Understanding metabolic antagonism ppt.pptx

Metabolic Antagonism

1. Metabolic ANTAGONISM Submitted To : Dr. Mohd Akbar Submitted By: Andleeb Altaf M. Pharm I st Year (MPC)

2. W hat is Metabolic Antagonism? I t is the process in which antimetabolites inhibits the use of metabolites which is another part of normal metabolism. In this phenomena a normal metabolite is inhibited by a molecule called Antimetabolite .

3. What are Antimetabolites? Antimetabolites are compounds that block the normal metabolic pathways operating in cells. They act by either replacing an endogenous compound in the pathway by a compound whose incorporation into the system either results in a product that can no longer play any further part in the pathway or inhibits an enzyme in the metabolic pathway in the cell. These are often similar in structure with the metabolites.

4. Classification of Antimetabolites Antimetabolites that are used to prevent the formation of DNA may be classified as: Antifolates Purine antimetabolites and Pyrimidine antimetabolites. Antimetabolites that inhibit enzyme action are also classified as enzyme inhibitors.

5. Antifolates F olic acid is usually regarded as the parent molecule of naturally occurring compounds known as Folates. In the body, folates are converted by a two-step process into tetrahydrofolates (FH4)by the action of the enzyme dihydrofolate reductase (DHFR) Tetrahydrofolic acid is an essential cofactor in the biosynthesis of purines & thymine, which are required for DNA synthesis

6. Folic acid antimetabolites have structures that resemble folic acid. They have a stronger affinity for DHFR than folic acid and act by inhibiting this enzyme. This has the effect of inhibiting the formation of purines and thymine required for DNA synthesis. This inhibits cell growth, which prevents replication and ultimately leads to cell death. Methotrexate is the only folate antimetabolite in clinical use which is used to treat a variety of cancers.

7. P urine Antimetabolites Purine antimetabolites are exogenous compounds with structures based on the purine nucleus such as 6-mercaptopurine and 6-thioguanine.

8. They inhibit the synthesis of DNA and in some cases RNA by a number of different mechanisms. For example 6-mercaptopurine is metabolised to the ribonucleotide 6-thioguanosine-5 , -phosphate which inhibits several pathways for the biosynthesis of endogenous purine nucleotides. 6-thioguanine is converted in the cell to the ribonucleotide 6-thioinosine-5 , -phosphate which disrupts DNA synthesis by being incorporated into the structure of DNA as a false nucleic acid.

9. Pyrimidine Antimetabolites Pyrimidine antimetabolites have structures that closely resemble those of the endogenous pyrimidine bases.

10. They usually act by inhibiting one or more of the enzymes that are required for DNA synthesis. For example Fluorouracil is metabolized by the same metabolic pathway as uracil to 5-fluoro-2’-deoxyuridylic acid (FUdRP). FUdRP inhibits the enzyme thymidylate synthetase, which is responsible for the transfer of a methyl group from the coenzyme methylenetetrahydrofolic acid (MeFH4) to the C5 atom of deoxyuridylic acid (UdRP). The presence of the unreactive C5-F bond in FUdRP blocks this methylation and as a result prevents the formation of deoxythymidylic acid (TdRP) and its subsequent incorporation into DNA.

11. Enzyme inhibitors Enzyme inhibitors may inhibit the enzymes directly responsible for the formation of nucleic acids or the variety of enzymes that catalyse the various stages in the formation of the pyrimidine and purine bases required for the formation of nucleic acids. Topoisomerases Enzyme inhibitors for Purine and Pyrimidine precursor systems.

12. Topoisomerases Topoisomerases are a group of enzymes that are responsible for the supercoiling, cleavage and rejoining of DNA. Their inhibition has the effect of preventing transcription, which ultimately leads to cell death. A number of compounds are believed to act by inhibiting these enzymes. Examples of topoisomerase inhibitors

13. Enzyme inhibitors for Purine and Pyrimidine precursor systems. A wide range of compounds also inhibit a number of the enzyme systems that are involved in the biosynthesis of purines and pyrimidines in bacteria. For example Sulphonamides inhibit dihydropteroate synthetase, which prevents the formation of folic acid. Trimethoprim inhibits dihydrofolate reductase which prevents the conversion of folic acid to tetrahydrofolate. In both of these examples the overall effect is the inhibition of purine and pyrimidine synthesis which results in the inhibition of the synthesis of DNA. Sequential blocking using sulphamethoxazole and trimethoprim

14. REFRENCES Thomas G. Fundamentals of medicinal chemistry. John Wiley & Sons; 2004 Apr 20. Kar A. Medicinal chemistry. New Age International; 2005.