Alendronate

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Please do NOT make changes to this Sandbox. Sandboxes 30-60 are reserved for use by Biochemistry 410 & 412 at Messiah College taught by Dr. Hannah Tims during Fall 2012 and Spring 2013.

1 Alendronate (Fosamax®)
2 History of Bisphosphonates
3 Structure and General Function
4 Target Proteins and Bone
- 4.1 Protein-Tyrosine-Phosphatases (PTP)
- 4.2 Farnesyl Pyrophosphate Synthase (FPPS)
  - 4.2.1 FPPS Natural Substrates
5 Side affects of Drug
6 References

Alendronate (Fosamax®)

Alendronate is commonly known for its use in treatment and prevention of osteoporosis in postmenopausal women and men, but is also used to treat Paget's disease (disease that results in deformed and enlarged bones).^[1] Alendronate belongs to the class of nitrogen-containing bisphosphonates, which are inorganic pyrophosphate analogues.

History of Bisphosphonates

Bisphosphonates were first synthesized in Germany in 1865, but were not studied biologically until 1968. In the interim time, they were used in the textile and fertilizer industries due to their apparent inhibitory effect on calcium carbonate. However, in 1968, a group in Switzerland found inorganic pyrophosphates in urine and plasma. In vitro testing of these molecules revealed that they inhibited calcium phosphate precipitation and dissolution, but were destroyed in vivo by phosphatases. These results led to the discovery of bisphosphonates, as they reacted in the prescribed manner.^[2]

Sodium alendronate was first marketed in 1994 as Fosamax® by Merck pharmaceutical. In 2008, Merck lost their U.S. patent on alendronate, allowing Barr Pharmaceuticals and Teva Pharmaceuticals USA to begin marketing generic forms of sodium alendronate. Other brand names for the drug include Fosamax+D®, Adronat, Alendros, Arendal, and Onclast.^[3]

Structure and General Function

^[4]

Alendronate is an aminobisphosphonate with a nonhydrolyzable P-C-P. Alendronate generally affects the activity of osteoclasts in bone. Osteoclasts are responsible for breaking down bone and also for bone resorption (losing bone substance). ^[5] When alendronate is present, bone resorption is inhibited and bone breakdown is diminished.

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 is bound to hydroxypatite and taken up into the osteoclsat during bone resorption.^[6]^[7]

Protein-Tyrosine-Phosphatases (PTP)

Protein-Tyrosine-Phosphatses (PTPs) are reported to have an effect on osteoclast formation and function.^[8] Initial reports indicated that alendronate inhibited several types of PTPs, though specific mechanisms are not known. The data does suggest that alendronate works as an antagonist, which means that, when bound, the alendronate does not elicit a response from the protein but rather disallows the binding of an agonist which would cause a change (likely activating) in the protein.^[9]^[10]^[11] A is given, so the binding site can be seen.

Farnesyl Pyrophosphate Synthase (FPPS)

Shown: The asymmetric subunit of FPPS, not the assumed biological molecule.

Drag the structure with the mouse to rotate

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.^[12]

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 to the active site of FPPS.^[13] In the active site, it appears that the alendronate interacts directly with , 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.^[14] The inhibition of post-translational prenylation of Ras is likely to cause cell apoptosis. ^[15]