Pyrimidine Synthesis

Summary

This is the second video in a three-part series on pyrimidine synthesis, a biochemical pathway. It covers the key steps, starting with glutamine and carbon dioxide to make carbamoyl phosphate, which is converted to uric acid. An important reaction uses PRPP to form OMP, which becomes UMP. UMP can be converted to common pyrimidines CTP or dTTP. Important drugs that inhibit enzymes in this pathway are highlighted, like leflunomide, hydroxyurea, 5-fluorouracil, methotrexate, trimethoprim, and pyrimethamine.

Takeaways

• 😀 The video covers part 2 of a 3-part series on pyrimidine synthesis
• 👩‍🔬 Glutamine + CO2 → carbamoyl phosphate, catalyzed by carbamoyl phosphate synthetase 2
• 🔬 Carbamoyl phosphate → orotic acid (3 steps); aspartate used in step 1
• 💊 Leflunomide inhibits dihydroorotate dehydrogenase
• ⚗️ Orotic acid + PRPP → UMP (very important step)
• 😮 PRPP used in 'very important' UMP step
• 🧪 UMP → UDP; can become dUDP or CTP
• 💉 Hydroxyurea, 5-fluorouracil, methotrexate, trimethoprim, pyrimethamine inhibit enzymes
• 🧠 Pneumonic: 'hydroxy UA → 2 RS' for ribonucleotide reductase
• 👨‍⚕️ 'Doctor prescribes' methotrexate, trimethoprim, pyrimethamine for dihydrofolate reductase

Q & A

What is the first step in pyrimidine synthesis?

The first step is the conversion of glutamine and carbon dioxide to carbamoyl phosphate by the enzyme carbamoyl phosphate synthetase 2.

What cofactor is used and converted in the step where UMP is synthesized from orotic acid?

PRPP (phosphoribosyl pyrophosphate) is used and its phosphoribosyl group is transferred to the pyrimidine base to form OMP.

What are the three intermediate steps in converting carbamoyl phosphate to orotic acid?

The three unlabeled intermediate steps use: 1) aspartate 2) generate water as a byproduct 3) require NAD+.

Which enzyme does the drug leflunomide inhibit?

Leflunomide inhibits dihydroorotate dehydrogenase, which is the enzyme that catalyzes the conversion of carbamoyl phosphate to orotic acid.

What is the folate cycle that runs in parallel to pyrimidine synthesis?

Tetrahydrofolate (THF) is converted to methylene-THF, which reduces to dihydrofolate (DHF) in pyrimidine synthesis. DHF cycles back to THF via dihydrofolate reductase.

Which drugs inhibit ribonucleotide reductase and thymidylate synthase?

Hydroxyurea inhibits ribonucleotide reductase. Fluorouracil inhibits thymidylate synthase.

What is the mnemonic for remembering enzymes inhibited by methotrexate and trimethoprim?

"The doctor prescribes" methotrexate, trimethoprim, or pyrimethamine reminds that these drugs inhibit dihydrofolate reductase (DHFR).

What molecules can UDP be converted into?

UDP can be converted into either dUDP or CTP by the enzymes ribonucleotide reductase or CTP synthase, respectively.

What are the final pyrimidine nucleotides synthesized through this pathway?

The end products are UMP, CTP, and dTMP which get converted to UDP, dUDP, and dTMP.

Why is PRPP important in both purine and pyrimidine synthesis?

PRPP donates activated ribose-5-phosphate groups that are incorporated into both purine and pyrimidine rings during their synthesis.