Enzymes involved in nucleotide synthesis

Enzymes involved in nucleotide synthesis represent a diverse class of metabolic proteins that facilitate the production of purine and pyrimidine nucleotides through de novo and salvage pathways [1, 5, 9]. These enzymes, such as dihydrofolate reductase (DHFR), thymidylate synthase (TYMS), and ribonucleotide reductase (RNR), provide the necessary precursors for DNA replication and RNA synthesis, which are essential for cellular growth and division [1, 2, 10]. Because rapidly proliferating cells, including malignant tumor cells and activated lymphocytes, depend heavily on these pathways, these enzymes have long been prioritized as therapeutic targets in oncology and immunology [1, 4, 8]. Drugs targeting these enzymes, collectively known as antimetabolites, include methotrexate, 5-fluorouracil, and mycophenolate mofetil [1, 2, 3]. By competitively inhibiting rate-limiting steps or acting as substrate analogs, these drugs deplete intracellular nucleotide pools or result in the incorporation of "false" nucleotides, thereby inducing cell cycle arrest and apoptosis [2, 5, 12, 15]. However, since these pathways are also active in healthy, fast-dividing tissues like bone marrow and the intestinal lining, therapy is often limited by significant toxicities such as myelosuppression and gastrointestinal distress [2, 11, 12].

Other names

Nucleotide metabolism enzymesNucleotide biosynthetic enzymesDe novo nucleotide synthesis enzymesPurine and pyrimidine synthesis enzymesNucleotide biosynthetic pathway enzymes

Inhibition of key rate-limiting enzymes in purine or pyrimidine biosynthesis pathways, leading to the depletion of deoxyribonucleotide and ribonucleotide pools, which halts DNA and RNA synthesis and induces cell cycle arrest or apoptosis; some agents also act as fraudulent substrates that incorporate into nucleic acid chains to cause termination or lethal mutations.