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

• 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

-cyclodextrin

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)

• Use cyclodextrin to perform the same chemistry with a covalent linkage to a PLP derivative

N

OH

OH

O P

O

O

OOH

O

O

OH

O

NH2

N

OH

NH2

O P

O

O

O

PLP pyruvic acidalanine

++

An Artificial Transaminase (Coenzyme Bound)

+

Compete for CD

Rates:

• phenylpyruvic acid 100x faster than pyruvic acid

• increase hydrophobicity → further rate increase (15 000x)

O

O

OH

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

cryptand

Binding via electrostatic forces & H-bonding

Example: Hydrolysis of ATP (mimics ATPase)

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

O2NO

OMeH

OH

O2NO

OH

HO

H

O

+

Make a TS mimic

O2NP

O

ORMimic:

Reaction to Study:

Mimics tetrahedral-like transition state

O2NP

O

ORScreen for

antibodies against your TS analogue

O2NO

OMeH

OH O2N

O

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