Lecture 4: Kinase Inhibitors Flashcards
What cellular processes are tyrosine kinases highly involved in?
- Metabolism
- Transcription
- Cell division and movement
- Apoptosis
What determines whether a protein can be phosphorylated by a tyrosine kinase?
If the protein has an exposed hydroxyl group to target.
How many tyrosine kinases do humans have usually?
Around 90 tyrosine kinases, with about 58 of these being receptor tyrosine kinases.
How many protein kinases do humans usually have?
Around 538.
What two conditions are related to protein kinase dysfunction?
Cancer and inflammatory disorders.
What is the reaction of protein kinases?
(MgATP 1−) + (protein-O:H) –> (O:PO3 2-) + (MgADP) + H+
What is required for the phosphorylation reaction of a protein by a protein kinase?
Presence of a divalent cation such as Mg2+. (And presence of free hydroxyl group).
What types of kinases are there?
Serine threonine kinases.
Tyrosine kinases.
Why are different kinases required for serine, threonine, and tyrosine?
Because the hydroxyl groups of serine and threonine are similar in size, they are both more polar than tyrosine, which is aromatic and thus less polar and larger.
What do 30% of human cancers contain in regards to MAP kinase cascade? What does this affect?
A mutation in the Ras GTPase, the in-built timer that will dephosphorylate Ras thus turning it off after a certain amount of time. This mutation means Ras is always active once phosphorylated, and results in cell proliferation.
What is the Philadelphia chromosome? How is it formed? What disease is it involved in?
BCR-ABL is a mutated tyrosine kinase found in 90% of CML cases.
It is formed in an error during recombination, resulting in the ABL gene, a tyrosine kinase on chromosome 9 being translocated to the end of chromosome 22, directly next to BCR, another gene coding for a serine/threonine kinase.
What specific changes occur between the ABL and BCR-ABL proteins?
The ABL protein normally has a myristate group that is membrane-bound, and in the inactive state, ABL will be closed next to the membrane. In an active state, this arm/cap will extend and project the ABL more into the cytoplasm, and other conformational changes open/activate the active site.
In BCR-ABL, the
What phases of CML are there?
- Chronic Phase
- Accelerated Phase
- Blast Phase
What is the survival rate of CML with and without Imatinib?
The 6-year survival rate is >75% with imatinib, when the survival rate would normally be around 2 years or so.
How was such a large drug as imatinib made to be more easily taken in by the body?
