RelativeResourceManager.pdf2 - Chapter 5 Enzyme...

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Unformatted text preview: Chapter 5 Enzyme Inhibi2on & Inac2va2on A) Why inhibit an enzyme? Many drugs are enzyme inhibitors. They slow down or block an enzyme’s ac2vity. Enzyme inhibitors:  ­bind to ac2ve site  ­hinder catalysis Substrate cannot be metabolized. Enzyme inhibitors are beneficial when: 1)  A cell has a deficiency in substrate  ­stops metabolism  ­ex.: γ ­aminobutyric acid (GABA) 2)  A cell has excess of a metabolite  ­substrate metabolized in excess  ­enzyme is blocked to prevent metabolism  ­ex.: xanthine oxidase xanthine oxidase xanthine uric acid excess = gout chemotherapy ­the use of drugs to combat foreign organisms or aberrant cells Discovery of lead compounds 1)  Design for a known enzyme  ­effect is known  ­exis2ng inhibitors have undesirable effects 2)  Design for an unknown enzyme  ­risky approach  ­must know metabolites formed by a disease  ­(We don’t know the effect of inhibi2ng the enzyme un2l we design the inhibitor.) Penicillin hUp:// ­resistance/ Two types of enzymes 1)  Reversible 2)  Irreversible (or enzyme inac2vator) penicillin B. Drug Resistance  ­when a formerly effec2ve drug dose is no longer effec2ve  ­muta2ons actually change the drug target making the drug no longer effec2ve  ­new drugs must be found tolerance ­when the body adapts to a drug and more of the drug is needed to get the same effect Mechanisms of drug resistance 1)  Altered drug uptake  ­uptake of the drug is prevented 2)  Overproduc2on of target enzymes  ­organism produces more enzymes in response to a drug 3) Altered target enzyme  ­enzyme mutates and drug doesn’t bind well 4) Produc2on of drug ­destroying enzyme  ­new enzymes are produced to destroy the drug An2bio2c Resistance •  Bacteria develop “defensive enzymes” to destroy an2bio2cs. •  β ­lactamases alter penicillin suscep2ble bond New an2bio2cs? Similar structure, but not β ­lactam C) Drug synergism When drugs are given in combina2on, their effects can be 1)  antagonis2c 2)  subaddi2ve 3)  addi2ve 4)  synergis2c ­effect is greater than the sum of the effects Drug synergism a)  Inhibit the drug ­destroying enzyme  ­2nd drug has no therapeu2c effect, but keeps the drug from being destroyed b)  Sequen2al blocking  ­inhibit 2 or more consecu2ve steps c)  Mul2ple drugs for same target  ­odds of resistance against 2 or more drugs are much higher ...
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