Fix alpha-tocopheryl quinone redox reactions

[Devlin-Moyer]

Main improvements in this PR:

As proposed in #611:

• Changes the GPR of MAR01801 to ENSG00000159228 or ENSG00000181019 and adds PMID:7005231 and PMID:16569397 as references
• Changes the GPR of MAR01808 to ENSG00000181019 and adds PMID:9271353 as a reference
• Edits MAR03047 to represent reduction of alpha-tocopheryl quinone with NADPH in the cytosol:
  • MAM01329c + MAM02039c + MAM02555c -> MAM01328c + MAM02554c
  • GPR: ENSG00000159228 or ENSG00000181019
  • references: PMID:7005231;PMID:16569397
• Edits MAR06500 to represent reduction of alpha-tocopheryl quinone by Complex I:
  • MAM01329c + 5 MAM02039m + MAM02553m -> MAM01329c + 4 MAM02039i + MAM02552m
  • GPR: (same as MAR06921) ENSG00000004779 and ENSG00000023228 and ENSG00000065518 and ENSG00000090266 and ENSG00000099795 and ENSG00000109390 and ENSG00000110717 and ENSG00000115286 and ENSG00000119013 and ENSG00000119421 and ENSG00000125356 and ENSG00000128609 and ENSG00000130414 and ENSG00000131495 and ENSG00000136521 and ENSG00000139180 and ENSG00000140990 and ENSG00000145494 and ENSG00000147123 and ENSG00000147684 and ENSG00000151366 and ENSG00000158864 and ENSG00000160194 and ENSG00000164258 and ENSG00000165264 and ENSG00000166136 and ENSG00000167792 and ENSG00000168653 and ENSG00000170906 and ENSG00000174886 and ENSG00000178127 and ENSG00000183648 and ENSG00000184752 and ENSG00000184983 and ENSG00000186010 and ENSG00000189043 and ENSG00000198695 and ENSG00000198763 and ENSG00000198786 and ENSG00000198840 and ENSG00000198886 and ENSG00000198888 and ENSG00000212907 and ENSG00000213619 and ENSG00000267855
  • references: PMID:16569397
• Creates MAR20189 to represent reduction of alpha-tocopheryl quinone by Complex III:
  • MAM01329c + 2 MAM01824m + 2 MAM02039m -> MAM01328c + 2 MAM01826m + 4 MAM02039i
  • GPR: (same as MAR06918) ENSG00000010256 and ENSG00000127540 and ENSG00000140740 and ENSG00000156467 and ENSG00000164405 and ENSG00000169021 and ENSG00000173660 and ENSG00000179091 and ENSG00000184076 and ENSG00000198727
  • references: PMID:16569397
• Creates MAR20190 to represent reduction of alpha-tocopheryl quinone with NADH in the cytosol:
  • MAM01329c + MAM02039c + MAM02553c -> MAM01328c + MAM02552c
  • GPR: ENSG00000181019
  • references: PMID:9271353

I hereby confirm that I have:

• Tested my code on my own computer for running the model
• Selected develop as a target branch
• Any removed reactions and metabolites have been moved to the corresponding deprecated identifier lists

[github-actions]

This PR has been automatically tested with GH Actions. Here is the output of the MACAW test:

Starting dead-end test...
 - Found 1525 dead-end metabolites.
 - Found 1332 reactions incapable of sustaining steady-state fluxes in either direction due to these dead-ends.
 - Found 1975 reversible reactions that can only carry steady-state fluxes in a single direction due to dead-ends.
Starting duplicate test...
 - Skipping redox duplicates because no redox_pairs and/or proton_ids were provided.
 - Found 447 reactions that were some type of duplicate:
   - 0 were completely identical to at least one other reaction.
   - 13 involve the same metabolites but go in the opposite direction or have the opposite reversibility as at least one other reaction.
   - 447 involve the same metabolites but with different coefficients as at least one other reaction.

This and a more detailed output from MACAW are also committed to data/macawResults/.

Note: In the case of multiple test runs, this post will be edited.

[feiranl]

@edkerk Could you help review this PR?

[JHL-452b]

Changes the GPR of MAR01808 to ENSG00000181019 or ENSG00000159348 or ENSG00000166394 or ENSG00000100243 or ENSG00000065615 or ENSG00000215883 and adds PMID:16569397 and PMID:9271353 as references.

MAR01808 (H+ [c] + NADH [c] + ubiquinone [c] --> NAD+ [c] + ubiquinol [c]) represent the reaction catalyzed by NADH dehydrogenase. However, only ENSG00000181019(NQO1) can encode NADH dehydrogenase in the updated gpr of MAR01808. Other genes related to NADH-cytochrome b5 reductase which do not enable to catalyze the reduction of ubiquinone. Additionally, I could not find evidence supporting this in the studies referenced by PMID:16569397 and PMID:9271353. Did I miss something, or do you have additional evidence to support your updated GPR? @Devlin-Moyer

[Devlin-Moyer]

So I'm realizing now that everything in PMID:16569397 was with rat liver extracts and not the human enzyme, but the part I had in mind was the last part of the results around figure 8 titled "3.7 Interaction of TQ with cytochrome b5 reductase" that shows that NADH-cytochrome b5 reductases can reduce ubiquinone (technically it just shows that rat liver microsomes can reduce ubiquinone, and they attribute that activity to NADH-cytochrome b5 reductases). PMID:9271353 was only there to support the inclusion of NQO1, since they compare its activity against alpha-tocopherol to its activity against ubiquinone (CoQ₁₀).

[Devlin-Moyer]

anyway I would be fine with changing the GPR of MAR01808 to just ENSG00000181019 and only adding PMID:9271353 to the references, since the evidence supporting the cytochrome b5 reductases' involvement in this is shaky

[JHL-452b]

Edits MAR06500 to represent reduction of alpha-tocopheryl quinone by Complex I:
MAM01329c + 5 MAM02039m + MAM02553m -> MAM01329c + 4 MAM02034i + MAM02552m

Please check the equation. MAM02034i in products may be not right.

[JHL-452b]

anyway I would be fine with changing the GPR of MAR01808 to just ENSG00000181019 and only adding PMID:9271353 to the references, since the evidence supporting the cytochrome b5 reductases' involvement in this is shaky

Agree. But the GPR of new added reaction MAR20190 should also be changed.

[Devlin-Moyer]

Edits MAR06500 to represent reduction of alpha-tocopheryl quinone by Complex I:
MAM01329c + 5 MAM02039m + MAM02553m -> MAM01329c + 4 MAM02034i + MAM02552m

Please check the equation. MAM02034i in products may be not right.

ah yep that was supposed to be MAM02039i, and I only made that typo in the PR message -- I correctly wrote MAM02039i when editing the YAML file

[github-actions]

This PR has been automatically tested with GH Actions. Here is the output of the gene essentiality test:

     cellLine     TP     TN     FP    FN     accuracy    sensitivity    specificity       F1         MCC   
    __________    __    ____    __    ___    ________    ___________    ___________    ________    ________

    {'DLD1'  }    38    2158    60    280    0.86593        0.1195        0.97295       0.18269     0.15884
    {'GBM'   }    34    2137    64    300    0.85641        0.1018        0.97092       0.15741     0.12758
    {'HCT116'}    47    2181    55    308     0.8599       0.13239         0.9754       0.20569     0.19061
    {'HELA'  }    32    2241    70    250    0.87659       0.11348        0.96971       0.16667     0.13322
    {'RPE1'  }    15    2179    83    258    0.86548      0.054945        0.96331      0.080863    0.029349
    {'all'   }     7    2379    95    112    0.92017      0.058824         0.9616      0.063348    0.021985

Note: In the case of multiple test runs, this post will be edited.