Cancer Biology: Molecular Basis of Drug Design

Question 1

Answer 1

Question 2

How is enzyme activity regulated?

Answer 2

1. Gene Expression – amount of enzyme (protein) synthesised
2. Feedback loop – very common regulatory mechanism, inhibition caused by product of the reaction or pathway.
3. Feed Forward Activation – product of a reaction activates a downstream enzyme, increasing substrate flow through the pathway
4. Allosteric Regulation – a regulator that binds to a site other than the active site. Alters activity through changes to the enzyme’s tertiary and quaternary structure.
5. Phosphorylation/Dephosphorylation – a common method in signal transduction, where addition/removal of a phosphate group can switch enzyme activity on or off.
6. Proteolysis – enzymes can be activated or inactivated by proteolytic cleavage

Question 3

What is phosphorylation??

Answer 3

Addition of a PHOSPHATE group to Serine, Threonine, Tyrosine residues

Very important in Cell Signalling events and the Cell Cycle

Question 4

What are Enzyme Inhibitors?

Answer 4

Inhibitors can bind to enzymes, slowing down the rate or even stopping reactions they catalyse.

Some inhibitors occur naturally in the cell, others are ‘artificial’ e.g. drugs

Inhibitors can be REVERSIBLE and IRREVERSIBLE

Question 5

What is IRREVERSIBLE INHIBITION?

Answer 5

An irreversible inhibitor reacts with the enzyme making it enzymatically inactive and the active enzyme cannot be regenerated.

The inhibitor binds covalently to the enzyme and cannot be removed.

e.g. aspirin – inhibits COX enzyme and therefore prostaglandin synthesis reducing pain, inflammation etc

Question 6

What is REVERSIBLE INHIBITION? What are the 3 types?

Answer 6

A reversible inhibitor can bind to the enzyme and then be released leaving the enzyme in its original condition.

There are 3 types of reversible inhibition: competitive, non-competitive and uncompetitive

Question 7

What are COMPETITIVE INHIBITORS?

Answer 7

• Compete with the substrate to get into the active site and therefore decrease catalytic activity
• Binds to the active site and blocks substrate access
• Similar in structure / shape to the substrate
• Increasing the substrate concentration decreases the effect of the inhibitor
• Inhibition is reversible

e.g. Ibuprofen inhibits COX reducing prostaglandin synthesis

Question 8

What are NON COMPETITIVE INHIBITORS?

Answer 8

• Binds to a different site on the enzyme
• Changes the shape of the active site
• Substrate cannot bind to the active site properly
• Cannot be overcome by increasing substrate concentration
• Inhibition is reversible
• Doxycycline, an antibiotic is a non-competitive inhibitor of a bacterial proteolytic enzyme (collagenase).

Question 9

What are UNCOMPETITIVE INHIBITORS?

Answer 9

• Binds to the Enzyme-Substrate Complex only
• Binding of substrate to enzyme creates a binding site for the inhibitor
• Inhibition is reversible