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CHMI 2227E Biochemistry I. Enzymes: Inhibition. Enzyme inhibition. VEGF-R. VEGF. Endothelial cell growth/migration. ZD6474. Endothelial cell. Enzyme inhibition Example 1 - VEGF Receptor inhibitors :. British Journal of Cancer (2005) 92(Suppl 1), S6 – S1. Vascular smooth muscle cell. - PowerPoint PPT Presentation
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CHMI 2227 - E.R. Gauthier, Ph.D. 1
CHMI 2227EBiochemistry I
Enzymes:- Inhibition
CHMI 2227 - E.R. Gauthier, Ph.D. 2
Enzyme inhibition
CHMI 2227 - E.R. Gauthier, Ph.D. 3
Enzyme inhibitionExample 1 - VEGF Receptor inhibitors:
British Journal of Cancer (2005) 92(Suppl 1), S6 – S1Endothelial cell
VEGF
VEGF-R
Endothelial cell growth/migration
ZD6474
CHMI 2227 - E.R. Gauthier, Ph.D. 4
Enzyme inhibitionExample 2 – Sildenafil:
Int.
J. Im
pot.
Res
. (20
04) 1
6, S
11–S
14
Endothelial cell Vascular smoothmuscle cell
Acetylcholine
Nitr
ic O
xide
Sy
ntha
se (N
OS)
NO
Arginine
NO Guanylate cyclase
GTP
cGMP
GMPMusclerelaxation Blood vessel
Dilation
PDE
Sildenafil
CHMI 2227 - E.R. Gauthier, Ph.D. 5
Enzyme inhibitionExample 3 – Acetaminophen (tylenol):
CHMI 2227 - E.R. Gauthier, Ph.D. 6
Trypsin inhibitor
Reversible Enzyme inhibition1- Competitive inhibition
P
CHMI 2227 - E.R. Gauthier, Ph.D. 7
Reversible Enzyme inhibition1- Competitive inhibition
CHMI 2227 - E.R. Gauthier, Ph.D. 8
Reversible Enzyme inhibition2- Uncompetitive inhibition
CHMI 2227 - E.R. Gauthier, Ph.D. 9
Reversible Enzyme inhibition2- Uncompetitive inhibition
Vmaxapp= Vmax / (1 + [I]/Ki)
Kmapp= Km / (1 + [I]/Ki)
CHMI 2227 - E.R. Gauthier, Ph.D. 10
Reversible Enzyme inhibition3- Noncompetitive inhibition
CHMI 2227 - E.R. Gauthier, Ph.D. 11
Reversible Enzyme inhibition3- Noncompetitive inhibition
Vmaxapp= Vmax / (1 + [I]/Ki)
CHMI 2227 - E.R. Gauthier, Ph.D. 12
Irreversible enzyme inhibition
CHMI 2227 - E.R. Gauthier, Ph.D. 13
Irreversible enzyme inhibition1. Group-specific inhibitors
CHMI 2227 - E.R. Gauthier, Ph.D. 14
Irreversible enzyme inhibition2. Affinity labels
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Irreversible enzyme inhibition3. Suicide inhibitors
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Irreversible enzyme inhibition3. Suicide inhibitors - penicillin
Structure of the bacterial cell wall
SugarsTetrapeptide
pentaGly bridges
Pen
CHMI 2227 - E.R. Gauthier, Ph.D. 17
Irreversible enzyme inhibition3. Suicide inhibitors - penicillin
Tetrapeptide
pentaGly bridge
Glycopeptide transpeptidase
Glycopeptide transpeptidase
Glycopeptide transpeptidase
Penicillin
CHMI 2227 - E.R. Gauthier, Ph.D. 18
Irreversible enzyme inhibition3. Suicide inhibitors - penicillin