Pyrimidine metabolism and related diseases (Homo sapiens)

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54312MitochondrionUrea cycleOrticaciduriatype ICAD-complexSubunit ofHyperammonaemiaN-Carbamoyl-beta-alanineCPS2RRM2BOMPDCuridineOTCdUMPdihydroorotateHCO3-dUDPBeta-alanineRRM2BTK2TPACTAspartateRRM1RRthymineUPCPS1DPDOPRTTSOMPcitrullinePRPPcytidineGLS2uracilCarbamoylaspartateuridineRRM2UMPS-complexorotidineUDPCTPUTPCDPCAD-complex2-DeoxyuridinedihydrothymineOrotatedTMPDHOCarbamoyl-phosphateDHODHCMPDihydrouracilOrnithineUMPH1(S)-beta-aminoisobutyrateN-Carbamyl-beta-aminoisobutyric acidthymidineUMPglutamineOrotatedihydroorotateCarbamoyl-phosphateglutamineDHPHCO3-CPS2DHOACTOPRTOMPDCUMPS-complex+ PRPPOroticaciduriatype IIBeta-alanine Alpha-ketoglutarate Transaminase DeficiencyMitochondrialribonucleotide reductasesubunit 2deficiencyType 8AType 8BThymidine phosphorylase deficiencyDihydropyrimidine dehydrogenase deficiencyDihydropyrimidinase deficiencyBeta-ureidopropionase deficiencyUMPH2UMPHUMPH1UMPH2UMPHPyrimidine 5'-nucleotidase I deficiencyPyrimidine 5'-nucleotidase I deficiencyBeta-aminoisobutyrate-pyruvate Transaminase DeficiencyDihydroorotate dehydrogenase deficiencyPyrimidine 5'-nucleotidasesuperactivityPyrimidine 5'-nucleotidasesuperactivityglutamateNH4+RR-complexThe two possible compositionsThymidine kinase 2 deficiencyRRM1


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).

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Ontology Terms



  1. Assmann B, Gohlich G, Baethmann M, Wevers RA, et al.; ''Clinical findings and a therapeutic trial in the first patient with beta-ureidopropionase deficiency''; Neuropediatrics, 2006 PubMed
  2. van Kuilenburg AB; ''Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil''; Eur J Cancer, 2004 PubMed
  3. Shanti Balasubramaniam, John A. Duley, John Christodoulou; ''Inborn errors of pyrimidine metabolism: clinical update and therapy''; Journal of Inherited Metabolic Disease, 2014 PubMed
  4. Qiu W, Zhou B, Darwish D, Shao J, Yen Y; ''Characterization of enzymatic properties of human ribonucleotide reductase holoenzyme reconstituted in vitro from hRRM1, hRRM2, and p53R2 subunits.''; , 2006 PubMed
  5. Blau, N., Duran, M., Gibson, K.M., Donisi-Vici, C.; ''Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, Chapter 41''; ISBN 978-3-642-40337-8, 2014


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103968view09:19, 18 April 2019IreneHemelChanged sizes of disease nodes
103920view08:04, 16 April 2019IreneHemelChanged urea cycle label to pathway node
103919view08:00, 16 April 2019IreneHemelUpdated OMIM links for several diseases
103918view07:48, 16 April 2019IreneHemelRemoved symbols in names references
103917view07:44, 16 April 2019IreneHemelChanged disease names to primary names in Blau book; Added alternative names diseases
103914view15:05, 15 April 2019IreneHemelModified description
103912view15:00, 15 April 2019IreneHemelModified description
103910view13:52, 15 April 2019IreneHemelModified description
103909view13:51, 15 April 2019IreneHemelModified description
103902view13:46, 15 April 2019IreneHemelChanged basic interaction to mim-conversion for side metabolites; changed lines for 2 diseases to graphical line
103901view13:39, 15 April 2019IreneHemelChanged separate complexes; added different options for RR
103894view07:41, 15 April 2019IreneHemelModified description
103884view12:52, 12 April 2019IreneHemelAdded literature
103858view11:57, 11 April 2019IreneHemelAdded disease and enzyme related to this disease
103853view10:13, 11 April 2019IreneHemelMoved complexes to separate part of pathway, added complex IDs
103852view09:50, 11 April 2019IreneHemelAdded Rhea IDs, split reaction into two parts, added alternative names for some metabolites
103848view06:51, 11 April 2019IreneHemelAdded Rhea IDs
103841view14:57, 10 April 2019IreneHemelAdded more Rhea IDs
103838view14:03, 10 April 2019IreneHemelAdded Rhea IDs for several reactions
103813view08:55, 9 April 2019IreneHemelAdded disease
103812view08:46, 9 April 2019IreneHemelAdded Uniprot IDs
103811view08:22, 9 April 2019IreneHemelChanged datanodes for enzymes from geneproduct to protein
102678view09:28, 17 January 2019DeSlModified description
102677view09:26, 17 January 2019DeSlChanged interactions to graphical lines for diseases.
98925view05:21, 16 October 2018EgonwModified description
98283view11:19, 16 August 2018EgonwReplaced secondary ChEBI IDs with primary IDs.
98262view12:59, 15 August 2018DeSlModified description
98261view12:57, 15 August 2018DeSlAdded IDs
98260view11:58, 15 August 2018DeSlAdded more IDs.
98259view11:49, 15 August 2018DeSlAdded IDs for added metabolites
98258view11:43, 15 August 2018DeSlConnected some more steps between CTP and cytidine; connected last diseases (several IDs where just for the gene, not the disease).
98257view10:55, 15 August 2018DeSlChanged diseases to textlabels, changed layout slightly.
98256view09:51, 15 August 2018DeSlModified description
98202view09:41, 7 August 2018MkutmonModified title
96741view06:02, 2 April 2018EgonwReplaced secondary ChEBI identifiers with primary identifiers.
96674view08:21, 26 March 2018DeSlAdded more disease nodes (still have to connect them to related proteins).
96668view13:37, 25 March 2018DeSlAdded complex linked to diseases
96667view13:21, 25 March 2018DeSlAdded more side metabolites, changed color of marker metabolites to purple
96666view13:09, 25 March 2018DeSlModified description
96546view21:18, 17 March 2018DeSlOntology Term : 'beta-ureidopropionase deficiency pathway' added !
96545view21:17, 17 March 2018DeSlOntology Term : 'dihydropyrimidine dehydrogenase deficiency pathway' added !
96544view21:17, 17 March 2018DeSlOntology Term : 'dihydropyrimidine dehydrogenase deficiency' added !
96543view21:17, 17 March 2018DeSlOntology Term : 'oroticaciduria 1 disease pathway' added !
96542view21:16, 17 March 2018DeSlOntology Term : 'orotic aciduria' added !
96541view21:14, 17 March 2018DeSlOntology Term : 'pyrimidine metabolic disorder' added !
96540view21:14, 17 March 2018DeSlOntology Term : 'pyrimidine metabolic pathway' added !
96539view21:13, 17 March 2018DeSlOntology Term : 'inborn error purine-pyrimidine metabolism disease pathway' added !
96536view21:11, 17 March 2018DeSlAdded lit. ref.
96531view20:58, 17 March 2018DeSlChanged KEGG genes datasource to Enzyme Nomenclature, removed EC for ID number.
96530view20:56, 17 March 2018DeSlAdded OMIM IDs for diseases

External references


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NameTypeDatabase referenceComment
(S)-beta-aminoisobutyrateMetaboliteCHEBI:57731 (ChEBI) aka (R)-3-amino-2-methylpropanoate
+ PRPPMetaboliteCHEBI:17111 (ChEBI)
2-DeoxyuridineMetaboliteCHEBI:16450 (ChEBI)
ACTProtein2.1.3.2 (KEGG Genes)
AspartateMetaboliteCHEBI:29991 (ChEBI)
Beta-alanineMetaboliteCHEBI:57966 (ChEBI)
CAD-complexGeneProductP27708 (Uniprot-TrEMBL)
CDPMetaboliteCHEBI:58069 (ChEBI) CDP 3-, charge needed for conversion can take place
CMPMetaboliteCHEBI:60377 (ChEBI) CMP (2-), charge needed for conversion can take place
CPS1ProteinP31327 (Uniprot-TrEMBL)
CPS2Protein6.3.5.5 (Enzyme Nomenclature)
CTPMetaboliteCHEBI:37563 (ChEBI)
Carbamoyl-phosphateMetaboliteCHEBI:58228 (ChEBI)
CarbamoylaspartateMetaboliteCHEBI:32814 (ChEBI) aka N-carbamoyl-L-aspartate
DHOProtein3.5.2.3 (Enzyme Nomenclature)
DHODHProteinQ02127 (Uniprot-TrEMBL)
DHPProteinQ14117 (Uniprot-TrEMBL)
DPDProteinQ12882 (Uniprot-TrEMBL)
DihydrouracilMetaboliteCHEBI:15901 (ChEBI)
GLS2ProteinQ9UI32 (Uniprot-TrEMBL)
HCO3-Metabolite17544 (ChEBI)
N-Carbamoyl-beta-alanineMetaboliteCHEBI:11892 (ChEBI) aka 3-(carbamoylamino)propanoate
N-Carbamyl-beta-aminoisobutyric acidMetaboliteCHEBI:74414 (ChEBI) aka 3-(carbamoylamino)-2-methylpropanoate
NH4+MetaboliteCHEBI:28938 (ChEBI)
OMPMetaboliteCHEBI:57538 (ChEBI) Orotidylic acid
OMPDCProtein4.1.1.23 (Enzyme Nomenclature)
OPRTProtein2.4.2.10 (Enzyme Nomenclature)
OTCProteinP00480 (Uniprot-TrEMBL)
OrnithineMetaboliteCHEBI:46911 (ChEBI)
OrotateMetaboliteCHEBI:30839 (ChEBI)
PRPPMetaboliteCHEBI:17111 (ChEBI)
RRProtein1.17.4.1 (Enzyme Nomenclature)
RRM1ProteinP23921 (Uniprot-TrEMBL)
RRM2BProteinQ7LG56 (Uniprot-TrEMBL)
RRM2ProteinP31350 (Uniprot-TrEMBL)
TK2ProteinO00142 (Uniprot-TrEMBL)
TPProteinP19971 (Uniprot-TrEMBL)
TSProteinP04818 (Uniprot-TrEMBL)
UDPMetaboliteCHEBI:58223 (ChEBI)
UMPMetaboliteCHEBI:57865 (ChEBI)
UMPH1ProteinQ9H0P0 (Uniprot-TrEMBL)
  • aka P5N1
  • Enzymes and reactions added with info from
UMPH2ProteinQ8TCD5 (Uniprot-TrEMBL)
  • aka NT5C
  • Enzymes and reactions added with info from
UMPHProtein3.1.3.5 (Enzyme Nomenclature)
  • aka P5N
  • Enzymes and reactions added with info from
UMPS-complexGeneProductP11172 (Uniprot-TrEMBL)
UPProteinQ9UBR1 (Uniprot-TrEMBL)
UTPMetaboliteCHEBI:46398 (ChEBI)
Urea cyclePathwayWP4571 (WikiPathways)
citrullineMetaboliteCHEBI:57743 (ChEBI)
cytidineMetaboliteCHEBI:17562 (ChEBI)
dTMPMetaboliteCHEBI:63528 (ChEBI)
dUDPMetaboliteCHEBI:60471 (ChEBI)
dUMPMetaboliteCHEBI:246422 (ChEBI)
dihydroorotateMetaboliteCHEBI:30864 (ChEBI)
dihydrothymineMetaboliteQ3027885 (Wikidata)
glutamateMetaboliteCHEBI:29985 (ChEBI)
glutamineMetaboliteCHEBI:58359 (ChEBI)
orotidineMetaboliteCHEBI:25722 (ChEBI)
thymidineMetaboliteCHEBI:17748 (ChEBI)
thymineMetaboliteCHEBI:17821 (ChEBI)
uracilMetaboliteCHEBI:17568 (ChEBI)
uridineMetaboliteCHEBI:16704 (ChEBI)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
2-Deoxyuridineuracilmim-conversion22825 (Rhea)
Aspartatemim-conversion20014 (Rhea)
CDPCMPmim-conversion11602 (Rhea)
CMPcytidinemim-conversion24676 (Rhea)
CTPCDPmim-conversion25239 (Rhea)
Carbamoyl-phosphateCarbamoylaspartatemim-conversion20014 (Rhea)
Carbamoyl-phosphatecitrullinemim-conversion19514 (Rhea)
Carbamoylaspartatedihydroorotatemim-conversion24298 (Rhea)
DihydrouracilN-Carbamoyl-beta-alaninemim-conversion16122 (Rhea)
HCO3-mim-conversion18030 (Rhea)
HCO3-mim-conversion18634 (Rhea)
N-Carbamoyl-beta-alanineBeta-alaninemim-conversion11185 (Rhea)
N-Carbamyl-beta-aminoisobutyric acid(S)-beta-aminoisobutyratemim-conversion37340 (Rhea)
NH4+Carbamoyl-phosphatemim-conversion18030 (Rhea)
OMPUMPmim-conversion11597 (Rhea)
Ornithinemim-conversion19514 (Rhea)
OrotateOMPmim-conversion10382 (Rhea)
UDPUTPmim-conversion25099 (Rhea)
UDPdUDPmim-conversion28028 (Rhea)
UMPUDPmim-conversion24401 (Rhea)
UMPuridinemim-conversion29360 (Rhea)
UTPCTPmim-conversion30337 (Rhea)
cytidineuridinemim-conversion16070 (Rhea)
dTMPthymidinemim-conversion19131 (Rhea)
dUMP2-Deoxyuridinemim-conversion28208 (Rhea)
dUMPdTMPmim-conversion12105 (Rhea)
dUMPdUDPmim-conversion30656 (Rhea)
dihydroorotateOrotatemim-conversion13514 (Rhea)
dihydrothymineN-Carbamyl-beta-aminoisobutyric acidmim-conversion37336 (Rhea)
glutamatemim-conversion15890 (Rhea)
glutamineCarbamoyl-phosphatemim-conversion18634 (Rhea)
glutamineNH4+mim-conversion15890 (Rhea)
thymidinedTMPmim-conversion19130 (Rhea)
thymidinethyminemim-conversion16038 (Rhea)
thyminedihydrothyminemim-conversion28793 (Rhea)
uracilDihydrouracilmim-conversion20191 (Rhea)
uridineuracilmim-conversion24389 (Rhea)
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