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. 2022 Aug 3;28:89. doi: 10.1186/s10020-022-00516-2

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© The Author(s) 2022

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — 5-fluorouracil (5FU) metabolism pathways. The structure and atom numbering of 5FU is shown in the lower right corner of the figure. Antimetabolite activation pathways are marked in red. The degradation pathway for pyrimidines is marked in blue. The thymidylate synthesis is marked in green. Steps in simplified metabolic pathways: 1. Capecitabine, a 5FU prodrug, is bioactivated in the liver in a two-step process to 5’-deoxy-5-fluorouridine (doxifluridine; DFUR), while tegafur, another 5FU prodrug, is bioactivated by CYP2A6. 2. DFUR is converted to 5FU by thymidine phosphorylase (TP). 3. 5FU is sequentially converted to 5-fluorouridine monophosphate (FUMP), diphosphate (FUDP) and triphosphate (FUTP), which is an active metabolite that is mistakenly incorporated into RNA, causing RNA damage. 4. FUDP is also sequentially converted to 5-fluoro-2’-deoxyuridine diphosphate (FdUDP) and triphosphate (FdUTP), which is an active metabolite that is mistakenly incorporated into DNA, causing DNA damage. 5. TP converts 5FU to 5-fluoro-2’-deoxyuridine (FdUR). 6. Thymidine kinase (TK) converts FdUR to 5-fluoro-2’-deoxyuridine monophosphate (FdUMP). 7. FdUMP is an active metabolite that irreversibly inhibits thymidylate synthase (TS), an enzyme that catalyzes the conversion of 2’-deoxyuridine monophosphate (dUMP) to 2’-deoxythymidine monophosphate (thymidylate; dTMP). 8. Cyclically dihydrofolate (H₂Folate) is reduced to tetrahydrofolate (H₄Folate) which is then converted to 5,10-methylenetetrahydrofolate (CH₂H₄Folate). Leucovorin (folinic acid) is converted to CH₂H₄Folate and then stabilizes the bond formed between TS and FdUMP. 9. Dihydropyrimidine dehydrogenase (DPD) catalyzes the first step of the breakdown of 5FU (mainly in the liver) to 5,6-dihydro-5-fluorouracil (DHFU), which is further broken down into α-fluoro-β-alanine, carbon dioxide and ammonia, excreted from the body. 10. Thymidylate can be salvaged by TK from thymidine (dT) derived from dead cells. 11. FdUTP can be converted to FdUMP by dUTP pyrophosphatase and then converted back to FdUDP by UMP-CMP kinase. Based on information from Longley et al. (2003) and maps in KEGG (Kanehisa et al. 2017)