Transcript Enzyme Mimics (Artificial Enzymes)

Enzyme Mimics (Artificial Enzymes)
• Reproduce the enzyme’s function
• Mimic a chemical reaction
– Chemical transformation (covalent bonds)
&/or
• Molecular recognition
– Mimic binding (H-bonding, hydrophobic, ionic, etc)
•
We have already seen two biomimetic catalytic systems:
– Organocatalysis with proline
– Koga’s crown ethers
• Things to consider:
– Needs to be an initial binding step
– Size: important for binding & release of product
– To be truly catalytic, there needs to be turnover
• Several examples of mimics found in research and
industry:
– We will look at:
• Cyclodextrins
• Cryptands
• Catalytic antibodies
Cyclodextrins
-cyclodextrin
• 6 (), 7 (), or 8 ()
glucose units
• Hydrophobic cavity
• Stable & water soluble
• Tunable (modify to
change properties)
• Several examples of its
use for biomimetic
catalysis:
– Condensation rxns
– Redox chemistry
– etc
cavity
• Research on cyclodextrin started in the 1930’s
– Very expensive & thought to be toxic
• 1970’s → non-toxic, but still $2000/kg
• Now → cheap! → 1000 tons/y
• Several industrial applications
– Self-tanning lotions, laundry drier sheets, flavorings, etc.
– Produced by environmentally-friendly technologies & renewable
materials
• Starch → cyclodextrin (action of CTGase)
Mimic of Ribonuclease A
• Hydrolyses RNA using two His residues for acid/base
catalysis (no general agreement on how)
• Mimic the Rib A system by attaching imidazole groups on
cyclodextrin
• Can use similar chemistry to a condensation reaction:
An Artificial Transaminase
• Recall transamination of AAs with pyridoxal phosphate
(PLP)
O
H
O
NH 2
O
HO
O P O
N
O
OH
+
HO
O P O
NH2
alanine
PLP
O
O
N
O
+
OH
O
pyruvic acid
• Use cyclodextrin to perform the same chemistry with a
covalent linkage to a PLP derivative
An Artificial Transaminase (Coenzyme
Bound)
Rates:
• phenylpyruvic acid 100x
faster than pyruvic acid
O
OH
+
O
Compete for CD
• increase hydrophobicity
→ further rate increase
(15 000x)
Other Coenzyme mimics
Benzoin condensation with thiazolium ion mimic (recall exp. 7, dilantin
synthesis):
(note the use of a 
cyclodextrin)
Some more mimics
NADH mimic
Flavin mimic
Dimeric
Cryptands
• Cryptands are multi-dendate ligands that bind cations
(“buried”)
– Similar to a crown ether, but usually more selective and they
exhibit stronger binding
– Nobel Prize 1987
Example: Hydrolysis of ATP (mimics ATPase)
Binding via electrostatic
forces & H-bonding
cryptand
Hydrolysis of ATP 500x
Catalytic Antibodies
• Exploit the excellent binding abilities that antibodies
possess
– Molecular recognition
• Construct a transition state analogue → screen for
antibodies against this molecule
Make a TS mimic
Reaction to Study:
O
O2N
O
+
OMe
H
O
H
H
O
H
O
O2N
OH
O
Mimic:
O2N
P
R
O
Mimics tetrahedral-like transition state
O
Screen for
antibodies
against your
TS analogue
P
O2N
R
O
O
O2N
+
OMe
H
O
O
H
O2N
OH
Catalyzes rxn by forcing
substrates into a TS-like
geometry (i.e. binding &
proximity effects)
• Catalytic antibodies are good for simple reactions, but
are limited by:
– Accuracy → transition state analogue
– Screening
• Applications: detoxification of cocaine