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CHMI 2227 - E.R. Gauthier, Ph.D. 1 CHMI 2227E Biochemistry I Enzymes: - Inhibition.

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1 CHMI 2227 - E.R. Gauthier, Ph.D. 1 CHMI 2227E Biochemistry I Enzymes: - Inhibition

2 CHMI 2227 - E.R. Gauthier, Ph.D.2 Enzyme inhibition

3 CHMI 2227 - E.R. Gauthier, Ph.D.3 Enzyme inhibition Example 1 - VEGF Receptor inhibitors: British Journal of Cancer (2005) 92(Suppl 1), S6 – S1 Endothelial cell VEGF VEGF-R Endothelial cell growth/migration ZD6474

4 CHMI 2227 - E.R. Gauthier, Ph.D.4 Enzyme inhibition Example 2 – Sildenafil: Int. J. Impot. Res. (2004) 16, S11–S14 Endothelial cell Vascular smooth muscle cell Acetylcholine Nitric Oxide Synthase (NOS) NO Arginine NO Guanylate cyclase GTP cGMP GMP Muscle relaxation Blood vessel Dilation PDE Sildenafil

5 CHMI 2227 - E.R. Gauthier, Ph.D.5 Enzyme inhibition Example 3 – Acetaminophen (tylenol):

6 CHMI 2227 - E.R. Gauthier, Ph.D.6 Trypsin inhibitor Reversible Enzyme inhibition 1- Competitive inhibition P

7 CHMI 2227 - E.R. Gauthier, Ph.D.7 Reversible Enzyme inhibition 1- Competitive inhibition

8 CHMI 2227 - E.R. Gauthier, Ph.D.8 Reversible Enzyme inhibition 2- Uncompetitive inhibition

9 CHMI 2227 - E.R. Gauthier, Ph.D.9 Reversible Enzyme inhibition 2- Uncompetitive inhibition Vmax app = Vmax / (1 + [I]/Ki) Km app = Km / (1 + [I]/Ki)

10 CHMI 2227 - E.R. Gauthier, Ph.D.10 Reversible Enzyme inhibition 3- Noncompetitive inhibition

11 CHMI 2227 - E.R. Gauthier, Ph.D.11 Reversible Enzyme inhibition 3- Noncompetitive inhibition Vmax app = Vmax / (1 + [I]/Ki)

12 CHMI 2227 - E.R. Gauthier, Ph.D.12 Irreversible enzyme inhibition

13 CHMI 2227 - E.R. Gauthier, Ph.D.13 Irreversible enzyme inhibition 1. Group-specific inhibitors

14 CHMI 2227 - E.R. Gauthier, Ph.D.14 Irreversible enzyme inhibition 2. Affinity labels

15 CHMI 2227 - E.R. Gauthier, Ph.D.15 Irreversible enzyme inhibition 3. Suicide inhibitors

16 CHMI 2227 - E.R. Gauthier, Ph.D.16 Irreversible enzyme inhibition 3. Suicide inhibitors - penicillin Structure of the bacterial cell wall Sugars Tetrapeptide pentaGly bridges Pen

17 CHMI 2227 - E.R. Gauthier, Ph.D.17 Irreversible enzyme inhibition 3. Suicide inhibitors - penicillin Tetrapeptide pentaGly bridge Glycopeptide transpeptidase Glycopeptide transpeptidase Glycopeptide transpeptidase Penicillin

18 CHMI 2227 - E.R. Gauthier, Ph.D.18 Irreversible enzyme inhibition 3. Suicide inhibitors - penicillin

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