Metabolism of Purines and Pyrimidines

Study Notes

Purines and pyrimidines are essential components of nucleotides, the building blocks of DNA and RNA.
The metabolism of these molecules involves both synthesis (de novo) and recycling (salvage pathways).

Adenine, guanine, hypoxanthine, and xanthine are purine bases. These are represented by specific chemical structures.
The structures show their nitrogen-containing ring systems.

Uracil, cytosine, and thymine are pyrimidine bases.
These are also represented by their chemical structures, showing the nitrogen-containing ring systems.

Nucleotides are composed of a nitrogenous base (purine or pyrimidine), a five-carbon sugar (ribose or deoxyribose), and one or more phosphate groups.
A β-N-glycosidic bond links the base to the sugar.
Nucleotides are classified as ribonucleotides (ribose sugar) and deoxyribonucleosides (deoxyribose sugar).

Nucleotide bases are aromatic heterocycles.
Purines consist of a pyrimidine ring fused to an imidazole ring.
Pyrimidines are single six-membered rings.
Nucleosides are formed by linking a nitrogenous base to a pentose sugar via a β-N-glycosidic bond.
Nucleotides are formed by connecting one or more phosphate groups to the sugar of a nucleoside.

De novo synthesis involves building the purine rings from simpler molecules like amino acids.
Salvage reactions synthesize purines from preformed bases or nucleosides.
Salvage pathways require less energy than de novo synthesis and are often regulated by feedback mechanisms.
Key substrates for purine nucleotide synthesis include purine bases (adenine, guanine, hypoxanthine), ribonucleosides, and PRPP.
Important coenzymes include tetrahydrofolate and NAD+.

Synthesis occurs primarily in the cytoplasm of many cells, predominantly in the liver.
Essential energy-consuming processes utilize ATP.
Critical substrates include 5-phosphoribosyl-1-diphosphate (PRDP/PRPP), amino acids (aspartic acid, glutamine, glycine), and tetrahydrofolate derivates.

De novo synthesis builds pyrimidine rings from simpler molecules like CO2, aspartate, and glutamine.
Salvage reactions synthesize pyrimidine nucleotides from preformed bases or nucleosides.
Key substrates include PRPP, carbamoyl phosphate, aspartate, and methylene-THF (for thymidine formation).
Reactions occur primarily in the cytoplasm, with carbamoyl phosphate formation in mitochondria.

Feedback inhibition plays a crucial regulatory role.
Key enzymes like PRPP synthetase and carbamoyl phosphate synthetase II are regulated by nucleotide concentrations.
Specific inhibitors like methotrexate impact purine synthesis and are important in medical contexts.

Dihydrofolate reductase converts folate to tetrahydrofolate using NADPH as a reducing agent. This reaction is critical for many biosynthetic pathways including nucleotide synthesis.
Methotrexate is a significant inhibitor of this reaction, impacting many metabolic processes.