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 include the bases adenine and guanine. Purine nucleotides can be newly synthesized (de novo synthesis) or recovered from degradation products (salvage pathway).

De novo synthesis of purine nucleotides


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 dihydrofolate by dihydrofolate reductase.

Inhibitors of de novo purine synthesis

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 consumption is a common cause of hyperuricemia for multiple reasons, including: increased purine nucleotide degradation during ethanol catabolism, high amounts of purines in alcoholic drinks (e.g., beer), and inhibition of the renal excretion of urate (promoted by increased lactic acid blood levels, 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

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

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

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 for the mitochondrial carbamoyl phosphate synthetase 1 of the urea cycle.

To remember that the CPS2 enzyme is located in the cytosol, think of “CyTWOsol”.

Phase 2: synthesis of UTP and CTP

Phase 3: synthesis of thymine-containing deoxyribonucleotides

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!

Inhibitors of pyrimidine synthesis

Inhibitors of pyrimidine and purine synthesis

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
    • CMPcytidine uridine uracil → dihydrouracil → 3-ureidopropionic acid → β-alanine
    • CMP can also be converted to UMP and further degraded.
  • Reaction steps in UMP degradation
  • Reaction steps in dTMP degradation
    • dTMP → thymidine thymine → dihydrothymine → β-ureidoisobutyric acid → β-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

last updated 11/05/2020
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