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)). Overview of pyrimidine metabolism and related diseases e8c AKA beta-alanine-alpha-ketoglutarate transaminase; or beta-alanyl-alpha-ketoglutarate transaminase (AKT) [PMID:7936305]. No annotations found in UniProt related to this name 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 cb9 Zwitterion needed for conversion to take place (4-) charge needed for conversion to take place (2-) charge needed for conversion to take place dd8 cb9 cb9 Orotidylic acid (3-) charge needed for conversion to take place AKA DPYD (1-) charge needed for conversion to take place aka N-carbamoyl-L-aspartate (2-) charge needed for conversion to take place (3-) charge needed for conversion to take place aka P5N1 Enzymes and reactions added with info from https://www.omim.org/entry/606224 aka 3-(carbamoylamino)propanoate aka UPB1 (1) charge needed for conversion to take place (2-) charge needed for conversion to take place Zwitterion needed for conversion to take place (3-) charge needed for conversion to take place cb9 AKA Beta-ketopropionate Annotated without knowledge of R/S configuration (2-) charge needed for conversion to take place methylmalonate semialdehyde aka 2-Methyl-3-oxopropanoic acid aka 2-methyl-3-oxopropanoate D configuration == R-annotation in ChEBI cb9 (2-) charge needed for conversion to take place aka 3-(carbamoylamino)-2-methylpropanoate (1-) charge needed for conversion to take place (4-) charge needed for conversion to take place Zwitterion needed for conversion to take place (3-) charge needed for conversion to take place (2-) charge needed for conversion to take place (2-) charge needed for conversion to take place Zwitterion needed for conversion to take place AKA DPYS aka NT5C Enzymes and reactions added with info from https://www.omim.org/entry/606224 aka P5N Enzymes and reactions added with info from https://www.omim.org/entry/606224 aka P5N1 Enzymes and reactions added with info from https://www.omim.org/entry/606224 aka NT5C Enzymes and reactions added with info from https://www.omim.org/entry/606224 aka P5N Enzymes and reactions added with info from https://www.omim.org/entry/606224 (1-) charge needed for conversion to take place L form of β-aminoisobutyric acid (BAIBA) cb9 methylmalonate semialdehyde aka 2-Methyl-3-oxopropanoic acid aka 2-methyl-3-oxopropanoate L configuration == S-annotation in ChEBI cb9 cb9 cb9 cb9 cb9 ef8 Enzymes and reactions added with info from https://www.omim.org/entry/606224 a02 Translocation d60 Enzymes and reactions added with info from https://www.omim.org/entry/606224 Translocation cb9 cb9 cb9 cb9 c73 ddd hypothesized aka Uridine Monophosphate Synthase Deficiency DISEASE CAD is a complex formed by carbamoyl phosphate synthethase 2 (CPS2), aspartate carbamoyltransferase (ACT) and digydroorotase (DHO) UMPS (UMP synthase complex) is a complex consisting of orotate phosphoribosyltransferase (OPRT) and OMP decarboxylase (OMPDC) Orotidine-5-monophosphate Decarboxylase Deficiency This disease has been merged with the type 1 deficiency, accoriding to OMIM (the text below is rephrased from there). "Even though Fox et al. (1969) identified an apparent new case of orotic aciduria (which was classified as type II orotic aciduria (Fox et al., 1973)). Given that measured enzyme ratios did not remain consistent, and that this apparent type II case was 'clinically indistinguishable' from a type I case diagnosed by the same team, that no confirmatory report had been found in the forty years since the initial report, and that the urinary OA/OR values did not indicate a selective defect in ODC, Bailey (2009) concluded that evidence for a separate category for this case was insecure." DISEASE aka Hyper-Beta Alaninaemia, Beta-alanine Alpha-ketoglutarate Transaminase Deficiency DISEASE ce3 aka Mitocondrial DNA Depletion Syndrome 8A and 8B From book of Blau: depletion syndrome type 8A and 8B are mentioned. DISEASE DISEASE DISEASE aka Mitochondrial Neurogastrointestinal Encephalopathy Syndrome DISEASE aka Thymine-uraciluria DISEASE aka Dihydropyrimidinuria DISEASE Dihydropyrimidinuria aka UMP Hydrolase Deficiency aka 41.15 (book of Blau) aka Hemolytic anemia due to uridine 5-prime monophosphate hydrolase deficiency DISEASE aka UMP Hydrolase Deficiency aka 41.15 (book of Blau) aka Hemolytic Anemia due to Uridine 5-prime Monophosphate Hydrolase Deficiency DISEASE aka Beta-aminoisobutyric Aciduria; BAIBA; Hyper-β-aminoisobutyric aciduria;Beta-aminoisobutyrate-pyruvate Transaminase Deficiency DISEASE aka Miller Syndrome DISEASE aka UMP Hydrolase Superactivity DISEASE aka UMP Hydrolase Superactivity DISEASE UMPS (UMP synthase complex) is a complex consisting of orotate phosphoribosyltransferase (OPRT) and OMP decarboxylase (OMPDC) aka Mitocondrial DNA Depletion Syndrome (Myopathic Type) DISEASE Enzymes and reactions added with info from https://www.omim.org/entry/606224 Enzymes and reactions added with info from https://www.omim.org/entry/606224 25030255 PubMed Inborn errors of pyrimidine metabolism: clinical update and therapy Journal of Inherited Metabolic Disease 2014 Shanti Balasubramaniam John A. Duley John Christodoulou pyrimidine metabolic disorder DOID:0050832 Disease 16541364 PubMed Clinical findings and a therapeutic trial in the first patient with beta-ureidopropionase deficiency Neuropediatrics 2006 16541364 PubMed Clinical findings and a therapeutic trial in the first patient with beta-ureidopropionase deficiency Neuropediatrics 2006 Assmann B Gohlich G Baethmann M Wevers RA et al. 30823446 PubMed Beta-Aminoisobutyric Acid as a Novel Regulator of Carbohydrate and Lipid Metabolism Nutrients 2019 Dmitrii A Tanianskii Natalia Jarzebska Andreas L Birkenfeld John F O'Sullivan Roman N Rodionov 10989432 PubMed Mammalian Methylmalonate-Semialdehyde Dehydrogenase Methods Enzymol. 2007 Natalia Y. Kedishvili Gary W. Goodwin Kirill M. Popov Robert A. Harris dihydropyrimidine dehydrogenase deficiency DOID:14218 Disease dihydropyrimidine dehydrogenase deficiency pathway PW:0002210 Pathway Ontology 16376858 PubMed Characterization of enzymatic properties of human ribonucleotide reductase holoenzyme reconstituted in vitro from hRRM1, hRRM2, and p53R2 subunits. 2006 16376858 PubMed Characterization of enzymatic properties of human ribonucleotide reductase holoenzyme reconstituted in vitro from hRRM1, hRRM2, and p53R2 subunits. Biochem Biophys Res Commun. 2006 Qiu W Zhou B Darwish D Shao J Yen Y beta-ureidopropionase deficiency pathway PW:0001603 Pathway Ontology 9783642403361 ISBN Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, Chapter 41 ISBN 978-3-642-40337-8 2014 Blau, N. Duran, M. Gibson, K.M. Donisi-Vici, C. 7936305 PubMed Pyridoxine-responsive hyper-beta-alaninemia associated with Cohen's syndrome Neurology 1994 J J Higgins C R Kaneski I Bernardini R O Brady N W Barton oroticaciduria 1 disease pathway PW:0001605 Pathway Ontology 15093568 PubMed Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil Eur J Cancer 2004 van Kuilenburg AB orotic aciduria DOID:0050833 Disease pyrimidine metabolic pathway PW:0000032 Pathway Ontology 31744820 PubMed Mevalonate Pathway Provides Ubiquinone to Maintain Pyrimidine Synthesis and Survival in p53-Deficient Cancer Cells Exposed to Metabolic Stress. Cancer Res 2020 Kaymak I Maier CR Schmitz W Campbell AD Dankworth B Ade CP Walz S Paauwe M Kalogirou C Marouf H Rosenfeldt MT Gay DM McGregor GH Sansom OJ Schulze A inborn error purine-pyrimidine metabolism disease pathway PW:0001776 Pathway Ontology disease pathway PW:0000013 Pathway Ontology