Enzyme Inhibitors

Application thought process: Some enzymes produce too much this can cause cancer

Reversible: These are reversible because they are connected through interactions (van der waals, hydrophobic effect, ionic interactions, etc. )

  • Competitive: bind to the active site, often have similar structure as substrate.

    • Vmax: unchanged

    • Km: increased by (1+[I]Ki)

    • Vmax is same; Km is increased

    • Example: O2 ; CO is a competitive inhibitor of oxygen. Binds with hemoglobin. Its stronger binding affinity prevents the movement of oxygen throughout the body.

    • Slope Increases in the presence of the inhibitor

  • Uncompetitive: binds to enzyme substrate only

    • Vmax’= Vmax/(1+[I]Ki)

    • Km’=Km/(1+[I]Ki)

    • Both Vmax and Km are decreased

    • Slope of of uncompetitive inhibitor is parallel to the slope of no inhibitor present. The x-intercept of uncompetitive inhibitor is less than the x-intercept of the non-inhibited.

  • Noncompetitive: binds to be enzyme substrate and enzyme

    • Vmax is decreased by (1+[I]Ki); Km is the same.

Irreversible Inhibitors: permanently kill enzymes through covalent modification or non-covalent tight interactions.

  • Thiols (C) and hydroxyls (STY) : are often the targets of inhibitors

    • Enzyme + Iodoacetamide → Inactivated Enzyme

    • Acetylcholinesterase + DIPF → Inactivated Enzyme

      • Neurological affect

    • Penicillin: potent inhibitor of glycopeptide transpeptidase(involved in cell wall synthesis)

      • Reactive peptide bond in Beta-lactam ring is cleaved by penicillin and kills the glycopeptide transpeptidase. No cell wall will form.

      • Glycopeptide transpeptidase + Penicillin → Penicillolyl-enzyme complex (enzymatically inactive)

  • Group Specific Reagents: react with amino acid chains

  • Reactive substrate analogs: Penicillin

  • Suicide inhibitors: Deprenyl; specifically attacks active site of enzymes

  • Transition-state analogs:

  • Catalytic Antibodies: recognizes certain antigens and blocks enzyme activity.

  • Search for Enzyme Inhibitors

    • Penicillin: long search because there are 100s of version of Beta-lactamases.

    • Screen small chemicals for effective enzyme inhibitors

    • Computer-aid drug design: aids in the designing of drugs that inhibit particular enzymes.

    • Novel physiological inhibitors: