PHSC1212 Biochemistry - Lecture 9: Enzyme Inhibition pt 1

Enzyme inhibitors

molecules that reduce an enzyme's activity

Endogenous, food preservatives, pesticides, poisons, drugs

enzyme inhibitors

Endogenous

enzyme inhibitors that originate in the body

NSAIDs, kinase inhibitors, ACE inhibitors

drugs that act by inhibiting enzymes examples

Nonsteroidal anti-inflammatory drug

What is an NSAID?

Angiotensin converting enzyme

What does ACE stand for?

CYP450 enzymes

What do drugs commonly inhibit?

Drug drug interactions

when one drug inhibits the enzymes that metabolize another drug

A drug's therapeutic effect or toxicity

What can drug-drug interactions affect due to inhibiting metabolism?

Grapefruit juice

contains a molecule that inhibits CYP3A4, increasing blood levels of many different drugs

Reversible and irreversible

two main categories of enzyme inhibition

Reversible

enzyme inhibition where the inhibitor can be removed from the enzyme

Competitive, noncompetitive, uncompetitive

categories of reversible inhibition

Irreversible

enzyme inhibition where the inhibitor binds permanently (often covalently)

Covalently

How does the inhibitor in irreversible inhibition often bind?

Replace enzyme

What is the only way to restore enzyme function if there is irreversible enzyme inhibition?

Competitive inhibitors

bind to the enzyme's active site and compete with the substrate; can only bind to free enzyme

Enzyme active site and only free enzyme

Where do competitive inhibitors bind?

Increasing substrate concentration can allow Vmax to be reached

Why is Vmax not affected by reversible competitive inhibition?

Decreased affinity, higher km

What appears to happen in competitive inhibition due to needing more substrate to reach 1/2 Vmax?

Increased Km, no change in Vmax

What effect do competitive inhibitors have on Km and Vmax?

Noncompetitive inhibitors

bind to a separate site from the active site; can bind free enzyme or enzyme substrate complex

Separate site from active and free enzyme or enzyme substrate complex

Where do noncompetitive inhibitors bind?

Conformational change to enzyme preventing product formation

In noncompetitive inhibition, what is the result?

Pure and mixed

two types of noncompetitive inhibition

Far away

Where do pure noncompetitive inhibitors bind in relation to the active site?

Near

Where do mixed noncompetitive inhibitors bind in relation to the active site?

No change in Km, decreased Vmax

What effect do pure noncompetitive inhibitors have on Km and Vmax?

Change in Km, decreased Vmax

What effect do mixed noncompetitive inhibitors have on Km and Vmax?

Pure noncompetitive

inhibition where the inhibitor binds far away from the active site; it has no preference for E vs ES; does not change Km

Doesn't change it

What effect does pure noncompetitive inhibition have on Km?

No preference for E or ES

What type of preference does pure noncompetitive inhibition have?

Mixed noncompetitive

inhibition where the inhibitor binds near the active site; it has a preference for E vs ES; changes Km

Changes it

What effect does mixed noncompetitive inhibition have on Km?

Preference for E or ES

What type of preference does mixed noncompetitive inhibition have?

Decreases

In both cases of noncompetitive inhibition (pure or mixed), what happens to Vmax?

Uncompetitive inhibitors

bind to a separate site from the active site; can bind only to the enzyme substrate complex

Separate site from active and only enzyme substrate complex

Where do uncompetitive inhibitors bind?

Higher substrate affinity, lower Km

What does reversible uncompetitive inhibition give the appearance of?

Decreased Km, decreased Vmax

What effect do uncompetitive inhibitors have on Km and Vmax?

Vmax and Km changed to same degree

Why are uncompetitive inhibition lines parallel?

Substrate cannot dissociate from enzyme giving appearance of higher affinity

Why does Km appear to be lower in uncompetitive inhibition?

Irreversible inhibitors

usually bind covalently to the enzyme and typically bind to the active site

Free sulfhydryl groups

Enzymes with what can be susceptible to covalent modification?

Pure noncompetitive inhibitors

What do irreversible inhibitors look similar to?

Decreased Vmax, no change in Km

What effect do pure noncompetitive inhibitors have on Vmax and Km?

No increase or decrease in affinity

Why doesn't Km change in irreversible inhibition?