GPR curation for Acyl-CoA hydrolysis, Acylglycerides metabolism and Nicotinate and nicotinamide metabolism

[JHL-452b]

Current behavior:

17 genes are discovered to be uncorrelated with their corresponding reactions in Acyl-CoA hydrolysis， Acylglycerides metabolism and Nicotinate and nicotinamide metabolism.

Gene	UniProtID	Reaction	GPR	Correlation	Manually check
ENSG00000136881	Q14032	MAR00242: (10Z)-heptadecenoyl-CoA + H2O --> (10Z)-heptadecenoic acid + CoA + H+	ENSG00000184227 or ENSG00000097021 or ENSG00000136881 or ENSG00000112304 or ENSG00000159445	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation. The gene ENSG00000136881 is involved in the amidation of bile acids with amino acids like taurine and glycine, as well as in acyl-CoA thioesterase activities involving long- and very long-chain acyl-CoAs. The provided reaction, which describes the hydrolysis of (10Z)-heptadecenoyl-CoA to (10Z)-heptadecenoic acid, CoA, and H+, does not align with the gene's known functions and catalytic activities. The gene's activities are specific to bile acid conjugation and the hydrolysis of saturated and other specific long-chain acyl-CoAs, while the provided reaction involves an unsaturated fatty acid, which is not mentioned as a substrate for the gene's enzymatic functions.	No Yes, but remove ENSG00000112304.
ENSG00000136881	Q14032	MAR00324: (11Z)-docosenoyl-CoA + H2O --> cis-cetoleic acid + CoA + H+	ENSG00000136881 or ENSG00000205669	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation. The gene ENSG00000136881 primarily catalyzes the amidation of bile acids with glycine and taurine and acts on various long-chain acyl-CoAs. The provided reaction involves the hydrolysis of (11Z)-docosenoyl-CoA to cis-cetoleic acid, which is not specifically mentioned within the multiple catalytic activities of the gene. Hence, there is no direct link between the gene's described functions and the given reaction.	No Yes, replace ENSG00000205669 with ENSG00000159445.
ENSG00000205669	Q3I5F7	MAR00332: H2O + tetracosanoyl-CoA --> CoA + H+ + lignocerate	ENSG00000136881 or ENSG00000205669	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation. The gene ENSG00000205669 catalyzes the hydrolysis of acyl-CoAs such as phytanoyl-CoA and pristanoyl-CoA into free fatty acids and CoASH. However, the reaction provided involves the hydrolysis of tetracosanoyl-CoA to produce lignocerate, which is not mentioned as a substrate for the gene's enzymatic activity. Hence, the gene does not correlate with the provided reaction.	No, replace ENSG00000205669 with ENSG00000159445.
ENSG00000136881	Q14032	MAR00354: (6Z,9Z,12Z,15Z)-octadecatetraenoyl-CoA + H2O --> CoA + H+ + stearidonic acid	ENSG00000184227 or ENSG00000097021 or ENSG00000136881	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation: The gene ENSG00000136881 catalyzes the amidation of bile acids with glycine and taurine and acts as an acyl-CoA thioesterase for long- and very long-chain fatty acids. However, the reaction provided involves (6Z,9Z,12Z,15Z)-octadecatetraenoyl-CoA, which is not mentioned in the catalytic activities of the gene described above. Therefore, the gene is not related to the provided reaction.	No Yes, add ENSG00000159445
ENSG00000177465	Q8N9L9	MAR03009: H2O + propanoyl-CoA --> CoA + H+ + propanoate	ENSG00000101473 or ENSG00000177465	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation. The gene ENSG00000177465 encodes a protein that catalyzes the hydrolysis of various acyl-CoAs into free fatty acids and coenzyme A (CoASH), specifically including succinyl-CoA, glutaryl-CoA, hexadecanoyl-CoA, octadecenoyl-CoA, octadecadienoyl-CoA, eicosatetraenoyl-CoA, decanoyl-CoA, dodecanoyl-CoA, tetradecanoyl-CoA, octadecanoyl-CoA, and eicosanoyl-CoA. The provided reaction, H2O + propanoyl-CoA --> CoA + H+ + propanoate, involves the hydrolysis of propanoyl-CoA, which is not mentioned as a substrate for the enzyme encoded by the gene. Consequently, there is no direct association between the gene and the specified reaction.	Yes No, replace ENSG00000177465 and ENSG00000101473 with ENSG00000172497 and ENSG00000159445
ENSG00000136881	Q14032	MAR00210: 5-tetradecenoyl-CoA + H2O --> CoA + H+ + physeteric acid	ENSG00000184227 or ENSG00000097021 or ENSG00000136881 or ENSG00000112304 or ENSG00000159445	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation: The gene ENSG00000136881 encodes for an enzyme that catalyzes the amidation of bile acids (BAs) with amino acids taurine and glycine, as well as the hydrolysis and conjugation of various long-chain acyl-CoAs. The reaction provided involves the conversion of 5-tetradecenoyl-CoA to CoA, H+, and physeteric acid, which is not related to the amidation of bile acids or the hydrolysis and conjugation activities described for this gene. Thus, there is no direct connection between the gene's functions and the specified reaction.	No Yes, remove ENSG00000112304.
ENSG00000136881	Q14032	MAR00426: (4Z,7Z,10Z,13Z,16Z)-docosapentaenoyl-CoA + H2O --> (4Z,7Z,10Z,13Z,16Z)-DPA + CoA + H+	ENSG00000136881 or ENSG00000205669	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation: The gene ENSG00000136881 encodes an enzyme that catalyzes the amidation of bile acids with taurine and glycine, as well as acts as an acyl-CoA thioesterase and conjugates glycine to various acyl-CoAs. However, the reaction provided involves the hydrolysis of (4Z,7Z,10Z,13Z,16Z)-docosapentaenoyl-CoA to produce (4Z,7Z,10Z,13Z,16Z)-DPA, CoA, and H+. This specific hydrolysis reaction is not one of the catalytic activities listed for the enzyme encoded by ENSG00000136881, which focuses on bile acids and various long-chain acyl-CoAs. Thus, the gene is not relevant to the reaction provided.	No Yes, replace ENSG00000205669 with ENSG00000159445
ENSG00000136881	Q14032	MAR00438: 10,13,16-docosatrienoyl-CoA + H2O --> 10,13,16-docosatriynoic acid + CoA + H+	ENSG00000136881 or ENSG00000205669	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation. The gene ENSG00000136881 is involved in catalyzing the amidation of bile acids with taurine and glycine, as well as acting as an acyl-CoA thioesterase that hydrolyzes long-chain acyl-CoAs to free fatty acids and CoA. The reaction provided, on the other hand, pertains to the hydrolysis of 10,13,16-docosatrienoyl-CoA to yield 10,13,16-docosatriynoic acid, CoA, and a proton. This specific reaction is not mentioned among the catalytic activities associated with the gene ENSG00000136881, making it unrelated.	No Yes, replace ENSG00000205669 with ENSG00000159445.
ENSG00000187021	P54315	MAR00665: H2O + TAG-LD pool --> 1,2-diacylglycerol-LD-TAG pool + H+ + fatty acid pool	ENSG00000006757 or ENSG00000079435 or ENSG00000100344 or ENSG00000101670 or ENSG00000114771 or ENSG00000134780 or ENSG00000164535 or ENSG00000166035 or ENSG00000170835 or ENSG00000175535 or ENSG00000177666 or ENSG00000182333 or ENSG00000187021 or ENSG00000203837 or ENSG00000266200	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation: According to the annotation, the gene ENSG00000187021 may function as an inhibitor of dietary triglyceride digestion and lacks detectable lipase activity towards various substrates such as triglycerides, diglycerides, phosphatidylcholine, galactolipids, or cholesterol esters. The provided reaction involves the hydrolysis of triglycerides (TAG) into 1,2-diacylglycerol, H+, and fatty acids, which is a lipase-mediated process. Since the gene lacks lipase activity, it cannot catalyze the reaction, making it unrelated.	Yes
ENSG00000187021	P54315	MAR00668: 1,2-diacylglycerol-LD-PI pool + H2O --> 1-acylglycerol-LD-PI pool + H+ + fatty acid pool	ENSG00000006757 or ENSG00000079435 or ENSG00000100344 or ENSG00000101670 or ENSG00000114771 or ENSG00000134780 or ENSG00000164535 or ENSG00000166035 or ENSG00000170835 or ENSG00000175535 or ENSG00000177666 or ENSG00000182333 or ENSG00000187021 or ENSG00000203837 or ENSG00000266200	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation: The gene ENSG00000187021 is described as potentially inhibiting dietary triglyceride digestion but does not exhibit detectable lipase activity towards various lipid substrates, including triglycerides, diglycerides, phosphatidylcholine, galactolipids, or cholesterol esters. The reaction given involves the conversion of 1,2-diacylglycerol to 1-acylglycerol with the release of a fatty acid, suggesting a hydrolytic activity on diacylglycerols, which the gene product lacks. Therefore, there is no direct functional or catalytic relation between the gene and the specified reaction.	Yes
ENSG00000205309	Q9NPB1	MAR04252: H2O + nicotinate ribonucleotide --> nicotinate D-ribonucleoside + 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 codes for an enzyme that dephosphorylates specifically the 5' and 2'(3')-phosphates of uracil and thymine deoxyribonucleotides, and has marginal activity towards dIMP and dGMP. The provided reaction involves the conversion of nicotinate ribonucleotide into nicotinate D-ribonucleoside and Pi, which does not fall within the specific substrates or activities described for the gene product.	No
ENSG00000076685	P49902	MAR04252: H2O + nicotinate ribonucleotide --> nicotinate D-ribonucleoside + 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 ENSG00000076685 encodes an enzyme with broad specificity nucleotidase and phosphotransferase activities, primarily involved in the dephosphorylation of purine nucleoside 5'-monophosphates and transferring phosphates between nucleosides. The gene's annotated functions and catalytic activities involve substrates such as IMP, GMP, XMP, inosine, and other nucleotides, but there is no mention of its involvement in the reaction "H2O + nicotinate ribonucleotide --> nicotinate D-ribonucleoside + Pi." Therefore, the gene is not relevant to the reaction provided.	No
ENSG00000205309	Q9NPB1	MAR04264: H2O + nicotinamide D-ribonucleotide --> nicotinamide ribonucleoside + Pi	ENSG00000014257 or ENSG00000076685 or ENSG00000116981 or ENSG00000122643 or ENSG00000125458 or ENSG00000135318 or ENSG00000141698 or ENSG00000185013 or ENSG00000205309	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation: The gene ENSG00000205309 encodes a protein that specifically dephosphorylates the 5' and 2'(3')-phosphates of uracil and thymine deoxyribonucleotides, protecting mitochondrial DNA replication from excess dTTP. The reaction provided involves the conversion of nicotinamide D-ribonucleotide to nicotinamide ribonucleoside and phosphate, which is unrelated to the function of this gene. Therefore, the gene is not relevant to the reaction.	No
ENSG00000076685	P49902	MAR04264: H2O + nicotinamide D-ribonucleotide --> nicotinamide ribonucleoside + Pi	ENSG00000014257 or ENSG00000076685 or ENSG00000116981 or ENSG00000122643 or ENSG00000125458 or ENSG00000135318 or ENSG00000141698 or ENSG00000185013 or ENSG00000205309	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation. The function of the gene ENSG00000076685 is primarily related to the dephosphorylation of 6-hydroxypurine nucleoside 5'-monophosphates and other related functions involving purine and pyrimidine nucleosides and nucleotides. However, the reaction provided involves the conversion of nicotinamide D-ribonucleotide to nicotinamide ribonucleoside and phosphate, which does not pertain to purine or pyrimidine nucleotides, thereby making the gene not relevant to this specific reaction.	No
ENSG00000162836	Q9NPH0	MAR04270: H2O + NADP+ --> NAD+ + Pi	ENSG00000014257 or ENSG00000102575 or ENSG00000142513 or ENSG00000155893 or ENSG00000162836 or ENSG00000183760	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation. The gene ENSG00000162836 encodes a protein that hydrolyzes lysophosphatidic acid (LPA) to monoacylglycerol and phosphate, with specific fatty acid chain preferences indicated. The provided reaction, H2O + NADP+ --> NAD+ + Pi, does not involve LPA or similar substrates. Therefore, the enzyme activity of the gene product does not match the reaction given.	No
ENSG00000198805	P00491	MAR04662: nicotinate D-ribonucleoside + Pi --> H+ + nicotinate + ribose-1-phosphate	ENSG00000198805	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation. The gene ENSG00000198805 catalyzes the phosphorolytic breakdown of beta-(deoxy)ribonucleoside molecules, preferentially acting on 6-oxopurine nucleosides including inosine and guanosine, resulting in the formation of free purine bases and pentose-1-phosphate. The reactions include the conversion of inosine and guanosine to alpha-D-ribose 1-phosphate and hypoxanthine or guanine, and the conversion of their deoxy forms to 2-deoxy-alpha-D-ribose 1-phosphate and hypoxanthine or guanine. However, the provided reaction involves nicotinate D-ribonucleoside and does not match any of the gene's annotated catalytic activities. Therefore, the gene is not relevant to the reaction provided.	No
ENSG00000109743	Q10588	MAR08788: H2O + NADP+ --> ADP-ribose-2-phosphate + H+ + nicotinamide	ENSG00000004468 or ENSG00000109743	Pending No, the gene is not relevant to the reaction provided. Analysis and explanation. The gene ENSG00000109743 encodes an enzyme that catalyzes the conversion of NAD(+) to cyclic ADP-beta-D-ribose (cADPR) and its hydrolysis to ADP-D-ribose (ADPR). However, the reaction provided describes the hydrolysis of NADP(+) to produce ADP-ribose-2-phosphate, H(+), and nicotinamide, which is not among the reactions catalyzed by the enzyme encoded by this gene according to the provided annotations. Therefore, the gene does not relate to the specific catalytic activity described in the reaction.	No

[Devlin-Moyer]

The AI is wrong about ENSG00000136881 (BAAT) being unable to catalyze MAR00210, MAR00242, MAR00324, MAR00354, MAR00426, and MAR00438; this paper showed that BAAT is capable of acting on unsaturated acyl-CoAs (figure 3), and BAAT is known to be localized to the cytosol, where all of those reactions occur.

The AI is right about ENSG00000205669 (ACOT6) being unable to catalyze MAR00332, but for the wrong reason: ACOT6 is not known to be catalytically active, so it shouldn't be associated with any reactions, which also includes MAR00324, MAR00426, and MAR00438.

The AI is right about ENSG00000177465 (ACOT4) being unable to catalyze MAR03009, but for the wrong reason: ACOT4 is peroxisomal (source), while MAR03009 occurs in the cytosol. ENSG00000101473 (ACOT8) shouldn't be associated with MAR03009 either; it's localized to mitochondria or peroxiomes but not the cytosol (source). Appropriate genes to associate with this reaction would be ENSG00000172497 (ACOT12) (source) and ENSG00000159445 (THEM4) (source). THEM4 is capable of hydrolyzing most acyl-CoAs, so it could also be associated with MAR00324, MAR00332, MAR00354, MAR00426, and MAR00438.

ENSG00000112304 (ACOT13 or THEM2) may not be appropriate to associate with MAR00210 or MAR00242, as this paper found that it was primarily active against aromatic acyl-CoAs, not aliphatic ones like heptadecenoic acid. All of the other genes associated with MAR00210 and MAR00242 seem appropriate.

To summarize:

• MAR00242: maybe remove ENSG00000112304, keep the rest
• MAR00324: keep ENSG00000136881 but replace ENSG00000205669 with ENSG00000159445
• MAR00332: keep ENSG00000136881 but replace ENSG00000205669 with ENSG00000159445
• MAR00354: add ENSG00000159445, keep the rest
• MAR03009: replace ENSG00000177465 and ENSG00000101473 with ENSG00000172497 and ENSG00000159445
• MAR00210: maybe remove ENSG00000112304, keep the rest
• MAR00426: keep ENSG00000136881 but replace ENSG00000205669 with ENSG00000159445
• MAR00438: keep ENSG00000136881 but replace ENSG00000205669 with ENSG00000159445

[JHL-452b]

Agree with your investigation. And I will go head with this issue.