Chapter 6: Reversible Inhibitors Flashcards
Reversible inhibitors
- Reduce the rate of enzyme-catalyzed reactions without permanently changing the structure of the enzyme
- Utilize weak, non-covalent interactions
Enzyme inhibitor (EI) complex
- Formed transiently
- Easily dissociates in regard to reversible enzyme inhibitors
Chemotherapies
- Function as reversible inhibitors of specific enzymes
Competitive inhibitors
- Try to bind to the same binding site on the enzyme molecule as the substrate
- Must resemble the enzyme’s natural substrate structurally
At low [S]
- Enzyme will tend to bind to the inhibitor
- Forms EI complex
- No catalysis
At high [S]
- Enzyme will bind substrate
- Effect of inhibitor will be minimal
In the presence of large amounts of substrate
- The effect of the inhibitor can be reversed and a genuine Vmax can be attained
In the presence of a competitive inhibitor
- The M/M constant (Km) increases by an amount ( 1 + 1/[Ki]) and 1/Km decreases
- Km increases
- 1/Km decreases
The slope of LWB
- Increased by a factor of 1 + [I]/Ki in the presence of a competitive inhibitor
- No change in Vmax
Non-competitive inhibitor
- Can interact with the enzyme or the ES complex with equal affinity to form EI or ESI complexes
- Both EI and ESI are catalytically inactive
Increasing substrate concentration with NCI
- No effect on the ability of the inhibitor to reduce reaction rate
Km in NCI
- Not altered in the presence of non-competitive inhibitor
- Vmax is reduced
Drugs as competitive inhibitors
- Antiviral
- Antibacterial
- Antitumor
Sulfonamides
- Bacteriostatic agents that resemble the p-aminobenzoic acid (PABA) utilized by bacteria in the synthesis of folic acid
Sulfanomide binding
- Binds to active site the enzyme dihydropteroate synthetase
Most anticancer agents are competitive inhibitors of these
- Thimydylate synthase
- Dihydrofolate reductase
Anticancer agents
- Often structurally resemble nitrogenous bases of nucleotides
- Able to inhibit DNA replication and cellular proliferation
Methotrexate (aminopterin)
- Competitive, almost irreversible inhibitor of dihydrofolate reductase
- Binds with dihydrofolate reductase with greater affinity than its natural substrate
Methotrexate usage
- Used effectively as a treatment for childhood leukemia
- Low doses: treats rheumatoid arthritis
3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA)
- Competitively inhibits the *** reductase enzyme that catalyzes the rate-limiting step in cholesterol biosynthesis
- Effective in reducing circulating LDL-cholesterol levels
Inhibiting HMG-CoA reductase activity in the liver
- The organ’s demand for cholesterol is increased
- Up regulates LDL receptor gene expression
- Increased clearance of plasma LDL
Angiotensin I-converting enzyme (ACE) inhibitors
- Reduce the production of angiotensin II form angiotensin I by the angiotensin converting enzyme of endothelial cells
Angiotensin II
- Stimulates secretion of aldosterone
- Promotes vasoconstriction of arterioles
Chemotherapies as NCIs
- Doxycycline
- Allopurinol
