Purines and pyrimidines


Purine and pyrimidine are fundamental components of nucleotides in DNA and RNA and are essential for the storage of information in the cell. They also serve as a basic framework for coenzymes and are involved in numerous enzymatic processes. Alterations in purine or pyrimidine metabolism can have a variety of consequences. For example, disorders of purine metabolism lead to increased amounts of uric acid in blood and can result in gout. Nucleotide synthesis inhibitors are used in tumor therapy; ribonucleotide reductase inhibitor, for instance, inhibits DNA replication in highly proliferative tumor cells by depriving the building blocks of DNA.

Purine metabolism

Purine nucleotides can be newly synthesized (de novo synthesis) or recovered from degradation products (salvage pathway).

De novo synthesis of purine nucleotides

  • Pathway: ribose 5-phosphatephosphoribosyl pyrophosphate (PRPP) → (10 steps) → inosine-5'-monophosphate (IMP) → (2 steps each) → adenosine-5'-monophosphate (AMP) or guanosine-5'-monophosphate (GMP)
  • Nitrogen or carbon donors: 2 glutamines : , glycine, aspartate, hydrogen carbonate (HCO3-), 2 tetrahydrofolic acids (THF)
  • Energy donators: ATP and GTP


  • PRPP synthesis
  • IMP synthesis
    • Key enzyme (committed step of the de novo synthesis): glutamine PRPP amidotransferase
    • Reaction: PRPP + glutamine → 5-phosphoribosylamine (PRA), glutamate, PPi
      • Four out of 10 steps require ATP hydrolysis
      • Two out of the 10 steps require THF as a cofactor
    • Regulation
      • Allosteric activation by PRPP
      • Allosteric inhibition by AMP, GMP, and IMP
  • AMP and GMP synthesis
    • AMP synthesis: oxygen atom at C6 atom of IMP exchanged by an amino group (NH2 group)
      • First reaction step: IMP + aspartate + GTP → adenylosuccinate + GDP + Pi
      • Enzyme: adenylosuccinate synthetase
      • Second reaction step: adenylosuccinate → adenosine-5'-monophosphate (AMP) + fumarate
      • Enzyme: adenylosuccinate lyase
    • GMP synthesis: attachment of an amino group to the C2 atom
      • First reaction step: IMP + H2O + NAD+xanthosine monophosphate (XMP) + NADH + H+
      • Enzyme: IMP dehydrogenase
        • Clinical significance: IMP dehydrogenase is inhibited by mycophenolic acid
      • Second reaction step: XMP + ATP + glutamine → guanosine-5'-monophosphate (GMP) + AMP + PPi + glutamate
      • Enzyme: guanylate synthetase (xanthylate aminase)
  • Kinases phosphorylate AMP and GMP: yield ATP and GTP, respectively.

GTP is involved in the synthesis of IMP to AMP, while ATP is involved in the synthesis of IMP to GMP!

Purine synthesis requires the 2 THF, which are reduced from DHF by dihydrofolate reductase.

Salvage pathway

Free purine bases can be directly attached to PRPP to yield purine nucleotides. This purine nucleotide synthesis pathway is associated with significantly less energy consumption than de novo synthesis.

HGPRT deficiency leads to Lesch-Nyhan syndrome!

Purine nucleotide degradation

Purine nucleotides are degraded via reaction steps that are different than those used for assembly. Because the purine ring system cannot be enzymatically cleaved in humans, purine is metabolized into uric acid and excreted in urine as urate anion.

Adenosine deaminase deficiency leads to SCID!

An overproduction (e.g., due to excessive purine-rich diet) or underexcretion (most common) of uric acid leads to hyperuricemia and predisposes to the join deposition of monosodium urate crystal, which causes gout.

Excessive alcohol is a common cause of hyperuricemia for multiple reasons, including: increasing purine nucleotide degradation during ethanol catabolism, being consumed in drinks with high amounts of purine (e.g., beer), possibly inhibiting the xanthine dehydrogenase, and inhibiting the renal excretion of urate by promoting lactic acid, dehydration, and possible ketoacidosis.

Uric acid resulting from purine degradation should not be confused with urea resulting from nitrogen of amino acid degradation.


Pyrimidine metabolism

Like purine nucleotides, pyrimidine nucleotides are also newly synthesized or recovered. However, in contrast to de novo synthesis of purine nucleotides, the basic ring structure in the de novo synthesis of pyrimidine nucleotides is synthesized first and then bound to activated ribose phosphate (i.e.., PRPP).

De novo synthesis of pyrimidine nucleotides

Pyrimidine nucleotides include the bases uracil, cytosine, and thymine, e.g. in the nucleoside triphosphates CTP (cytidine triphosphate), dTTP (deoxythymidine triphosphate) and UTP (uridine triphosphate). In pyrimidine nucleotide synthesis, uridine monophosphate (UMP) is initially formed, which can be phosphorylated to UDP and UTP. CTP can then be synthesized from UTP. For the synthesis of thymine-containing deoxyribonucleotides, additional reaction steps are required: First, deoxy-UMP (dUMP) is formed and is then methylated to dTMP (deoxythymidine monophosphate), which is catalyzed by thymidylate synthase.

Phase 1: synthesis pathway from aspartate and cytosolic carbamoyl phosphate to UMP

  • Pathway: synthesis of carbamoyl phosphate from glutamine and bicarbonate → addition of aspartate yields carbamoyl aspartatedihydroorotateorotic acid → transfer to PRPP yields OMP (orotidine monophosphate) → UMP (uridine monophosphate) + CO2
  • Nitrogen or carbon donors: glutamine, bicarbonate (HCO3-), aspartate
  • Involved enzyme complexes
  • Key reaction: aspartate + carbamoyl phosphate → carbamoyl aspartic acid + Pi
  • Regulation:
    • CPS2 activity of the CAD enzyme
      • Activation: PRPP and ATP
      • Inhibition: UTP
    • Inhibition of the dihydroorotase activity of the CAD enzyme and dihydroorotate dehydrogenase by orotic acid

Principle of synthesis:
Glutamine + HCO3- + 2 ATP + H2O → carbamoyl phosphate + glutamate + 2 ADP + Pi
Carbamoyl phosphate + aspartate→ carbamoyl aspartate + Pi
Carbamoyl aspartic acid → → (in 2 steps to) orotic acid
Orotic acid + PRPP → → (in 2 steps to) UMP

UMP synthase deficiency leads to orotic aciduria characterized by megaloblastic anemia and orotic acid crystalluria!

The cytosolic carbamoyl phosphate synthetase 2 of pyrimidine synthesis should not be mistaken with the mitochondrial carbamoyl phosphate synthetase 1 of the urea cycle!

Phase 2: synthesis of UTP and CTP

  • Pathway: UMP → UDP → UTP → CTP
  • Enzymes:

Phase 3: synthesis of thymine-containing deoxyribonucleotides

  • Description: dTMP (thymidylate) formation from dUMP through methylation
    • dUMP formation: UDP reduction to dUDP by ribonucleotide reductasephosphorylation to dUTP → dissociation of pyrophosphate → dUMP
  • Enzyme: : thymidylate synthase
  • Reaction: dUMP + N5, N10-methylene tetrahydrofolate (THF) → dTMP + dihydrofolic acid
  • Cofactor: N5, N10-methylene THF (folic acid derivative) as a methyl group carrier
  • Subsequently: phosphorylation of dTMP to dTDP and dTTP by specific kinases using ATP

The synthesis rate of thymine-containing deoxyribonucleotides depends on the folic acid supply!

Methotrexate and 5-fluorouracil both inhibit DNA synthesis by interfering with the formation of thymine-containing deoxyribonucleotides!

Recovery of pyrimidine nucleosides

Pyrimidine nucleosides can be converted to pyrimidine nucleotides by kinases using ATP. Free pyrimidine bases without sugar residues cannot be recovered.

Degradation of pyrimidine nucleotides

In contrast to purine nucleotides, pyrimidine nucleotides can be completely degraded and used for energy generation.

  • Pathway: Pyrimidine nucleotides (CMP, UMP, dTMP) → pyrimidine nucleosides → cleavage of the sugar residue yields free bases → cleavage of pyrimidine ring → β-alanine or β-aminoisobutyric acid → further conversion to malonyl-CoA or methylmalonyl-CoA
  • Location: cytoplasm (especially in hepatic and renal cells)
  • Reaction steps in CMP degradation
    • CMP → cytidineuridineuracil → dihydrouracil → 3-ureidopropionic acidβ-alanine
    • CMP can also be converted to UMP and further degraded.
  • Reaction steps in UMP degradation
    • UMPuridineuracil → dihydrouracil → 3-ureidopropionic acidβ-alanine
  • Reaction steps in dTMP degradation
    • dTMP → thymidine → thymine → dihydrothymine → β-ureidoisobutyric acidβ-aminoisobutyric acid

Synthesis of deoxyribonucleotides

Deoxyribonucleotides containing the purine bases adenine and guanine and the pyrimidine bases cytosine and thymine are required for DNA synthesis. Except for thymine-containing deoxyribonucleotides, the other dNTPs (deoxyribonucleoside triphosphates) are synthesized by the reduction of ribonucleotides (via ribonucleotide reductase).

The reducing equivalents for the reduction of ribonucleotides to deoxyribonucleotides are provided by NADPH+H+.

Hydroxyurea prevents nucleotide synthesis (thus decreasing DNA synthesis) by inhibiting ribonucleotide reductase.

Clinical significance

  • 1. Yamamoto T, Moriwaki Y, Takahashi S. Effect of ethanol on metabolism of purine bases (hypoxanthine, xanthine, and uric acid). Clin Chim Acta. 2005; 356(1-2): pp. 35–57. doi: 10.1016/j.cccn.2005.01.024.
last updated 12/17/2018
{{uncollapseSections(['0oce0W0', 'Yocn0W0', 'bocH0W0', 'aocQ0W0', 'zwcrle0'])}}