Main Ideas!- Enzyme inhibition can be reversible or irreversible!- Reversible types: competitive, non-competitive, and uncompetitive!- Irreversible type: mediated by covalent E-I binding or modification of enzyme by inhibitor!- Most drugs are competitive inhibitors!- Can analyze a new inhibitor drug for its mode of action using the Lineweaver-Burk Plot!- The ideal drug is small, target specific w/high target affinity, doesn't stay around forever, and is cheap to produce!!1) Understand the different types of enzyme inhibition - Enzyme inhibition - Most drugs are enzyme inhibitors and inhibit catalytic activity of an enzyme by binding to it!- Can block signaling pathways!- Different types of enzyme inhibition - Competitive (transition state inhibitors): often look sim. to the substrate, E will bind to the I instead of the S. I and S compete for the same site on E.!- binding is reversible !- I often chemically resembles S, but can't be converted into P!- Decreases the affinity of E and S for each other!- Km is sim. to the dissociation constant, so if affinity of E and S goes down, Km will go UP!- Vmax doesn't change because if you pump in enough S you will have enough S to outcompete the I, it just takes more substrate to get there !- Non-competitive: inhibitor will bind elsewhere on the enzyme, doesn't interefere w/S binding, makes it so E can't catalyze the rxn and convert S--> P!- binding is reversible!- can bind both E and ES complex!- inhibitor binding doesn't affect affinity of E for S (So doesn't change Km!)!- REDUCES Vmax because you can't outcompete--inhib will always be in the way !- Uncompetitive: Inhibitor only binds to ES complex (not E or S alone)!- Reversible binding!- Occurs mostly in multi-substrate rxn !- inhibitor often chemically looks like 2nd substrate, but can't react w/1st substrate!- inhibitor is uncompetitive for S1, but is competitive for S2!- very rare, not efficient!- DECREASES both Km and Vmax. Km goes down because the inhib stabilizes the ES complex!- Suicide or irreversible inhibitor (e.g. form covalent complex w/E or modify E)!- I binds covalently to either substrate binding sites or active sites!- is irreversible!- Ex. Aspirin acetylates COX2 in prostglandin biosynthesis (inflammation/pain response pathway) pathway! 2) Be able to graphically distinguish between the different forms of enzyme inhibition 3) Know the characteristics of common drugs that function as enzyme inhibitors and be able to describe examples - Ex. Competitive inhibition - PABA is used by bacteria to make folic aid. Sulfanilamide is a structural analog, so it inhibits the E that incorps PABA!- Use: inhibit bacterial growth!- Ex. competitive or suicide inhibition - Xanthine oxidase uses the wrong substrate (competitive) and then turns around and gets killed for it (suicide)!- Use: treat disorders of hyperuricemic (urate nephropathy, gout)!- Characteristics of common drugs - Most are competitive inhibitors and rarely covalently modify proteins (exception= aspirin)!- high specifity for site of action!- often hydrophobic, diffuse thru membranes!- small molecules, less than 1000 Da!- rapidly cleared, don't accumulate in
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