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

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Presentation transcript:

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

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

CHMI 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

CHMI 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

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

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

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

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

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

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

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

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

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

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

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

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

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

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