Slides 11 Chemistry Advanced Le Gresley

Enzymes
With Adam Le Gresley
Mohammed sofyan Alqadsi, fas.cn11@gmail.com

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Aims
To introduce enzymes and identify

why they are important drug targets
To introduce enzyme inhibitors and

categorise them as reversible /
irreversible and competitive /
non-competitive
To consider the mode of action of

aspirin

Aims
What are enzymes?
• Reactions occurring in the body:
• take place in aqueous solution
• must work efficiently and in excellent yields
• must be reliable

Aims
• How do these factors differ from lab based organic

chemistry?
• In order for biological chemistry to work there

are complex catalysts called enzymes which control
the reactions
What is the definition of a catalyst?

An Example of an Enzyme
• The reaction of carbon dioxide with water is

necessary to help remove CO2 from tissues into
the blood stream to be returned to the lungs
CO2 + H2O HCO3- + H+
• This reaction would be too slow to sustain life

if uncatalyzed
• The carbonic anhydrase enzyme speeds the reaction

rate up by over 1 million times
Note: ase
the end of their name

Enzymes are special types of proteins
They work by
• Binding the substrate(s)

[substrates are the reactants]
• Binding other molecules (cofactors)

which help with the reaction [these
would be the reagents in lab synthesis]
• Doing the reaction
• Releasing the product

Cartoon representation
substrate
enzyme Substrate binds
Products are released Reaction occurs

Enzymes are specific
An enzyme will only catalyze a certain type of reaction using certain substrates
E.g: OH OH
O O O OH
Me
a-glucosidase + Me OH
HO HO
OH OH
OH OH
OH
O O
Me
a-glucosidase
HO No reaction
OH
OH

Roles of Enzymes
• The recognition and catalytic abilities of enzymes

come about through specific interactions with the
functional groups in the active site
E.g. Esterase enzymes these are found in

the bloodstream and throughout the body
• Any drug containing an ester which enters the

bloodstream is normally hydrolyzed by esterases
• Esterases have the ability to bind a wide range of

substrates

Roles of Enzymes
• Pro-drugs are often activated by esterases
• The enzyme works by binding the substrate and

a molecule of water
• Acidic and basic groups in the active site catalyze

the reaction

Mechanism 1
O O
H
esterase O
active site
R
R O
O
H H
NH

Mechanism 1
O O
H O
O
R R OH
R O
OH
+
H
+
NH O
H R H
H
Compare -

Metal containing enzymes
Around a third of enzymes require the

presence of a metal ion for activity
• Metal-activated enzymes associate loosely with ions

(usually from group 1 or 2) to adopt structural shapes
• Metalloenzymes contain tightly bound metals

(usually from the transition block) which can:
• Bind substrates in specific orientations
• Carry out RedOx reactions (with change

in metal oxidation state)
• Stabilise negative charges

Carbonic Anhydrase is a Metalloenzyme
THR 199
HIS 64 GLU 106
HIS 96
BACK 244 H
ZN
GLU 117
HIS 119
GLN 92
HIS 94
J Am Chem Soc (1981) 103, 1545

Coordination
Zn is tetrahedrally coordinated to the imidazole (Im) rings of 3 histidine

residues and a water
Im H Im O
2+ + 2+
Zn O H Zn O C
Im Im
Im H Im H O
O
Im Im
2+ +H 2+ C
Zn O Zn O
Im Im O
Im H Im H
O
+
H HO
O

Enzymes and Drugs
• Not only are enzymes important in maintaining

the reactions in the body, they are also important
in regulating drug action:
• Enzymes bring about drug metabolism
• Enzymes activate pro-drugs
• Enzymes can themselves be drug targets
• Some disease states arise through the

malfunctioning of an enzyme
• If the body is attacked by foreign invaders, e.g.

microorganisms or viruses, then these can be
halted by interference with their enzymes

Enzyme Inhibitors
• Enzymes are generally targeted by inhibitors

which prevent them from working
• These are molecules which can bind in the enzyme

and prevent substrates or cofactors from binding
• The reaction which the enzyme would normally

catalyze cannot then take place
• How would you go about designing an enzyme

inhibitor?

Reversible inhibitors 1
• It is found that some enzyme inhibitors block the active site by binding in a similar
way to the substrate
• There will be equilibria between bound and unbound substrate and bound and unbound
inhibitor:
substrate
enzyme
+
inhibitor

Reversible inhibitors 2
• The enzyme will be effectively prevented from working when the concentration of the
inhibitor is greater than the concentration of substrate
• At lower concentrations of the inhibitor some enzyme molecules will be inhibited and some
will be binding substrate the enzyme activity will be reduced
• Inhibitors which work in this way are described as reversible
excess substrate reaction proceeds excess inhibitor reaction does not proceed

Irreversible inhibitors
• Some inhibitors will bind to the enzyme permanently X

e.g. by making covalent bonds to it .. CH2
OH
• This inhibition cannot be overcome by increasing inhibitor
the concentration of substrate and is described
as irreversible enzyme
X is a leaving group
• Generally reversible inhibition comes on quickly,
as soon as the concentration of inhibitor near
the enzyme rises
CH2
• Irreversible inhibition may take time to come on O
as it may take time for the covalent bonds to form
Inhibitor is covalently bound to

the enzyme in the active site

Competitive and Non-competitive Inhibition
• The example of reversible inhibition described

previously can also be described as competitive
inhibition
• The substrate and inhibitor molecules compete

for the same binding site
• The example of irreversible inhibition is an example

of non-competitive inhibition since once the inhibitor
binds it stays put the substrate cannot then
compete to bind

Competitive and Non-competitive Inhibition
• The inhibitors studied so far all bind in the active

site of the enzyme some inhibitors bind in
alternative places
• These binding sites are called allosteric sites
• Inhibitors binding at allosteric sites change the shape

of the enzyme, hence preventing substrate binding at
the active site

Allosteric binding 1
substrate
inhibitor
enzyme
allosteric binding site
Inhibitor binds at the allosteric site, the active site changes shape and
the substrate can no longer bind

Allosteric binding 2
• This inhibition is reversible because the inhibitor

is not permanently bound at the allosteric site
• The binding is an equilibrium
• If the concentration of the inhibitor drops then the

enzyme is less likely to be bound to the inhibitor and
enzyme activity increases

Irreversible enzyme inhibition an example
Aspirin is a pro-drug for salicylic acid
O O
C C
OH OH
O OH
C
O CH
aspirin salicyclic acid
What type of metabolic transformation converts aspirin to salicylic acid?

Biological role of aspirin
• Aspirin is used to treat pain and inflammation
• Salicyclic acid inhibits the enzyme cyclooxygenase (COX)
• COX is important in the body for the biosynthesis of prostaglandins

these are responsible for pain and inflammation
• By inhibiting the production of prostaglandins, pain can be alleviated
COX inhibited by salicylic acid
prostaglandins

Dieses Dokument gehört: Mohammed sofyan Alqadsi
Hinweis: Dieses Dokument ist urheberrechtlich geschützt. Die Vervielfältigung,

Verbreitung, Wieder- bzw. Weitergabe und sonstige Nutzung ist ohne die schriftliche
Genehmigung der Lecturio GmbH nicht gestattet.


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Enzymes

With Adam Le Gresley

Mohammed sofyan Alqadsi, fas.cn11@gmail.com

To introduce enzymes and identify

To introduce enzyme inhibitors and

To consider the mode of action of

Mohammed sofyan Alqadsi, fas.cn11@gmail.com

What are enzymes?

• Reactions occurring in the body:

• take place in aqueous solution

• must work efficiently and in excellent yields

Mohammed sofyan Alqadsi, fas.cn11@gmail.com

• How do these factors differ from lab based organic

• In order for biological chemistry to work there

What is the definition of a catalyst?

Mohammed sofyan Alqadsi, fas.cn11@gmail.com

• The reaction of carbon dioxide with water is

CO2 + H2O HCO3- + H+

• This reaction would be too slow to sustain life

• The carbonic anhydrase enzyme speeds the reaction

Mohammed sofyan Alqadsi, fas.cn11@gmail.com

• Binding the substrate(s)

• Binding other molecules (cofactors)

• Doing the reaction

• Releasing the product

Mohammed sofyan Alqadsi, fas.cn11@gmail.com

enzyme Substrate binds

Products are released Reaction occurs

Mohammed sofyan Alqadsi, fas.cn11@gmail.com

Mohammed sofyan Alqadsi, fas.cn11@gmail.com

• The recognition and catalytic abilities of enzymes

E.g. Esterase enzymes these are found in

• Any drug containing an ester which enters the

• Esterases have the ability to bind a wide range of

Mohammed sofyan Alqadsi, fas.cn11@gmail.com

• Pro-drugs are often activated by esterases

• The enzyme works by binding the substrate and

• Acidic and basic groups in the active site catalyze

Mohammed sofyan Alqadsi, fas.cn11@gmail.com

Mohammed sofyan Alqadsi, fas.cn11@gmail.com

Mohammed sofyan Alqadsi, fas.cn11@gmail.com

Around a third of enzymes require the

• Metal-activated enzymes associate loosely with ions

• Metalloenzymes contain tightly bound metals

• Bind substrates in specific orientations

• Carry out RedOx reactions (with change

• Stabilise negative charges

Mohammed sofyan Alqadsi, fas.cn11@gmail.com

J Am Chem Soc (1981) 103, 1545

Mohammed sofyan Alqadsi, fas.cn11@gmail.com

Zn is tetrahedrally coordinated to the imidazole (Im) rings of 3 histidine

Mohammed sofyan Alqadsi, fas.cn11@gmail.com

• Not only are enzymes important in maintaining

• Enzymes bring about drug metabolism

• Enzymes activate pro-drugs

• Enzymes can themselves be drug targets

• Some disease states arise through the

• If the body is attacked by foreign invaders, e.g.

Mohammed sofyan Alqadsi, fas.cn11@gmail.com

• Enzymes are generally targeted by inhibitors

• These are molecules which can bind in the enzyme

• The reaction which the enzyme would normally

• How would you go about designing an enzyme

Mohammed sofyan Alqadsi, fas.cn11@gmail.com