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SysBioChalmers / Human-GEM

The generic genome-scale metabolic model of Homo sapiens
https://sysbiochalmers.github.io/Human-GEM-guide/
Creative Commons Attribution 4.0 International
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remove non-metabolic gene from Phenylalanine, tyrosine and tryptophan biosynthesis #471

Closed feiranl closed 1 year ago

feiranl commented 1 year ago

Description of the issue:

gene Reasons Subsystems RxnIDs
ENSG00000059588 remove, substrates should be tRNA Phenylalanine, tyrosine and tryptophan biosynthesis MAR06710;MAR06737
ENSG00000145331 remove, substrates should be tRNA Phenylalanine, tyrosine and tryptophan biosynthesis MAR06710;MAR06737
ENSG00000146834 remove, no enough supporting evidence Phenylalanine, tyrosine and tryptophan biosynthesis MAR06710;MAR06737
ENSG00000162851 remove, substrate is rRNA Phenylalanine, tyrosine and tryptophan biosynthesis MAR06710;MAR06737
ENSG00000250305 remove, substrate is tRNAs Phenylalanine, tyrosine and tryptophan biosynthesis MAR06710;MAR06737

Current feature/value/output:

Expected feature/value/output:

I hereby confirm that I have:

haowang-bioinfo commented 1 year ago

The high number of isoenzymes in GPR rules of these two reactions (MAR06710 and MAR06737) appears to be suspicious.

feiranl commented 1 year ago

Maybe there are still some of them are related to RNA modification rather than the amino acid synthesis. I can double check all of them.

JonathanRob commented 1 year ago

Since the reactions are methylations, a lot of the isozymes are probably different types of methyltransferases. So it is a bit similar to the issue of the generic phosphorylation reaction having all the kinases associated with it. Maybe only a subset of these actually catalyze the reactions involving these specific substrates, and the others could be removed, but I'm not sure.

haowang-bioinfo commented 1 year ago

Since the reactions are methylations, a lot of the isozymes are probably different types of methyltransferases. So it is a bit similar to the issue of the generic phosphorylation reaction having all the kinases associated with it. Maybe only a subset of these actually catalyze the reactions involving these specific substrates

it does appear so - many are methyltransferases catalyzing other substrates than beta-carboline or salsolinol

Maybe there are still some of them are related to RNA modification rather than the amino acid synthesis. I can double check all of them.

sounds good, will also test with GPT model

feiranl commented 1 year ago

The high number of isoenzymes in GPR rules of these two reactions (MAR06710 and MAR06737) appears to be suspicious.

After GPT check and manual check, all genes are actually not associated with these two reactions. GeneID GPT substrate answer Manual check Comment
ENSG00000170439 The substrates of this enzyme are hydrogen sulfide and other thiol compounds including dithiothreitol, 7alpha-thiospironolactone, L-penicillamine, and captopril. thiol related change substrate
ENSG00000101247 The substrates of this enzyme are Arg-111 of NDUFS7 and possibly methyltransferase. May also have methyltransferase activity not sure
ENSG00000010165 The substrates of this enzyme are EEF1A1 and EEF1A2. therefore involved in the regulation of mRNA translation remove
ENSG00000029639 The substrates of this enzyme are S-adenosyl-L-methionine and mitochondrial 12S rRNA. dimethylates mitochondrial 12S rRNA remove
ENSG00000059588 The substrates of this enzyme are S-adenosyl-L-methionine and HIV-1 TAR RNA. should be rna remove
ENSG00000066651 An enzyme responsible for methylating a guanosine nucleotide at position 10 (m2G10) on tRNAs. The substrate of the enzyme is a guanosine nucleotide at position 10 (m2G10) on tRNAs. tRNA methyltransferase remove
ENSG00000067365 The substrate of this enzyme is the amino acid lysine (KIN) at position 135. Protein N-lysine methyltransferase remove
ENSG00000068438 The substrates of this enzyme are tRNAs and nucleotides. should be rna remove
ENSG00000071462 Enzyme methylates the N(7) position of a guanine in 18S rRNA; enzyme adapter protein TRM112 helps; enzyme potentiates transactivation by glucocorticoid, mineralocorticoid, androgen, and progesterone receptors; enzyme required for maintenance of dimethylation on histone H3 'Lys-79' (H3K79me2). The substrates of this enzyme are guanine in 18S rRNA, TRM112, glucocorticoid, mineralocorticoid, androgen, progesterone receptors, and histone H3 'Lys-79' (H3K79me2). RNA methyltransferase remove
ENSG00000087995 The enzyme S-adenosyl-L-methionine-dependent methyltransferase methylates N(3)-methylcytidine of residue 32 of tRNA(Thr)(UGU) and tRNA(Arg)(CCU). The substrates of this enzyme are S-adenosyl-L-methionine, tRNA(Thr)(UGU), tRNA(Arg)(CCU), N6-threonylcarbamoylation, and N(3)-methylcytidine. tRNA anticodon loop remove
ENSG00000100462 Arginine methyltransferase The substrates of this enzyme are arginine residues. should be protein according to Uniprot remove
ENSG00000100483 The substrate of this enzyme is Lys-315 of VCP/p97. protein lysine methyltransferase remove
ENSG00000101574 The substrates of this enzyme are RNAs and DNA. methylate both RNAs and DNA remove
ENSG00000103037 The substrates of this enzyme are Lys-310 of the RELA subunit of NF-kappa-B complex, Lys-8 of H2AZ, and PAK4. protein lysine methyltransferase remove
ENSG00000105202 Substrates of this enzyme are RNAs, proteins, U6 snRNAs, and histone H2A. methylate both RNAs and proteins remove
ENSG00000108592 The substrates of this enzyme are 34S pre-rRNA, 18S rRNA, 40S ribosomal subunit, and HIV-1 RNA. act on RNA remove
ENSG00000110871 The substrates of this enzyme are 2-polyprenyl-6-methoxy-1,4-benzoquinol (DDMQH2) and 2-polyprenyl-3-methyl-6-methoxy-1,4-benzoquinol (DMQH2). should consider change rxn to Rhea 28286 change
ENSG00000111218 The enzyme is an S-adenosyl-L-methionine-dependent and membrane-associated arginine methyltransferase that can catalyze the formation of omega-N monomethylarginine (MMA) and asymmetrical dimethylarginine (aDMA) in proteins such as NIFK, myelin basic protein, histone H4, H2A and H2A/H2B dimer. The substrates of this enzyme are S-adenosyl-L-methionine, omega-N monomethylarginine (MMA), asymmetrical dimethylarginine (aDMA), NIFK, myelin basic protein, histone H4, H2A and H2A/H2B dimer, and EWS protein. protein arginine methyltransferase remove
ENSG00000111641 The substrates of this enzyme are S-adenosyl-L-methionine and cytosine 4447 in 28S rRNA. involved in ribosomal assembly remove
ENSG00000114735 The substrate of this enzyme is N5-glutamine and the GGQ motif of the mitochondrial translation release factor MTRF1L. peptide involved remove
ENSG00000117481 The substrates of this enzyme are 5-methylcytosine rRNA and 16S rRNA. RNA involved remove
ENSG00000122435 The substrates of this enzyme are cytidine(4) in tRNA(Pro) and tRNA(Gly)(GCC), and adenosine(4) in tRNA(His). trna involved remove
ENSG00000122687 The substrate of this enzyme is S-adenosyl-L-methionine and the product is 2'-O-methyluridine at position 1369 in the 16S mitochondrial large subunit ribosomal RNA (mtLSU rRNA). RNA involved remove
ENSG00000123427 The substrates of this enzyme are Lys-165 of EEF1A1 and EEF1A2, aminoacyl-tRNA, and GTP. protein involved remove
ENSG00000123600 The substrates of this enzyme are N(3)-methylcytidine, tRNA(Ser)(UCN), tRNA(Thr) and potentially mRNAs. trna involved remove
ENSG00000123600 The substrates of this enzyme are mitochondrial tRNA (Ser)(UCN), tRNA(Thr), and possibly mRNAs. tRNA methyltransferase remove
ENSG00000126457 The substrates of this enzyme are arginyl residues present in proteins such as ESR1, histone H2, H3 and H4, ILF3, HNRNPA1, HNRNPD, NFATC2IP, SUPT5H, TAF15, EWS, HABP4, SERBP1, RBM15, FOXO1, CHTOP and MAP3K5/ASK1. should be protein according to Uniprot remove
ENSG00000126749 Enzyme methylates pseudouridine at position 1248 (Psi1248) in 18S rRNA The substrate of this enzyme is pseudouridine at position 1248 (Psi1248) in 18S rRNA. Ribosomal RNA remove
ENSG00000127804 The substrates of this enzyme are mRNAs, U6 snRNAs, 7SK snRNA, 7SL RNA, and the MALAT1 long non-coding RNA. RNA N6-adenosine-methyltransferase remove
ENSG00000130305 The substrates of this enzyme are S-adenosyl-L-methionine and cytosine 3782. rRNA methyltransferase remove
ENSG00000132275 The substrates of this enzyme are unknown. Ribosomal related remove
ENSG00000132600 The substrates of this enzyme are arginine residues in the small nuclear ribonucleoproteins Sm D1 (SNRPD1) and Sm D3 (SNRPD3), histone H4 'Arg-3', histone H2A, and myelin basic protein (MBP). Protein related remove
ENSG00000137574 The substrates of this enzyme are 7-monomethylguanosine (m7G) caps of snRNAs and snoRNAs. snRNAs and snoRNAs related remove
ENSG00000137760 This enzyme catalyzes the methylation of 5-carboxymethyl uridine to 5-methylcarboxymethyl uridine at the wobble position of the anticodon loop in tRNA. The substrates of this enzyme are 5-carboxymethyl uridine and 5-methylcarboxymethyl uridine. DNA repair protein remove
ENSG00000138382 This enzyme catalyzes the methylation of the 6th position of adenine in position 1832 of 18S rRNA. The substrate of this enzyme is adenine in position 1832 of 18S rRNA. rRNA related remove
ENSG00000139160 The substrates of this enzyme are protein-lysine and flavoprotein ETFB. Protein-lysine methyltransferase remove
ENSG00000139780 The substrates of this enzyme are proteins and lysine. Protein-lysine methyltransferase remove
ENSG00000142453 The substrates of this enzyme are arginyl residues, histone H3 at 'Arg-17', EP300/P300, PABPC1, ELAVL1, ELAV4, ACACA/acetyl-CoA carboxylase and PARP1. protein involved remove
ENSG00000143499 Protein-lysine N-methyltransferase that methylates both histones and non-histone proteins The substrates of this enzyme are histone H3, p53/TP53, RB1, and other non-histone proteins. Protein-lysine N-methyltransferase remove
ENSG00000144401 The substrates of this enzyme are Lys-561 in HSPA1, Lys-564 in HSPA2, Lys-585 in HSPA5, Lys-563 in HSPA6, and Lys-561 in HSPA8. Protein-lysine methyltransferase remove
ENSG00000145194 The substrates of this enzyme are big endothelin-1, neurotensin, angiotensin I, substance P, proenkephalin-derived peptides, and prodynorphin-derived peptides. not related to SAM remove
ENSG00000145331 This enzyme catalyzes the formation of N(1)-methylguanine at position 9 (m1G9) in tRNAs The substrates of this enzyme are S-adenosyl-L-methionine, guanine, and tRNAs. tRNAs related remove
ENSG00000145388 The substrates of this enzyme are N6-methyladenosine (m6A) and mRNAs. mRNAs related remove
ENSG00000146834 The substrates of this enzyme are S-adenosyl-L-methionine, 7SK snRNA, positive transcription elongation factor b (P-TEFb), little elongation complex (LEC), and LARP7. snRNA related remove
ENSG00000150456 The substrate of this enzyme is EEF1A at 'Lys-79'. Protein N-lysine methyltransferase remove
ENSG00000156239 The substrates of this enzyme are proteins, Lys-12 of histone H4, Glu residue of proteins with a Gly-Gln-Xaa-Xaa-Xaa-Arg motif, ETF1 on 'Gln-185', and monomethylarsonous acid (3+). histone related remove
ENSG00000160310 The substrates of this enzyme are arginyl residues in proteins such as STAT3, FBL, and histone H4. protein related remove
ENSG00000162623 S-adenosyl-L-methionine and guanosine tRNA related remove
ENSG00000162851 This enzyme methylates two specific adjacent adenosines in the loop of a conserved hairpin near the 3'-end of 12S mitochondrial rRNA. The substrates of this enzyme are two specific adjacent adenosines in the loop of a conserved hairpin near the 3'-end of 12S mitochondrial rRNA. rRNA methyltransferase remove
ENSG00000164169 The substrates of this enzyme are arginine, omega-N monomethylarginine (MMA), and symmetrical dimethylarginine (sDMA). protein related remove
ENSG00000165055 The substrates of this enzyme are S-adenosyl-L-methionine, N(3)-methylcytidine, residue 32 of tRNA(Thr)(UGU), and tRNA(Arg)(CCU). tRNA related remove
ENSG00000165275 This enzyme catalyzes the formation of N(1)-methylguanine at position 9 (m1G9) in tRNAs. The substrates of this enzyme are S-adenosyl-L-methionine and tRNAs. tRNA methyltransferase remove
ENSG00000165644 The substrates of this enzyme are molecules that contain an O-methyl group. Putative O-methyltransferase remove
ENSG00000165792 The substrates of this enzyme are S-adenosyl-L-methionine and mitochondrial small ribosomal subunit (mt-SSU). RNA methyltransferase remove
ENSG00000168806 Methyltransferase in wybutosine biosynthesis pathway. The substrates of this enzyme are S-adenosyl-L-methionine, leucine residues, and alpha-leucine ester residues. tRNA related remove
ENSG00000169519 The substrates of this enzyme are N4-methylcytidine (m4C) and mitochondrial 12S rRNA. rRNA related remove
ENSG00000171806 Protein-L-histidine N-tele-methyltransferase monomethylates RPL3 to regulate translation elongation. The substrates of this enzyme are Protein-L-histidine and RPL3. protein methyltransferase remove
ENSG00000171861 The substrates of this enzyme are S-adenosyl-L-methionine and Gm1370 in the 16S mitochondrial large subunit ribosomal RNA (mtLSU rRNA). RNA related remove
ENSG00000174173 Substrates of this enzyme are mitochondrial tRNA, MT-ND5 mRNA, and adenosine residues. tRNA related remove
ENSG00000178694 This enzyme mediates methylation of cytosine to 5-methylcytosine (m5C) at position 34 of mt-tRNA(Met). The substrates of this enzyme are cytosine and mt-tRNA(Met). RNA methyltransferase remove
ENSG00000179299 The substrate of this enzyme is S-adenosyl-L-methionine. RNA related remove
ENSG00000180917 This enzyme methylates mRNA and small nuclear RNA (snRNA) Substrates RNA related remove
ENSG00000181038 The substrate of this enzyme is histone H3 at Arg-17. Histone methyltransferase remove
ENSG00000181090 The substrates of this enzyme are histone H3 (H3K9me1 and H3K9me2, H3K27me), p53/TP53 (Lys-373), and mitochondrial function-related genes. Histone methyltransferase remove
ENSG00000183955 The substrates of this enzyme are histone H4, p53/TP53, and nucleosomes. Protein-lysine N-methyltransferase remove
ENSG00000185238 The substrates of this enzyme are proteins with arginine residues. Protein-arginine N-methyltransferase remove
ENSG00000185432 The substrates of this enzyme are likely involved in the assembly and release stages of hepatitis C virus (HCV). not related remove
ENSG00000186666 O-methyltransferase that specifically monomethylates the 5'-monophosphate of cytoplasmic histidyl tRNA (tRNA(His)) and pre-miRNAs. The substrates of this enzyme are the 5'-monophosphate of cytoplasmic histidyl tRNA (tRNA(His)) and pre-miRNAs. RNA 5'-monophosphate methyltransferase remove
ENSG00000188573 The substrates of this enzyme are S-adenosyl-L-methionine, pre-ribosomal RNA, and proteins containing glutamine residues. both RNAs and proteins remove
ENSG00000198890 The substrates of this enzyme are arginyl residues, histone H3 'Arg-2', H2A and H4 'Arg-3', HMGA1, POLB, CRTC2, GPS2, and SIRT7. Protein related remove
ENSG00000203791 The substrate of this enzyme is EEF1A at 'Lys-318'. Protein-lysine methyltransferase remove
ENSG00000204371 The substrates of this enzyme are Histone methyltransferase remove
ENSG00000205629 The substrate of this enzyme is the carboxyl group of the C-terminal leucine residue of protein phosphatase 2A catalytic subunits. Protein related remove
ENSG00000206562 S-adenosyl-L-methionine-dependent methyltransferase that methylates residue 32 of the tRNA anticodon loop The substrates of this enzyme are S-adenosyl-L-methionine and residue 32 of the tRNA anticodon loop. tRNA related remove
ENSG00000214756 Protein-lysine methyltransferase that trimethylates citrate synthase. The substrate of this enzyme is protein-lysine and citrate synthase. Protein-lysine methyltransferase remove
ENSG00000241058 S-adenosyl-L-methionine-dependent methyltransferase that specifically methylates the C5 position of cytosine 72 in tRNA(Thr)(TGT) and tRNA(Cys)(GCA). The substrates of this enzyme are tRNA(Thr)(TGT), tRNA(Cys)(GCA), and tRNA(Thr)(AGT). RNA methyltransferase 6 remove
ENSG00000250305 The substrates of this enzyme are specific arginine and glutamic acid tRNAs with wobble uridines. tRNA methyltransferase remove
ENSG00000278619 The substrates of this enzyme are S-adenosyl-L-methionine and Gm1145 in the 16S mitochondrial large subunit ribosomal RNA (mtLSU rRNA). rRNA methyltransferase 1 remove
haowang-bioinfo commented 1 year ago

@feiranl nice results! Good correlation between manual curation and GPT curation could be observed.

haowang-bioinfo commented 1 year ago

After GPT check and manual check, all genes are actually not associated with these two reactions.

Both manual and GPT curations showed that all genes of MAR06710 and MAR06737 (they have identical GPRs) encode methytransferases for substrates of DNAs, RNAs, or proteins. None of them are found with substrates beta-carboline or salsolinol.

There could be two follow-up implementation options: 1) remove all these genes, as well as two reactions; 2) remove these genes, but retain the two reactions as blank GPR rules, assuming that proper enzyme encoding genes can be found later

Given their distribution as dead-end reactions in the network, I lean toward the option 1.

haowang-bioinfo commented 1 year ago

The two reactions (MAR06710 and MAR06737) have identical GPRs and each has 72 genes, 65 of which just get involve in these two reactions.

ENSG00000132275: MAR06710, MAR06737
ENSG00000165275: MAR06710, MAR06737
ENSG00000143499: MAR06710, MAR06737
ENSG00000278619: MAR06710, MAR06737
ENSG00000132600: MAR06710, MAR06737
ENSG00000241058: MAR06710, MAR06737
ENSG00000160310: MAR06710, MAR06737
ENSG00000205629: MAR06710, MAR06737
ENSG00000188573: MAR06710, MAR06737
ENSG00000071462: MAR06710, MAR06737
ENSG00000165644: MAR06710, MAR06737
ENSG00000138382: MAR06710, MAR06737
ENSG00000180917: MAR06710, MAR06737
ENSG00000206562: MAR06710, MAR06737
ENSG00000101247: MAR06710, MAR06737
ENSG00000130305: MAR06710, MAR06737
ENSG00000181038: MAR06710, MAR06737
ENSG00000170439: MAR06710, MAR06737
ENSG00000165792: MAR06710, MAR06737
ENSG00000185238: MAR06710, MAR06737
ENSG00000111218: MAR06710, MAR06737
ENSG00000185432: MAR06710, MAR06737
ENSG00000101574: MAR06710, MAR06737
ENSG00000144401: MAR06710, MAR06737
ENSG00000114735: MAR06710, MAR06737
ENSG00000164169: MAR06710, MAR06737
ENSG00000111641: MAR06710, MAR06737
ENSG00000117481: MAR06710, MAR06737
ENSG00000126457: MAR06710, MAR06737
ENSG00000122435: MAR06710, MAR06737
ENSG00000126749: MAR06710, MAR06737
ENSG00000029639: MAR06710, MAR06737
ENSG00000145194: MAR06710, MAR06737
ENSG00000122687: MAR06710, MAR06737
ENSG00000214756: MAR06710, MAR06737
ENSG00000139160: MAR06710, MAR06737
ENSG00000108592: MAR06710, MAR06737
ENSG00000105202: MAR06710, MAR06737
ENSG00000087995: MAR06710, MAR06737
ENSG00000145388: MAR06710, MAR06737
ENSG00000127804: MAR06710, MAR06737
ENSG00000123427: MAR06710, MAR06737
ENSG00000162623: MAR06710, MAR06737
ENSG00000198890: MAR06710, MAR06737
ENSG00000168806: MAR06710, MAR06737
ENSG00000067365: MAR06710, MAR06737
ENSG00000174173: MAR06710, MAR06737
ENSG00000123600: MAR06710, MAR06737
ENSG00000150456: MAR06710, MAR06737
ENSG00000178694: MAR06710, MAR06737
ENSG00000156239: MAR06710, MAR06737
ENSG00000171806: MAR06710, MAR06737
ENSG00000203791: MAR06710, MAR06737
ENSG00000171861: MAR06710, MAR06737
ENSG00000186666: MAR06710, MAR06737
ENSG00000068438: MAR06710, MAR06737
ENSG00000137760: MAR06710, MAR06737
ENSG00000139780: MAR06710, MAR06737
ENSG00000165055: MAR06710, MAR06737
ENSG00000100462: MAR06710, MAR06737
ENSG00000010165: MAR06710, MAR06737
ENSG00000103037: MAR06710, MAR06737
ENSG00000100483: MAR06710, MAR06737
ENSG00000179299: MAR06710, MAR06737
ENSG00000169519: MAR06710, MAR06737
ENSG00000137574: MAR06710, MAR06737, MAR00024
ENSG00000142453: MAR06710, MAR06737, MAR00024
ENSG00000066651: MAR06710, MAR06737, MAR09519
ENSG00000110871: MAR06710, MAR06737, MAR06908
ENSG00000204371: MAR06710, MAR06737, MAR08027, MAR08026, MAR04241, MAR06977, MAR06975, MAR06976, MAR08025
ENSG00000181090: MAR06710, MAR06737, MAR08027, MAR08026, MAR04241, MAR06977, MAR06975, MAR06976, MAR08025
ENSG00000183955: MAR06710, MAR06737, MAR08027, MAR08026, MAR04241, MAR06977, MAR06975, MAR06976, MAR08025
feiranl commented 1 year ago

I believe we should get rid of these two reactions and their gene-protein-reaction associations. I was uncertain before because I was worried that if we got rid of too many reactions, it might become confusing if we want to add them back in the future. However, I now realize that even if we do decide to bring them back, we can still use the same reaction IDs, so it wouldn't be as complicated as I initially thought. So now I vote for remove.

mihai-sysbio commented 1 year ago

When in doubt, I would lean towards the answer supported by validation.

feiranl commented 1 year ago

Then I will remove those two rxns.

mihai-sysbio commented 1 year ago

After removing these reactions, one should also remove metabolites that would not be used in the model anymore, such as MAM02045c and MAM00156c.