Irreversible Inhibition.pptx

Irreversible Inhibition

1. Irreversible Inhibition Sonal Meshram

2. Irreversible Inhibition : Introduction It inactivates an enzyme by bonding covalently to a particular group at the active site. The inhibitor-enzyme bond is so strong that the inhibition cannot be reversed by the addition of excess substrate. The nerve gases, especially Diisopropyl fluorophosphate (DIFP), irreversibly inhibit biological systems by forming an enzyme-inhibitor complex with a specific OH group of serine situated at the active sites of certain enzymes. The peptidases trypsin and chymotrypsin contain serine groups at the active site and are inhibited by DIFP.                      

3. Irreversible inhibitors are covalently or noncovalently bound to the target enzyme and dissociates very slowly from the enzyme. There are three types of irreversible inhibitors:

4. Group specific reagents

5. Affinity labels (Reactive substrate analogs )

6. Suicide inhibitors (Mechanism-based inhibitors) 

7. Clinical Importance of Suicide Inhibitors Aspirin: Anti-inflammatory action Aspirin acetylates a serine residue in the active centre of cyclooxygenase thus inhibiting the PG synthesis and the inflammation subsides 5-fluorouracil: Used in cancer therapy, 5-fluorouracil (5-Fu) is converted to fluorodeoxyuridylate (Fdump) by the enzymes of the salvage pathway. Fdump so formed inhibits the enzyme thymidylate synthase thus inhibiting nucleotide synthesis. 

8. Difluoromethylornithine (DFMO) Ornithine decarboxylase (ODC) catalyzes the conversion of ornithine to putrescine which is necessary for polyamine synthesis When the ODC in Trypanosoma is inhibited ; multiplication of the parasite is arrested. Therefore, inhibitors of ODC enzyme such as difluoromethylornithine (DFMO) has been found to be effective against trypanosomiasis (sleeping sickness). DFMO is initially inert, but on binding with the enzyme, forms irreversible covalent complex with the co-enzyme (pyridoxal phosphate) and the amino acid residues of the enzyme. In mammalian cells, the turnover rate of ODC is very high, and so the inhibition by DFMO is only transient. So, DFMO kills the parasites with no side effects to the patient.  Allopurinol: The best example of suicide inhibition. The drug is used in treatment of gout, as it inhibits the enzyme xanthine oxidase thus decreasing the uric acid formation. allopurinol gets oxidized by the enzyme xanthine oxidase itself to form “alloxanthine” a more potent effective and stronger inhibitor of xanthine oxidase thus potentiating the action of allopurinol

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