||
<scene name='Sandbox_59/Fpps/2'>FPPS</scene> is considered the main target protein of aminobisphosphonates (including alendronate). FPPS is the prenyl transferase in the HMG-CoA Reductase Pathway, which forms cholesterol (sterols and terpenoids) from acetyl CoA. It reacts with 3-isopentenyl pyrophosphate. | <scene name='Sandbox_59/Fpps/2'>FPPS</scene> is considered the main target protein of aminobisphosphonates (including alendronate). FPPS is the prenyl transferase in the HMG-CoA Reductase Pathway, which forms cholesterol (sterols and terpenoids) from acetyl CoA. It reacts with 3-isopentenyl pyrophosphate (IPP) to form geranyl pyrophosphate (GGP). Researchers discovered that alendronate inhibits FPPS because they found a build-up of IPP in the cell, but less GGP.<ref>http://www.ncbi.nlm.nih.gov/pubmed/10620343</ref> | ||
The identified mechanism of alendronate on FPPS begins with the absorption of the alendronate into the osteoclast via binding to hydroxyapatite. Once in the osteoclast, the <scene name='Sandbox_59/Active_site_ligand_space_fill/2'>alendronate binds</scene> to the active site of FPPS.<ref>Fisher et. all. ''Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro''.Cell Biology, Vol. 96, pp. 133–138, January 1999</ref> In the active site, it appears that the alendronate interacts directly with <scene name='Sandbox_59/Active_site_ligand/2'>three Asp residues</scene>, not allowing the IPP to bind, and effectively daectivating FPPS. | |||
The deactivation of FPPS causes a disruption of prenylation in the cell and thus affects various GTPases. For instance, it will incorrectly activate the GTPases Rho, Rac, and Cdc42.<ref>http://www.ncbi.nlm.nih.gov/pubmed/16734383</ref> The inhibition of post-translational prenylation of Ras is likely to cause cell apoptosis. <ref>http://www.ncbi.nlm.nih.gov/pubmed/9556058</ref> | |||
