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Pathway Description
Fluorouracil Metabolism
Homo sapiens
Metabolic Pathway
Created: 2019-03-11
Last Updated: 2023-10-25
Fluorouracil, sold as Adrucil, Carac, Efudex, Efudix and others, is a medication used to treat various forms of cancer. It consists of a fluorine atom on the 5th carbon of a uracil molecule, and is treated similarly to the uracil during metabolism by the body, but the fluorouracil tends to be absorbed more readily by tumor cells than healthy cells, allowing it to target cancer cells.
Capecitabine is one of the prodrugs that can be metabolized into fluorouracil. First, it is converted to 5'-deoxy-5-fluorocytidine by liver carboxylesterase 1 in the endoplasmic reticulum, and then by cytidine deaminase into 5'-deoxy-5-fluorouridine. Finally, it is converted into fluorouracil by thymidine, which removes the 5'-deoxyribose-1-phosphate from it.
Tegafur is another prodrug that may be converted to fluorouracil, this time by cytochrome P450 2A6 in the endoplasmic reticulum membrane.
From this point, fluorouracil can be converted to 5,6-dihydro-5-fluorouracil by dihydropyrimidine dehydrogenase, which adds a hydrogen ion to it. The 5,6-dihydro-5-fluorouracil can then have a water molecule added by dihydropyrimidinase, forming alpha-fluoro-beta-ureidopropionic acid. Finally, this is converted to alpha-fluoro-beta-alanine by beta-ureidopropionase, which is an end product of the pathway, and is then excreted.
Fluorouracil can also be converted to and from 5-fluorouridine by uridine phosphorylase 2, which is then converted to 5-fluorouridine monophosphate by urudine-cytidine kinase-like 1. 5-fluorouridine monophosphate is also formed from fluorouracil via catalysis by uridine 5'-monophosphate synthase. Regardless of the pathway through which it is created, 5-fluorouridine monophosphate is converted to 5-fluorouridine diphosphate by UMP-CMP kinase, which adds a phosphate group to it. Whithin the mitochondria, mucleoside diphosphate kinase 6 adds one final phosphate group to it, forming 5-fluorouridine triphosphate, another end product of the pathway.
If it does not enter the mitochondria, 5-fluorouridine diphosphate can instead be converted to 5-fluorodeoxyuridine diphosphate by the ribonucleoside-diphosphate reductase complex.
Finally, fluorouracil may be converted to and from floxuridine by thymidine phosphorylase, which then is converted to 5-fluorodeoxyuridine monophosphate by cytosolic thymidine kinase. This molecule also forms 5-fluorodeoxyuridine diphosphate via UMP-CMP kinase, bringing these two branches of the pathway together. Regardless of its origin, 5-fluorodeoxyuridine diphosphate can be converted to 5-fluorodeoxyuridine triphosphate by nucleoside diphosphate kinase 6 in the mitochondria. It may stop there, or be converted back to 5-fluorodeoxyuridine monophosphate by deoxyuridine 5'-triphosphate nucleotidohydrolase, also in the mitochondria.
References
Fluorouracil Metabolism References
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Pubmed: 9409631
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Pubmed: 2726448
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Pubmed: 2748347
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Pubmed: 8083224
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Pubmed: 9135003
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Pubmed: 9464498
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Pubmed: 3279416
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Pubmed: 2624233
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Pubmed: 9042911
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Pubmed: 12849978
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Pubmed: 11780052
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