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The Chemical Nature of Enzyme Catalysis
PO
LAR
NO
N-
PO
LAR
Tyr* His
Gly
Acidic Neutral Basic
Asp
Glu GlnCys
Asn Ser*
Thr* Lys
Arg
AlaVal
IleLeu Met
Phe TrpPro
*OH
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Amino acids
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• Acid-Base Catalysis• Covalent catalysis: Nucleophilic
catalysis• Metal ion catalysis• Electrostatic catalysis• Transition state binding• Proximity-Orientation effect
Enzyme Catalysis
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Acid-Base Catalysis
• An acid is a "proton donor" and a base is a "proton acceptor”
• In acid catalysis and base catalysis a chemical reaction is catalyzed by an acid or a base.
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HO
H
Acid-Base Catalysis
CO=
NH
HCH
NH
+
C- OOH
OH
-d
+d
HO
H
CO=
NH
HCH
CO=
NH
HCH
CO=
NH
HCH
Acid-baseCatalysis Acid
catalysis
Basecatalysis
Both
NH
+
C- OO
HO
H
Keto enol
Slow Fast Fast Very Fast
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Acid-Base Catalysis
• Hydrolases: Hydrolysis of esters, peptides, phosphate
• Isomerases: Tautomesism (keto enol; amino:imino)
Side chains of Asp/Glu/ His/Cys/Tyr/Lys act as general acid/base
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Covalent catalysis: Nucleophilic catalysis
Decarboxylation of acetoacetate in to acetone
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Covalent catalysis: Nucleophilic catalysis
1. The enzyme forms a covalent bond to the substrate at some point during reaction
2. Lysine in the active site forms a Schiff base with the acetoacetate. (amine nucleophilically attack carboxyl group)
3. The positive charge of the Schiff base then facilitates decarboxylation (new electrophilic group withdraw electron from reaction centre)
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Covalent catalysis: Nucleophilic catalysis
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Covalent catalysis: Nucleophilic catalysis
N
H
H
:B
O+
H-A
N
H
CH
HOH N
H
C + OH-
Schiff base (w PLP)
N+
HCN+
H
Lys
CH3
2-O3PO
H
O-
H2CO
CH2 CO
O-
CO2
H2C
O-
CH2
H+
H2CO
CH3
acetoacetate Enolate Acetone
RNH2
OH-
N+R H
H2C CH2 CO
O-
CO2
H2C
N
CH2
H+
H2C
N+
CH3
OH-
RNH2
R HR H
Schiff base (imine)
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Activity Regulation: Metal ion catalysis
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Metal ion catalysis
1. Bind to substrate for proper orientation2. Mediate oxidation reduction reaction3. Metal-Electrostatic catalysis
Metal-Electrostatic catalysis1. Charge stablization (similar to or better
than Proton (pH not altered & >1charge2. Promote nucleophilic cartalysis3. Promote reaction through charge shielding
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Metal ion catalysis: Charge stablization
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Metal ion catalysis: nucleophilic cartalysis
OH- is a weak nucleophilic agent but in presence of Zn it becomes a good nucleophilic
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Nucleophilic cartalysis: carboxypeptidase
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Activity Regulation: Electrostatic catalysis
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Electrostatic catalysis: serine protease
Ser195
His 57
Asp 102
H–O–CH2
O
C–O -
=
Active Ser
H–N N
C C
C
H
H
CH2
Ser195
His 57
Asp 102
- O–CH2
OC–O–H
=
N N–H
C C
C
H
H
CH2
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Substrate
If enzyme just binds substrate then there will be no further reaction
Transition state Product
Enzyme not only recognizes substrate, but also induces the formation of transition state
X
Activity Regulation: transition state binding
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Activity Regulation: transition state binding
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Preferred binding of the transition state complexTransition state analogues are competitive inhibitors
N
CCOO-
H
H
N
C-
H
COO-
N
CH
COO-
H
L-proline
proline racemase
planar TSD-proline
H+ H+
NCOO-
H
pyrrole-2-carboxylate
N+COO-
H
D-1-pyrroline-2-carboxylate
competitive inhibitors
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Activity Regulation: Proximity-Orientation effect