GPR curation for Pyrimidine metabolism

[JHL-452b]

Current behavior:

29 genes are discovered to be uncorrelated with their corresponding reactions in Pyrimidine metabolism.

Gene	UniProtID	Reaction	GPR	Correlation	Manually check
ENSG00000143156	Q9Y5B8	MAR04006: ADP + UTP <=> ATP + UDP	ENSG00000103024 or ENSG00000103202 or ENSG00000143156 or ENSG00000172113 or ENSG00000239672 or ENSG00000243678	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation: The gene ENSG00000143156 is described as having kinase activity, 3'-5' exonuclease activity, and being involved in microtubule functions within cilia axoneme and centrosomes, as indicated by multiple PubMed references. However, it does not have nucleoside diphosphate kinase activity, which would be required for the catalysis of the reaction ADP + UTP <=> ATP + UDP.	No
ENSG00000143156	Q9Y5B8	MAR04028: ADP + CTP <=> ATP + CDP	ENSG00000103024 or ENSG00000103202 or ENSG00000143156 or ENSG00000172113 or ENSG00000239672 or ENSG00000243678	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation. The gene ENSG00000143156 encodes a protein with intrinsic kinase activity and 3'-5' exonuclease activity, but it does not possess nucleoside diphosphate kinase activity, which is required to catalyze the reaction ADP + CTP <=> ATP + CDP. Therefore, this gene is unrelated to the specified reaction.	No
ENSG00000141698	Q969T7	MAR04056: dTMP + H2O --> Pi + thymidine	ENSG00000014257 or ENSG00000076685 or ENSG00000116981 or ENSG00000122643 or ENSG00000125458 or ENSG00000135318 or ENSG00000141698 or ENSG00000146587 or ENSG00000185013 or ENSG00000205309	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation: According to the text, the gene ENSG00000141698 encodes an enzyme that specifically hydrolyzes 7-methylguanosine monophosphate (m(7)GMP) to 7-methylguanosine and inorganic phosphate, and also has weak activity for CMP. Its catalytic activity is detailed for m(7)GMP, CMP, and general ribonucleoside 5'-phosphates. However, the reaction provided is the hydrolysis of dTMP to Pi and thymidine, which involves thymidine monophosphate (dTMP) rather than any of the substrates specified for the enzyme encoded by this gene. Thus, the reaction involving dTMP is not related to the gene ENSG00000141698.	No Yes
ENSG00000076685	P49902	MAR04056: dTMP + H2O --> Pi + thymidine	ENSG00000014257 or ENSG00000076685 or ENSG00000116981 or ENSG00000122643 or ENSG00000125458 or ENSG00000135318 or ENSG00000141698 or ENSG00000146587 or ENSG00000185013 or ENSG00000205309	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation: The gene ENSG00000076685 encodes a cytosolic 5'-nucleotidase with broad specificity, catalyzing the dephosphorylation of various nucleoside monophosphates such as IMP, GMP, and their deoxy forms, but there is no mention of it catalyzing the dephosphorylation of dTMP to thymidine. The reaction provided describes the conversion of dTMP to thymidine, which is outside the scope of the enzymatic activities specified for this gene. Therefore, the gene and the reaction are not related.	No Yes
ENSG00000125458	Q8TCD5	MAR04177: CMP + H2O --> cytidine + Pi	ENSG00000014257 or ENSG00000076685 or ENSG00000116981 or ENSG00000122643 or ENSG00000125458 or ENSG00000135318 or ENSG00000141698 or ENSG00000146587 or ENSG00000185013 or ENSG00000205309	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation. The annotated function of the gene ENSG00000125458 involves the dephosphorylation of deoxyribonucleotides by removing the phosphate group specifically from dUMP, dTMP, and to a lesser extent from dGMP, dCMP, and dAMP. However, the reaction provided describes the conversion of CMP to cytidine and Pi (inorganic phosphate), which involves dephosphorylation of a ribonucleotide CMP, not a deoxyribonucleotide. Therefore, the gene's function does not match the described reaction.	No
ENSG00000205309	Q9NPB1	MAR04177: CMP + H2O --> cytidine + Pi	ENSG00000014257 or ENSG00000076685 or ENSG00000116981 or ENSG00000122643 or ENSG00000125458 or ENSG00000135318 or ENSG00000141698 or ENSG00000146587 or ENSG00000185013 or ENSG00000205309	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation. The gene ENSG00000205309 dephosphorylates specifically the 5' and 2'(3')-phosphates of uracil and thymine deoxyribonucleotides and protects mitochondrial DNA replication from excess dTTP. It has only marginal activity towards dIMP and dGMP. The reaction provided involves CMP and the conversion to cytidine and Pi, which is unrelated to the specified activity of the gene.	No
ENSG00000205309	Q9NPB1	MAR04179: CMP + H2O --> cytidine + Pi	ENSG00000014257 or ENSG00000076685 or ENSG00000116981 or ENSG00000122643 or ENSG00000125458 or ENSG00000135318 or ENSG00000141698 or ENSG00000146587 or ENSG00000185013 or ENSG00000205309	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation. The gene ENSG00000205309 encodes for an enzyme that specifically dephosphorylates the 5' and 2'(3')-phosphates of uracil and thymine deoxyribonucleotides, protecting mitochondrial DNA replication from excess dTTP. It has little activity towards dIMP and dGMP. However, the reaction described involves the conversion of CMP to cytidine and Pi, which does not align with the enzyme's function because CMP is a cytidine monophosphate nucleotide, not related to uracil or thymine deoxyribonucleotides.	No
ENSG00000141560	Q9HA64	MAR04182: cytidine + GTP --> CMP + GDP + H+	ENSG00000116199 or ENSG00000141560 or ENSG00000162408 or ENSG00000167363 or ENSG00000172456	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation: The gene ENSG00000141560 encodes for ketosamine-3-kinase, which is involved in protein deglycation by phosphorylating ribuloselysine and psicoselysine on glycated proteins. However, the reaction described (cytidine + GTP --> CMP + GDP + H+) involves cytidine and GTP, molecules not related to the function of ketosamine-3-kinase. Therefore, the gene and the reaction are not connected.	No
ENSG00000172456	Q96C11	MAR04182: cytidine + GTP --> CMP + GDP + H+	ENSG00000116199 or ENSG00000141560 or ENSG00000162408 or ENSG00000167363 or ENSG00000172456	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation. The gene ENSG00000172456 encodes a protein that catalyzes the ATP-dependent phosphorylation of D-ribulose at C-5 to form D-ribulose 5-phosphate, which is related to a metabolite repair mechanism or regulating D-ribulose 5-phosphate recycling in the pentose phosphate pathway. However, the reaction provided involves cytidine and GTP producing CMP, GDP, and H+, which does not align with the gene's function and catalytic activity specified above.	No
ENSG00000167363	Q9H479	MAR04182: cytidine + GTP --> CMP + GDP + H+	ENSG00000116199 or ENSG00000141560 or ENSG00000162408 or ENSG00000167363 or ENSG00000172456	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation. The gene ENSG00000167363 encodes for fructosamine-3-kinase, which is involved in the phosphorylation of fructoselysine residues on glycated proteins, generating fructoselysine-3 phosphate, and is also capable of phosphorylating psicosamines and ribulosamines. The annotated reactions involving this gene include those catalyzing the conversion of ATP and N(6)-(D-fructosyl)-L-lysyl-[protein], ATP and N(6)-D-ribulosyl-L-lysyl-[protein], and ATP and N(6)-(D-psicosyl)-L-lysyl-[protein], resulting in corresponding phosphorylated products and ADP. However, the provided reaction "cytidine + GTP --> CMP + GDP + H+" does not align with the enzymatic functions of fructosamine-3-kinase, as it involves different substrates and products unrelated to the activities of the gene's encoded protein.	No
ENSG00000162408	Q5SY16	MAR04182: cytidine + GTP --> CMP + GDP + H+	ENSG00000116199 or ENSG00000141560 or ENSG00000162408 or ENSG00000167363 or ENSG00000172456	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation: The gene ENSG00000162408 encodes a polynucleotide kinase involved in phosphorylating the 5'-hydroxyl groups of RNA and DNA substrates, specifically required for rRNA processing and pre-rRNA processing of internal transcribed spacer 2 (ITS2). It does not participate in the reaction cytidine + GTP --> CMP + GDP + H+, which describes a different catalytic activity not associated with this gene.	No
ENSG00000188833	Q5MY95	MAR04192: CTP + H2O --> CDP + H+ + Pi	ENSG00000138185 or ENSG00000168032 or ENSG00000188833	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation. The gene ENSG00000188833 encodes for Canalicular ectonucleoside NTPDase, which hydrolyzes gamma- and beta-phosphate residues of nucleotides such as ATP, ADP, UTP, and UDP. However, the provided reaction describes the hydrolysis of CTP to CDP, H+, and Pi, which is not mentioned as a substrate for the enzyme encoded by ENSG00000188833. Thus, the gene and the reaction are not related.	Yes, CTP belongs to nucleotides
ENSG00000141698	Q969T7	MAR04484: dTMP + H2O --> Pi + thymidine	ENSG00000014257 or ENSG00000076685 or ENSG00000116981 or ENSG00000122643 or ENSG00000125458 or ENSG00000135318 or ENSG00000141698 or ENSG00000146587 or ENSG00000185013 or ENSG00000205309	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation: The gene ENSG00000141698 encodes an enzyme specifically hydrolyzing 7-methylguanosine monophosphate (m(7)GMP) to 7-methylguanosine and inorganic phosphate, with weak activity for CMP, and poor activity toward UMP and purine nucleotides. However, the given reaction involves the hydrolysis of dTMP (deoxythymidine monophosphate) to form thymidine and inorganic phosphate. There is no documented catalytic activity of the encoded enzyme related to dTMP hydrolysis, making the gene irrelevant to the provided reaction.	No
ENSG00000116981	Q9BXI3	MAR04484: dTMP + H2O --> Pi + thymidine	ENSG00000014257 or ENSG00000076685 or ENSG00000116981 or ENSG00000122643 or ENSG00000125458 or ENSG00000135318 or ENSG00000141698 or ENSG00000146587 or ENSG00000185013 or ENSG00000205309	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation. The gene ENSG00000116981 encodes an enzyme that hydrolyzes ribonucleotide and deoxyribonucleotide monophosphates, with known substrates including AMP, dCMP, and IMP. However, the provided reaction involves the hydrolysis of dTMP to produce phosphate (Pi) and thymidine, which is not mentioned as a substrate or specific reaction in the gene's known catalytic activities. Therefore, the gene does not relate to the reaction involving dTMP.	No
ENSG00000076685	P49902	MAR04484: dTMP + H2O --> Pi + thymidine	ENSG00000014257 or ENSG00000076685 or ENSG00000116981 or ENSG00000122643 or ENSG00000125458 or ENSG00000135318 or ENSG00000141698 or ENSG00000146587 or ENSG00000185013 or ENSG00000205309	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation: The gene ENSG00000076685 encodes for a broad specificity cytosolic 5'-nucleotidase involved in the dephosphorylation of 6-hydroxypurine nucleoside 5'-monophosphates and the transfer of phosphates between nucleosides. The reactions catalyzed by this enzyme, as detailed in the annotation, involve substrates such as IMP, GMP, inosine, deoxyinosine, guanosine, and others related to purine and some pyrimidine nucleotides. However, the provided reaction involves the hydrolysis of dTMP (thymidine monophosphate) to produce Pi (inorganic phosphate) and thymidine. There is no evidence from the provided annotations that the gene or its encoded enzyme is involved in the specific dephosphorylation of dTMP, thus making it irrelevant to the given reaction.	No
ENSG00000205309	Q9NPB1	MAR04510: dCMP + H2O --> deoxycytidine + Pi	ENSG00000014257 or ENSG00000076685 or ENSG00000116981 or ENSG00000122643 or ENSG00000125458 or ENSG00000135318 or ENSG00000141698 or ENSG00000146587 or ENSG00000185013 or ENSG00000205309	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation: The gene ENSG00000205309 encodes an enzyme that specifically dephosphorylates the 5' and 2'(3')-phosphates of uracil and thymine deoxyribonucleotides, protecting mitochondrial DNA replication from excess dTTP. The provided reaction involves the hydrolysis of dCMP to deoxycytidine and Pi, which is not relevant to the enzyme's function of dephosphorylating uracil and thymine deoxyribonucleotides. Therefore, the enzyme encoded by ENSG00000205309 does not catalyze the given reaction.	No
ENSG00000125877	Q9BY32	MAR04643: dUTP + H2O --> dUMP + H+ + PPi	ENSG00000125877 or ENSG00000128951	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation: The gene ENSG00000125877 encodes a pyrophosphatase that hydrolyzes non-canonical purine nucleotides (ITP, dITP, dHAPTP, XTP) into their monophosphate derivatives to prevent their incorporation into RNA and DNA. However, the reaction provided involves the hydrolysis of dUTP to dUMP, which is not listed among the substrates of the encoded enzyme. Hence, the gene is not linked to the provided reaction.	No
ENSG00000130717	Q9HA47	MAR04676: cytidine + dUTP --> CMP + dUDP + H+	ENSG00000130717 or ENSG00000143179 or ENSG00000198276	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation: The gene ENSG00000130717 encodes an enzyme that phosphorylates uridine and cytidine to uridine monophosphate (UMP) and cytidine monophosphate (CMP) using ATP or GTP as phosphate donors. It does not involve deoxyribonucleosides. The reaction provided, "cytidine + dUTP --> CMP + dUDP + H+," involves dUTP (a deoxyribonucleoside triphosphate) which is not a substrate for the enzyme encoded by this gene. Therefore, the gene and the reaction are not related.	No
ENSG00000188833	Q5MY95	MAR02124: dTDP + H2O <=> dTMP + H+ + Pi	ENSG00000138185 or ENSG00000168032 or ENSG00000188833	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation: The gene ENSG00000188833 encodes a canalicular ectonucleoside NTPDase which catalyzes the hydrolysis of gamma- and beta-phosphate residues of nucleotides with activity towards ATP, ADP, UTP, and UDP, leading to the formation of ribonucleoside 5'-phosphate. However, the provided reaction involves the conversion of dTDP to dTMP, H+, and Pi, which is not within the specified substrate range (ATP, ADP, UTP, UDP) or the products of the NTPDase activity described for this gene.	No Yes
ENSG00000188833	Q5MY95	MAR02125: dTTP + H2O <=> dTDP + H+ + Pi	ENSG00000138185 or ENSG00000168032 or ENSG00000188833	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation: The gene ENSG00000188833 encodes for a canalicular ectonucleoside NTPDase, which catalyzes the hydrolysis of gamma- and beta-phosphate residues of nucleotides such as ATP, ADP, UTP, and UDP, but not AMP. The provided reaction involves the hydrolysis of dTTP to dTDP, which is not within the substrate specificity of the gene's product. Therefore, the annotated function and catalytic activity of this gene do not align with the provided reaction.	No Yes
ENSG00000146587	Q9NYW8	MAR04177: CMP + H2O --> cytidine + Pi	ENSG00000014257 or ENSG00000076685 or ENSG00000116981 or ENSG00000122643 or ENSG00000125458 or ENSG00000135318 or ENSG00000141698 or ENSG00000146587 or ENSG00000185013 or ENSG00000205309	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation: The gene ENSG00000146587 encodes a protein that may repress E2F-dependent transcription and promote AR-dependent transcription. However, it does not have any specified catalytic activity and thus cannot catalyze the reaction CMP + H2O --> cytidine + Pi. Therefore, there is no relationship between the gene and the reaction.	No
ENSG00000116199	O75063	MAR04182: cytidine + GTP --> CMP + GDP + H+	ENSG00000116199 or ENSG00000141560 or ENSG00000162408 or ENSG00000167363 or ENSG00000172456	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation: The gene ENSG00000116199 encodes a protein responsible for the 2-O-phosphorylation of xylose in the glycosaminoglycan-protein linkage region of proteoglycans. Its catalytic activity involves the reaction of a specific protein-linked serine residue with ATP to produce a phosphorylated xylose derivative, ADP, and H+. In contrast, the reaction provided involves the conversion of cytidine and GTP to CMP, GDP, and H+, which is unrelated to the function and catalytic activity of the gene described.	No
ENSG00000092964	Q16555	MAR04346: 5,6-Dihydrouracil + H2O --> 3-ureidopropionate + H+	ENSG00000092964 or ENSG00000147647	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation: The gene ENSG00000092964 is involved in neuronal development, axon growth, and signaling, and has no known catalytic activity related to the hydrolysis of 5,6-Dihydrouracil to 3-ureidopropionate. The provided function does not indicate any involvement in the specified reaction.	No
ENSG00000146587	Q9NYW8	MAR04484: dTMP + H2O --> Pi + thymidine	ENSG00000014257 or ENSG00000076685 or ENSG00000116981 or ENSG00000122643 or ENSG00000125458 or ENSG00000135318 or ENSG00000141698 or ENSG00000146587 or ENSG00000185013 or ENSG00000205309	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation. The gene ENSG00000146587 is described to potentially repress E2F-dependent transcription and promote AR-dependent transcription. The reaction, however, involves the hydrolysis of dTMP to produce Pi and thymidine, a biochemical process that does not align with the described functions of the gene, which lack any catalytic activity or involvement in nucleotide metabolism.	No
ENSG00000167900	P04183	MAR06623: deoxyuridine + dGTP --> dGDP + dUMP + H+	ENSG00000167900	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation. The gene ENSG00000167900 encodes an enzyme involved in nucleotide metabolism, specifically in the conversion of thymidine into thymidine monophosphate (dTMP) as part of the salvage pathway. The described reaction for this gene involves ATP and thymidine, producing ADP, dTMP, and H+. Conversely, the unrelated reaction provided involves deoxyuridine and dGTP, producing dGDP, dUMP, and H+, with no overlap in substrates or products with the enzyme's known activity.	No
ENSG00000143156	Q9Y5B8	MAR04030: ADP + CTP <=> ATP + CDP	ENSG00000103024 or ENSG00000103202 or ENSG00000143156 or ENSG00000172113 or ENSG00000239672 or ENSG00000243678	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation. Based on the annotation, the gene ENSG00000143156 possesses intrinsic kinase and 3'-5' exonuclease activities, with a role in microtubule organization and motile cilia function. However, the reaction involves nucleoside diphosphate kinase activity, which the gene does not exhibit according to the provided annotations. Therefore, the gene and the reaction are not related.	No
ENSG00000154269	O14638	MAR04127: H2O + UDP-glucose --> glucose-1-phosphate + 2.0 H+ + UMP	ENSG00000154269 or ENSG00000183828 or ENSG00000197594	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation: The gene ENSG00000154269 codes for a hydrolase enzyme that metabolizes extracellular nucleotides but does not show any activity related to the conversion of UDP-glucose to glucose-1-phosphate and UMP. The enzyme primarily acts on ATP, GTP, UTP, and CTP, and its catalytic activities involve the hydrolysis of nucleotide triphosphates to monophosphates and diphosphates. The provided reaction involves UDP-glucose, which falls outside the substrate specificity of the enzyme encoded by the gene. Therefore, the gene and the reaction are not related.	No
ENSG00000125458	Q8TCD5	MAR04179: CMP + H2O --> cytidine + Pi	ENSG00000014257 or ENSG00000076685 or ENSG00000116981 or ENSG00000122643 or ENSG00000125458 or ENSG00000135318 or ENSG00000141698 or ENSG00000146587 or ENSG00000185013 or ENSG00000205309	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation: The gene ENSG00000125458 encodes an enzyme that dephosphorylates deoxyribonucleotides, specifically showing a preference for dUMP and dTMP. However, the reaction described (CMP + H2O --> cytidine + Pi) involves the dephosphorylation of CMP, which is a ribonucleotide, not a deoxyribonucleotide. The gene's annotated function does not include activity towards ribonucleotides like CMP, thus it is not relevant to the described reaction.	No
ENSG00000125877	Q9BY32	MAR04211: H2O + UTP --> H+ + PPi + UMP	ENSG00000125877	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation. The gene ENSG00000125877 encodes an enzyme that primarily hydrolyzes non-canonical purine nucleotides such as inosine triphosphate (ITP), deoxyinosine triphosphate (dITP), and xanthosine triphosphate (XTP) to their respective monophosphate derivatives. The enzyme¡¯s activity prevents the incorporation of non-canonical purines into RNA and DNA. However, the reaction provided involves the hydrolysis of UTP, a canonical pyrimidine nucleotide, to UMP and pyrophosphate (PPi). Since the gene¡¯s function is specific to non-canonical purines, it does not participate in the reaction involving UTP.	No

[feiranl]

ENSG00000205309 for MAR04177, ENSG00000205309 for MAR04179, ENSG00000167363 for MAR04182, ENSG00000141698 for MAR04484, ENSG00000116981 for MAR04484, ENSG00000076685 for MAR04484, ENSG00000205309 for MAR04510, ENSG00000125877 for MAR04643, ENSG00000143156 for MAR04030 should be removed due to the localization

Keep ENSG00000141698 and ENSG00000076685 for MAR04056 and ENSG00000188833 for MAR02124 and MAR02125 due to the general functions towards other pyrimidines.

[feiranl]

This issue primarily addresses the misannotation of non-metabolic enzymes with metabolic reactions and incorrect compartment localization.

[JHL-452b]

ENSG00000205309 for MAR04177, ENSG00000205309 for MAR04179, ENSG00000167363 for MAR04182, ENSG00000141698 for MAR04484, ENSG00000116981 for MAR04484, ENSG00000076685 for MAR04484, ENSG00000205309 for MAR04510, ENSG00000125877 for MAR04643, ENSG00000143156 for MAR04030 should be removed due to the localization

Agree to remove these genes from their corresponding reactions.

Keep ENSG00000141698 and ENSG00000076685 for MAR04056 and ENSG00000188833 for MAR02124 and MAR02125 due to the general functions towards other pyrimidines.

Agree to remove ENSG00000141698 and ENSG00000076685 for MAR04056. But I think it seems there might be a more reasonable to remove of ENSG00000188833 with MAR02124 and MAR02125. The AI's judgment criterion here is that ENSG00000188833 functions as NTPDase only for nucleotides, not deoxynucleotides (dTTP, dTDP).

[JHL-452b]

Fixed by #932