Overview
This lecture covers the four main types of enzyme inhibition—competitive, non-competitive, uncompetitive, and irreversible (suicide)—with examples and effects on key enzyme kinetics parameters Km and Vmax.
Competitive Inhibition
- Competitive inhibitors resemble the substrate and bind to the enzyme's active site, blocking substrate access.
- Increasing substrate concentration can overcome inhibition, restoring enzyme activity (Lachatlier’s principle).
- Km (substrate concentration at half Vmax) increases because more substrate is needed to reach half-maximal velocity.
- Vmax (maximum velocity) remains unchanged because inhibition can be overcome at high substrate concentrations.
- Examples: Statins (inhibit HMG-CoA reductase), ACE inhibitors (inhibit angiotensin converting enzyme).
Non-Competitive Inhibition
- Non-competitive inhibitors bind to an allosteric site, not the active site, on either free enzyme or enzyme-substrate complex.
- Binding can occur regardless of whether the substrate is present.
- Km remains unchanged because substrate binding affinity isn’t affected.
- Vmax decreases because some enzymes are always inactive and cannot form the product, regardless of substrate concentration.
- Examples: Monoamine oxidase inhibitors, oxamic acid (inhibits lactate dehydrogenase).
Uncompetitive Inhibition
- Uncompetitive inhibitors bind only to the enzyme-substrate complex at an allosteric site formed during binding.
- Prevents formation of product by stabilizing the enzyme-substrate-inhibitor complex.
- Both Km and Vmax decrease: lower substrate concentration causes lower Km, and enzyme saturation is never achieved, so Vmax drops.
- Examples: Arsenic (inhibits glyceraldehyde 3-phosphate dehydrogenase), lithium (in phosphoinositide pathway).
Irreversible (Suicide) Inhibition
- Irreversible inhibitors (suicide inhibitors) bind covalently to the enzyme, often by mimicking the substrate.
- Enzyme is permanently inactivated and cannot be regenerated.
- These inhibitors are not reversible and permanently reduce enzyme activity.
- Examples: Sarin gas (inhibits acetylcholinesterase), aspirin (inhibits cyclooxygenase).
Key Terms & Definitions
- Km (Michaelis constant) — Substrate concentration at which enzyme velocity is half of Vmax; reflects substrate affinity.
- Vmax — Maximum rate of reaction when enzyme is saturated with substrate.
- Competitive inhibitor — Molecule that binds to the enzyme's active site, competing with the substrate.
- Non-competitive inhibitor — Molecule that binds to an allosteric site on the enzyme or enzyme-substrate complex, reducing overall enzyme activity.
- Uncompetitive inhibitor — Molecule that binds only to the enzyme-substrate complex, further inhibiting product formation.
- Irreversible (suicide) inhibitor — Molecule that binds covalently and permanently inactivates the enzyme.
Action Items / Next Steps
- Review the effects of each inhibitor type on Km and Vmax.
- Study the Michaelis-Menten curve and Lineweaver-Burk plot as discussed in the next lecture.