Pyrimidine metabolism and related diseases (WP4225)
Homo sapiens
Overview of pyrimidine metabolism and related diseases. Pyrimidine metabolism is important for the synthesis of thymine, cytosine and uracil, some of the building blocks for DNA and RNA and they also have functions in signal transduction and energy transport. The pathway can be split up in 3 parts, one is the de novo synthesis of pyrimidines, starting with glutamine and ending at UMP. From here the UMP can either be used in the nucleic acid synthesis (up) or broken down to Beta-alanine or (S)-beta-aminoisobutyrate. Disorders in the metabolism of pyrimidine are mostly caused by enzyme defects (highlighted in pink, one disease is depicted in orange, since there appears to be no clinical difference between type 2 and 1 of orotic aciduria, therefore researchers believe that type 2 does not exist officially). The clinical presentation of pyrimidine disorders is very diverse, because of the diversity in biological function. The severity of the disorder is determined by the severity of the defect and the function of the normal enzyme. Metabolic markers are highlighted in dark purple. Complexes mentioned in pathway are pictured in bottom left corner. The link to the Urea cycle is depicted for clarity. This pathway was inspired by Chapter 41 of the book of Blau (ISBN 3642403360 (978-3642403361)).
For a description of pathway objects, see the WikiPathways Legend.
Authors
Roel Hacking , Denise Slenter , Egon Willighagen , Martina Summer-Kutmon , Irene Hemel , Friederike Ehrhart , Finterly Hu , Eric Weitz , and Daniela DiglesActivity
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Cited In
- Heterogeneity of Lipid and Protein Cartilage Profiles Associated with Human Osteoarthritis with or without Type 2 Diabetes Mellitus (2021).
- Identification of high‐dimensional omics‐derived predictors for tumor growth dynamics using machine learning and pharmacometric modeling (2021).
- Exome-wide association analysis identifies novel risk loci for alcohol-associated hepatitis (2024).
- Extending inherited metabolic disorder diagnostics with biomarker interaction visualizations (2023).
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Organisms
Homo sapiensCommunities
Inherited Metabolic Disorders (IMD) Pathways Rare DiseasesAnnotations
Pathway Ontology
orotic aciduria 1 pathway beta-ureidopropionase deficiency pathway disease pathway pyrimidine metabolic pathway inborn error of purine-pyrimidine metabolism pathway dihydropyrimidine dehydrogenase deficiency pathwayDisease Ontology
orotic aciduria pyrimidine metabolic disorder dihydropyrimidine dehydrogenase deficiency| Label | Type | Compact URI | Comment |
|---|---|---|---|
| (S)-Beta-aminoisobutyrate | Metabolite | chebi:57731 | aka (R)-3-amino-2-methylpropanoate; myokine, β-aminoisobutyric acid (BAIBA); D form of β-aminoisobutyric acid (D-BAIBA)Zwitterion needed for conversion to take place |
| Glutamine | Metabolite | chebi:58359 | Zwitterion needed for conversion to take place |
| Orotate | Metabolite | chebi:30839 | |
| UTP | Metabolite | chebi:46398 | (4-) charge needed for conversion to take place |
| Carbamoyl-phosphate | Metabolite | chebi:58228 | (2-) charge needed for conversion to take place |
| L-Valine | Metabolite | chebi:57762 | |
| CoQ10 | Metabolite | chebi:46245 | |
| Thymidine | Metabolite | chebi:17748 | |
| OMP | Metabolite | chebi:57538 | Orotidylic acid (3-) charge needed for conversion to take place |
| Acetyl-CoA | Metabolite | chebi:15351 | |
| Aspartate | Metabolite | chebi:29991 | (1-) charge needed for conversion to take place |
| Carbamoylaspartate | Metabolite | chebi:32814 | aka N-carbamoyl-L-aspartate(2-) charge needed for conversion to take place |
| CDP | Metabolite | chebi:58069 | (3-) charge needed for conversion to take place |
| N-Carbamoyl-beta-alanine | Metabolite | chebi:11892 | aka 3-(carbamoylamino)propanoate |
| Uridine | Metabolite | chebi:16704 | |
| CoQ10 - H2 (reduced) | Metabolite | chebi:64183 | |
| Ornithine | Metabolite | chebi:46911 | (1) charge needed for conversion to take place |
| Dihydrouracil | Metabolite | chebi:15901 | |
| Cytidine | Metabolite | chebi:17562 | |
| Dihydrothymine | Metabolite | chebi:27468 | |
| UMP | Metabolite | chebi:57865 | (2-) charge needed for conversion to take place |
| Citrulline | Metabolite | chebi:57743 | Zwitterion needed for conversion to take place |
| dUDP | Metabolite | chebi:60471 | (3-) charge needed for conversion to take place |
| Malonate semialdehyde | Metabolite | chebi:57700 | AKA Beta-ketopropionateAnnotated without knowledge of R/S configuration |
| dUMP | Metabolite | chebi:246422 | (2-) charge needed for conversion to take place |
| D-methylmalonatesemialdehyde | Metabolite | chebi:141212 | methylmalonate semialdehyde aka 2-Methyl-3-oxopropanoic acid aka 2-methyl-3-oxopropanoateD configuration == R-annotation in ChEBI |
| Uracil | Metabolite | chebi:17568 | |
| CMP | Metabolite | chebi:60377 | (2-) charge needed for conversion to take place |
| Orotidine | Metabolite | chebi:25722 | |
| N-Carbamyl-beta-aminoisobutyric acid | Metabolite | chebi:74414 | aka 3-(carbamoylamino)-2-methylpropanoate(1-) charge needed for conversion to take place |
| CTP | Metabolite | chebi:37563 | (4-) charge needed for conversion to take place |
| Beta-alanine | Metabolite | chebi:57966 | Zwitterion needed for conversion to take place |
| PRPP | Metabolite | chebi:17111 | |
| UDP | Metabolite | chebi:58223 | (3-) charge needed for conversion to take place |
| Thymine | Metabolite | chebi:17821 | |
| HCO3- | Metabolite | chebi:17544 | |
| 2-Deoxyuridine | Metabolite | chebi:16450 | |
| dTMP | Metabolite | chebi:63528 | (2-) charge needed for conversion to take place |
| Dihydroorotate | Metabolite | chebi:30864 | |
| + PRPP | Metabolite | chebi:17111 | |
| Glutamate | Metabolite | chebi:29985 | (1-) charge needed for conversion to take place |
| NH4+ | Metabolite | chebi:28938 | |
| L-BAIBA | Metabolite | chebi:58655 | L form of β-aminoisobutyric acid (BAIBA) |
| L-methylmalonatesemialdehyde | Metabolite | chebi:62413 | methylmalonate semialdehyde aka 2-Methyl-3-oxopropanoic acid aka 2-methyl-3-oxopropanoateL configuration == S-annotation in ChEBI |
| Propionyl-CoA | Metabolite | chebi:57392 | |
| UMPS-complex | GeneProduct | uniprot:P11172 | |
| CAD-complex | GeneProduct | uniprot:P27708 | |
| RRM1 | Protein | uniprot:P23921 | |
| RRM2 | Protein | uniprot:P31350 | |
| MMSDH | Protein | uniprot:Q02252 | |
| RRM2B | Protein | uniprot:Q7LG56 | |
| TK2 | Protein | uniprot:O00142 | |
| OTC | Protein | uniprot:P00480 | |
| DPD | Protein | uniprot:Q12882 | AKA DPYD |
| DHO | Protein | eccode:3.5.2.3 | |
| GLS2 | Protein | uniprot:Q9UI32 | |
| UMPH1 | Protein | uniprot:Q9H0P0 | aka P5N1Enzymes and reactions added with info from https://www.omim.org/entry/606224 |
| UP | Protein | uniprot:Q9UBR1 | aka UPB1 |
| CPS1 | Protein | uniprot:P31327 | |
| TS | Protein | uniprot:P04818 | |
| OPRT | Protein | eccode:2.4.2.10 | |
| OMPDC | Protein | eccode:4.1.1.23 | |
| AGXT2 | Protein | uniprot:Q9BYV1 | |
| TP | Protein | uniprot:P19971 | |
| DHODH | Protein | uniprot:Q02127 | |
| ACT | Protein | eccode:2.1.3.2 | |
| beta-alanine-pyruvate transaminase | Protein | eccode:2.6.1.18 | |
| CPS2 | Protein | eccode:6.3.5.5 | |
| RR | Protein | eccode:1.17.4.1 | |
| DHP | Protein | uniprot:Q14117 | AKA DPYS |
| ACT | Protein | kegg.genes:2.1.3.2 | |
| UMPH2 | Protein | uniprot:Q8TCD5 | aka NT5CEnzymes and reactions added with info from https://www.omim.org/entry/606224 |
| UMPH | Protein | eccode:3.1.3.5 | aka P5NEnzymes and reactions added with info from https://www.omim.org/entry/606224 |
| ABAT | Protein | uniprot:P80404 |
References
- Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases [Internet]. Blau N, Duran M, Gibson KM, Dionisi-Vici C. Springer; 2014. 0 p. Available from: https://books.google.com/books/about/Physician_s_Guide_to_the_Diagnosis_Treat.html?hl=&id=wJRBnwEACAAJ OpenLibrary Worldcat
- Pyridoxine-responsive hyper-beta-alaninemia associated with Cohen’s syndrome. Higgins JJ, Kaneski CR, Bernardini I, Brady RO, Barton NW. Neurology. 1994 Sep;44(9):1728–32. PubMed Europe PMC Scholia
- Mammalian methylmalonate-semialdehyde dehydrogenase. Kedishvili NY, Goodwin GW, Popov KM, Harris RA. Methods Enzymol. 2000;324:207–18. PubMed Europe PMC Scholia
- Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil. van Kuilenburg ABP. Eur J Cancer. 2004 May;40(7):939–50. PubMed Europe PMC Scholia
- Characterization of enzymatic properties of human ribonucleotide reductase holoenzyme reconstituted in vitro from hRRM1, hRRM2, and p53R2 subunits. Qiu W, Zhou B, Darwish D, Shao J, Yen Y. Biochem Biophys Res Commun. 2006 Feb 10;340(2):428–34. PubMed Europe PMC Scholia
- Clinical findings and a therapeutic trial in the first patient with beta-ureidopropionase deficiency. Assmann B, Göhlich G, Baethmann M, Wevers RA, Van Gennip AH, Van Kuilenburg ABP, et al. Neuropediatrics. 2006 Feb;37(1):20–5. PubMed Europe PMC Scholia
- Inborn errors of pyrimidine metabolism: clinical update and therapy. Balasubramaniam S, Duley JA, Christodoulou J. J Inherit Metab Dis. 2014 Sep;37(5):687–98. PubMed Europe PMC Scholia
- Beta-Aminoisobutyric Acid as a Novel Regulator of Carbohydrate and Lipid Metabolism. Tanianskii DA, Jarzebska N, Birkenfeld AL, O’Sullivan JF, Rodionov RN. Nutrients. 2019 Feb 28;11(3):524. PubMed Europe PMC Scholia
- Mevalonate Pathway Provides Ubiquinone to Maintain Pyrimidine Synthesis and Survival in p53-Deficient Cancer Cells Exposed to Metabolic Stress. Kaymak I, Maier CR, Schmitz W, Campbell AD, Dankworth B, Ade CP, et al. Cancer Res. 2020 Jan 15;80(2):189–203. PubMed Europe PMC Scholia