Lecture on Pyrimidine Synthesis and Metabolism

Overview

• Discussion on pyrimidine synthesis in metabolism.
• Importance of pyrimidines in human health.
• Drugs inhibiting protein synthesis in disease states like cancer.

What are Pyrimidines?

• Six-membered nitrogenous bases: Cytosine, Uracil, Thymine.
• Mnemonic: "CUT the pyramids" for Cytosine, Uracil, Thymine.
• Important in RNA and DNA synthesis.
• Uracil is the analog of Thymine in RNA.

Pyrimidine Synthesis Requirements

• Glutamine, Aspartate, Tetrahydrofolate (derivative of folic acid, Vitamin B9).
• Importance of adequate Vitamin B9 in diet.

Pyrimidine Synthesis Pathway

1. Carbamoyl Phosphate Synthesis

   • Enzyme: Carbamoyl Phosphate Synthase II (CPS II).
   • Glutamine, ATP, CO2 processed to produce Carbamoyl Phosphate.

2. Aspartate Transcarbamoylase

   • Converts Carbamoyl Phosphate to Carbamoyl Aspartate.

3. Formation of Orotic Acid

   • Via Dihydroorotate Dehydrogenase.
   • Targeted by drugs like Leflunomide (used in rheumatoid arthritis).

4. PRPP Synthesis

   • Pentose Phosphate Pathway produces Ribose-5-Phosphate.
   • PRPP Synthase converts it to PRPP.
   • PRPP combines with Orotic Acid to form Orotidine Monophosphate (OMP).

5. Conversion to UMP

   • Enzyme: OMP Decarboxylase.
   • Inhibited by UMP and CMP.

6. Formation of dTMP

   • UDP converted to dUDP, then dUMP.
   • Enzyme: Thymidylate Synthase converts dUMP to dTMP.
   • Requires N5, N10-methylene tetrahydrofolate (Vitamin B9).
   • Targeted by Methotrexate and 5-Fluorouracil (chemotherapy drugs).

7. Further Conversions

   • dTMP → dTDP → dTTP.
   • UDP can also convert to UTP (RNA production).

Pyrimidine Salvage Pathway

• Breakdown of DNA releases Cytosine and Thymine.
• Uracil and Thymine can be recycled using ribose and deoxyribose phosphate.
• Salvage pathway limited by low levels of ribose/deoxyribose phosphate.

Importance of De Novo Synthesis

• Limited salvage pathway due to scarcity of cofactors.
• Necessitates de novo pyrimidine synthesis for adequate pyrimidine levels.

Conclusion

• Understanding of pyrimidine synthesis pathways critical for human health and disease treatment.
• Drugs targeting these pathways are vital in treating diseases like cancer.

Note: This lecture emphasized the biochemical pathways of pyrimidine synthesis and their regulation, highlighting their relevance in medicine and cellular metabolism.