Nucleoside and nucleotide synthesis

The nucleoside and nucleotide synthesis pathway is a fundamental metabolic network responsible for producing the purine and pyrimidine building blocks required for DNA replication and RNA transcription [1]. This pathway is a cornerstone therapeutic target in oncology, infectious diseases, and immunology because rapidly dividing cells—such as cancer cells, activated lymphocytes, or replicating viruses—require a continuous and elevated supply of nucleotides [2]. Drugs targeting this pathway, collectively known as antimetabolites, function by inhibiting key enzymes such as dihydrofolate reductase (DHFR), thymidylate synthase (TS), or ribonucleotide reductase (RNR), or by acting as chemical analogs that are mistakenly incorporated into nucleic acids to disrupt cellular function [3][4]. Examples include methotrexate for cancer and rheumatoid arthritis, 5-fluorouracil for solid tumors, and mycophenolate mofetil for organ transplant rejection [5][6]. However, because these pathways are essential for the maintenance of healthy tissues with high turnover, clinical use is often constrained by significant toxicities, particularly bone marrow suppression and gastrointestinal distress [2]. (Sources: [1] https://www.ncbi.nlm.nih.gov/books/NBK553142/ [2] https://pubmed.ncbi.nlm.nih.gov/11264372/ [3] https://pubchem.ncbi.nlm.nih.gov/compound/Methotrexate [4] https://www.uniprot.org/uniprotkb/P04818/entry [5] https://www.cancer.gov/about-cancer/treatment/types/chemotherapy/antimetabolites-hp-pdq [6] https://go.drugbank.com/drugs/DB00688)

Other names

Purine and pyrimidine metabolismNucleotide biosynthesisDe novo and salvage nucleotide pathwaysNucleoside metabolic process

Drugs targeting this pathway act as antimetabolites by either competitively inhibiting rate-limiting enzymes (e.g., dihydrofolate reductase or thymidylate synthase) or by being incorporated into DNA/RNA as fraudulent analogs, leading to chain termination, strand breaks, or lethal mutations.