华中科技大学课件上20 lecture14_reactionrate.pptVIP

Kinetic Scheme for Irreversible Inhibitors The irreversible inhibitors do not function by destroying protein structure but by specifically altering the active site of their target. reversible non-covalent complex (EI or ESI) covalently modified dead-end complex EI* Extremes of pH or temperature usually cause denaturation of all protein structure, which is a non-specific effect. Suicide Inactivators Suicide inactivator is relatively unreactive. When the inactivator binds to the active site of a specific enzyme, it undergoes the first few chemical steps of the normal enzymatic reaction, but then it is converted to a very reactive compound that combines irreversibly with the enzyme. These compounds are also called mechanism-based inactivators because they hijack the normal enzyme reaction mechanism to inactivate the enzyme. Suicide inactivators play a significant role in rational drug design (合理药物设计), a modern approach to obtaining new pharmaceutical agents in which chemists synthesize novel substrates based on knowledge of substrates and reaction mechanisms. Enzyme Inhibitors Enzyme inhibitors are molecular agents that interfere with catalysis, slowing or halting enzymatic reactions. Reversible inhibitors Competitive inhibitors (竞争性抑制剂) Uncompetitive inhibitors (反竞争性抑制剂) Mixed inhibitors Noncompetitive inhibitors (非竞争性抑制剂) Irreversible inhibitors Uses of Inhibitors Uses of Inhibitors Chemotherapy (化疗) Methotrexate (氨甲喋呤) Pesticides (杀虫剂) Acetylcholinesterase (乙酰胆碱酯酶) inhibitors Herbicides (除草剂) Glyphosate (草甘膦) Natural poisons Glycoalkaloids (糖苷生物碱 ) Ricin (蓖麻毒素) Dihydrofolate Reductase Dihydrofolate reductase (二氢叶酸还原酶; DHFR) is an enzyme that reduces dihydrofolate to tetrahydrofolate (四氢叶酸). Tetrahydrofolate and its derivatives are essential for purine and thymidylate synthesis, which are important for cell proliferation and cell growth. Folate Methotrexate Methotrexate (氨甲喋呤) Methotrexate is a competitive inhibitor of DHFR. The affinity of methotrexate for DHFR