Biochemistry II lectures 3&4 Flashcards
What is a Transition State Analogue?
-a drug that binds to and therefore inhibits an enzyme because the drug resembles the transition state of a reaction normally catalyzed by the enzyme
What is an irreversible inhibitor?
-compounds that chemically modify and inactivate an enzyme
-mimics natural substrate and binds active site
What are some examples of irreversible inhibitors?
-dihydrofolate reductase (mimics dihydrofolate)
-aspirin inhibition of cyclo-oxygenases (acetylates a serine residue and blocks substrate access to active site)
-mechanism-based irreversible inhibitor: utilize the enzyme catalytic properties to generate a chemically active species (AKA suicide inhibitors, trojan-horses, and enzyme-activated substrate inhibitors)
What is an example of a mechanism-based irreversible inhibitor?
Myeloperoxidase (MPO) is therapeutic target and inhibitor is 2-thioxanthines (TX2)
-works by covalently attaching to heme
What is a type of covalent inhibitor?
-Acetylcholine esterase is therapeutic target; targeted by sarin and can be displaced by pralidoxime (complex will not breakdown)
-enzyme is disabled for hours/days at a time
How is Darunavir successful as a target for AIDS therapy?
-Protease inhibitor
-overcomes drug resistance by targeting aspartic acids to inactivate protease
-targets active site residues; NOT catalytic residues; takes advantage of polyprotic backbone of the polypeptide chain
How do statins work to lower cholesterol?
-competitive binding with HMG-CoA (not with NADPH)
-prevents mevalonate from being produced
-no steric conflict because L-a-11 is no longer observed
-extremely similar structure; very good Ki; higher affinity than HMG-CoA Reductase
What is Drug Selectivity?
-binding affinity for one receptor relative to the affinity for a second receptor
-how well the drug dosage produces the desired therapeutic effect relative to adverse side effects
How does selectivity benefit NSAIDS?
selectively inhibits COX-2 over COX-1; avoids gastrointestinal bleeding
-difference is COX-2 has valine residue and COX-1 has an isoleucine residue near active site (causes steric hindrance)
-no change in affinity=no change in selectivity
What does IC50 stand for?
-total concentration of inhibitor needed to reach 50% inhibition
-selectivity is defined by comparing equilibrium constants (IC50) ratio
Why is an allosteric site advantageous to target over catalytic sites?
-allosteric sites have more chemical/spatial differences than catalytic sites which can improve specificity for a particular enzyme
-can be many more allosteric sites available to target on an enzyme; increases chances for finding a pocket unique to a particular enzyme
What is an example of an allosteric inhibitor being developed now?
-PTP4A(3) is being inhibited
-noncompetitive inhibitor
Why is Cooperativity important?
-Cooperativity creates a small substrate concentration range for the enzyme to become active (sigmoidal curve)
Which of the following phrases is NOT an accurate description of an allosteric effector that inhibits an enzyme?
1. it binds at a site other than the catalytic site
2. binding often results in a conformational change
3. it binds at a site other than where the substrate binds
4. it shifts a sigmoidal initial velocity curve to the right
5. it can increase the apparent Km
6. it lowers the enzymatic activity
7. it shows competitive binding kinetics
8. it can be an analogue of a cofactor
- it shows competitive binding kinetics
Rosuvastatin is known to lower cholesterol and to inhibit HMG-coA reductase by competitively binding with HMG-coA. Rosuvastatin is competitive with HMG-coA because
1. the apparent affinity of Rosuvastatin is increased in the presence of HMG-coA
2. the presence of HMG-coA does not affect the binding of Rosuvastatin to HMG-coA reductase
3. the rosuvastatin binding site overlaps only part of the binding site of HMG-coA
4. Rosuvastatin does not bind to an allosteric site
- the presence of HMG-coA does not affect the binding of Rosuvastatin to HMG-coA reductase
