AA9 Pyrimidines

What are the two main types of nitrogenous bases?

Purines (2 rings: A, G) and Pyrimidines (1 ring: C, U, T).

What is the main difference between a nucleotide and a nucleoside?

• Nucleoside = base + sugar

  • Nucleotide = base + sugar + ≥1 phosphate group

In pyrimidine biosynthesis, when is the ribose added?

The pyrimidine ring is built first, then the ribose-phosphate (from PRPP) is added.

What does PRPP stand for?

Phosphoribosyl pyrophosphate.

What enzyme synthesizes PRPP?

PRPP synthetase (also called ribose phosphate pyrophosphokinase).

What substrates are needed to make PRPP?

Ribose-5-phosphate (from the pentose phosphate pathway) + ATP.

: What role does PRPP play in nucleotide synthesis?

It provides the activated ribose-phosphate backbone for both de novo and salvage pathways.

What are the substrates for CPS2?

Glutamine (as N source), CO₂, and 2 ATP.

What is the product of the CPS2 reaction?

Carbamoyl phosphate.

Where is CPS2 located and why is this important?

In the cytosol;

its product is used for pyrimidine synthesis rather than the urea cycle.

What enzyme catalyzes the first committed step in pyrimidine biosynthesis?

Aspartate transcarbamoylase (ATCase).

What reaction does ATCase catalyze?

Aspartate + carbamoyl phosphate → carbamoyl aspartate.

What enzyme catalyzes the ring closure in pyrimidine biosynthesis?

Dihydroorotase.

What complex includes the first three enzymes of pyrimidine synthesis?

The CAD complex (CPS2, ATCase, and dihydroorotase).

What is formed when the ring closes?

Dihydroorotate.

Which enzyme forms a carbon-carbon double bond to make orotate?

Dihydroorotate dehydrogenase.

What enzyme adds PRPP to orotate to form OMP?

Orotate phosphoribosyl transferase.

What enzyme converts OMP to UMP?

Orotate decarboxylase.

What enzyme converts UTP to CTP?

CTP synthetase.

What enzyme catalyzes the conversion of dUMP to dTMP?

Thymidylate synthase.

What distinguishes uracil and thymine?

Thymine has a methyl group; uracil does not.

What distinguishes ribose vs. deoxyribose sugars?

Ribose has a hydroxyl (-OH) on the 2′ carbon; deoxyribose has a hydrogen (-H).

What does the CAD complex produce?

Converts glutamine, CO₂, ATP, and aspartate → dihydroorotate (closed ring).

What happens when orotate reacts with PRPP?

OMP (orotidine monophosphate) is formed — the first nucleotide of the pathway.

What type of reaction converts OMP → UMP?

Decarboxylation.

What happens when UMP is phosphorylated?

It becomes UDP, then UTP.

What is needed to form CTP from UTP?

Glutamine (as the nitrogen donor).

What molecule donates a carbon group during dTMP synthesis?

Methylene tetrahydrofolate (methylene-THF).

What is the role of folic acid in thymidine synthesis?

Provides a methyl (CH₂) group via methylene-THF for the conversion of dUMP → dTMP.

What enzyme regenerates tetrahydrofolate (THF) from dihydrofolate (DHF)?

Dihydrofolate reductase.

Why is thymidylate synthase clinically important?

It’s targeted by anti-cancer drugs that block DNA synthesis in rapidly dividing cells.

Which enzyme is inhibited by CTP in bacteria?

Aspartate transcarbamoylase (ATCase).

What inhibits CPS2?

UTP.

What activates CPS2?

PRPP.

How is CTP synthetase regulated?

Activated by GTP (ensures balanced C-G base pairing).

Why is tight regulation necessary for nucleotide synthesis?

To maintain balanced pools of nucleotides and conserve resources, since nucleotides aren’t stored.

What are the two main ways the body obtains nucleotides?

De novo synthesis and salvage pathways.

What happens if mitochondrial carbamoyl phosphate leaks into the cytosol due to an OTC deficiency?

It contributes to pyrimidine synthesis and can lead to orotic aciduria.

What are two causes of orotic aciduria?

1. Urea cycle disorder (OTC deficiency, with hyperammonemia).
2. Pyrimidine synthesis defect (UMP synthase deficiency, without hyperammonemia).