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SysBioChalmers / Human-GEM

The generic genome-scale metabolic model of Homo sapiens
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Overlapping Duplicate Beta-Oxidation Reactions for (4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoyl-CoA #772

Open Devlin-Moyer opened 11 months ago

Devlin-Moyer commented 11 months ago

Current behavior:

There are a number of redundant beta-oxidation reactions for (4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoyl-CoA:

ID Reaction Notes
MAR05408 (4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoyl-CoA [m] + FAD [m] --> FADH2 [m] + 2,4,7,10,13,16,19-Docosaheptenoyl Coenzyme A [m] round 1, step 1
MAR05412 H+ [m] + NADPH [m] + 2,4,7,10,13,16,19-Docosaheptenoyl Coenzyme A [m] --> NADP+ [m] + 3,7,10,13,16,19-Docosahexenoyl Coenzyme A [m] round 1, step 2
MAR05410 3,7,10,13,16,19-Docosahexenoyl Coenzyme A [m] --> 2,7,10,13,16,19-Docosahexenoyl Coenzyme A [m] round 1, step 3
MAR05403 CoA [m] + H2O [m] + NAD+ [m] + 2,7,10,13,16,19-Docosahexenoyl Coenzyme A [m] --> acetyl-CoA [m] + H+ [m] + NADH [m] + 5,8,11,14,17-Eicosapentenoyl Coenzyme A [m] round 1, step 4
MAR05376 CoA [m] + FAD [m] + H2O [m] + NAD+ [m] + 5,8,11,14,17-Eicosapentenoyl Coenzyme A [m] --> acetyl-CoA [m] + FADH2 [m] + H+ [m] + NADH [m] + 3,6,9,12,15-Octadecapentenoyl Coenzyme A [m] round 2
MAR05370 3,6,9,12,15-Octadecapentenoyl Coenzyme A [m] --> 2,6,9,12,15-Octadecapentenoyl Coenzyme A [m] round 3, step 1
MAR05369 CoA [m] + H2O [m] + NAD+ [m] + 2,6,9,12,15-Octadecapentenoyl Coenzyme A [m] --> acetyl-CoA [m] + H+ [m] + NADH [m] + 4,7,10,13-Hexadecatetraenoyl Coenzyme A [m] round 3, step 2
MAR05298 FAD [m] + 4,7,10,13-Hexadecatetraenoyl Coenzyme A [m] --> FADH2 [m] + 2,4,7,10,13-Hexadecapentaenoyl Coenzyme A [m] round 4, step 1
MAR05312 H+ [m] + NADPH [m] + 2,4,7,10,13-Hexadecapentaenoyl Coenzyme A [m] --> NADP+ [m] + 3,7,10,13-Hexadecatetraenoyl Coenzyme A [m] round 4, step 2
MAR05306 3,7,10,13-Hexadecatetraenoyl Coenzyme A [m] --> 2,7,10,13-Hexadecatetraenoyl Coenzyme A [m] round 4, step 3
MAR05242 CoA [m] + H2O [m] + NAD+ [m] + 2,7,10,13-Hexadecatetraenoyl Coenzyme A [m] --> acetyl-CoA [m] + H+ [m] + NADH [m] + 5,8,11-Tetradecatrienoyl Coenzyme A [m] round 4, step 4
MAR05177 CoA [m] + FAD [m] + H2O [m] + NAD+ [m] + 5,8,11-Tetradecatrienoyl Coenzyme A [m] --> acetyl-CoA [m] + FADH2 [m] + H+ [m] + NADH [m] + 3,6,9-Dodecatrienoyl Coenzyme A [m] round 5
MAR05090 3,6,9-Dodecatrienoyl Coenzyme A [m] --> 2,6,9-Dodecatrienoyl Coenzyme A [m] round 6, step 1
MAR05083 CoA [m] + H2O [m] + NAD+ [m] + 2,6,9-Dodecatrienoyl Coenzyme A [m] --> acetyl-CoA [m] + H+ [m] + NADH [m] + 4,7-Decadienoyl Coenzyme A [m] round 6, step 2
MAR04978 FAD [m] + 4,7-Decadienoyl Coenzyme A [m] --> FADH2 [m] + 2,4,7-Decatrienoyl Coenzyme A [m] round 7, step 1
MAR05001 H+ [m] + NADPH [m] + 2,4,7-Decatrienoyl Coenzyme A [m] --> NADP+ [m] + 3,7-Decadienoyl Coenzyme A [m] round 7, step 2
MAR04988 3,7-Decadienoyl Coenzyme A [m] --> 2,7-Decadienoyl Coenzyme A [m] round 7, step 3
MAR04984 CoA [m] + H2O [m] + NAD+ [m] + 2,7-Decadienoyl Coenzyme A [m] --> acetyl-CoA [m] + H+ [m] + NADH [m] + 5-Octenoyl Coenzyme A [m] round 7, step 4
MAR06320 CoA [m] + FAD [m] + H2O [m] + NAD+ [m] + 5-Octenoyl Coenzyme A [m] --> acetyl-CoA [m] + FADH2 [m] + H+ [m] + NADH [m] + 3-Hexenoyl Coenzyme A [m] round 8
MAR06281 3-Hexenoyl Coenzyme A [m] --> (2E)-hexenoyl-CoA [m] round 9, step 1
MAR03157 (2E)-hexenoyl-CoA [m] + H2O [m] --> (S)-hydroxyhexanoyl-CoA [m] round 9, step 2
MAR03158 (S)-hydroxyhexanoyl-CoA [m] + NAD+ [m] --> 3-oxohexanoyl-CoA [m] + H+ [m] + NADH [m] round 9, step 3
MAR03160 3-oxohexanoyl-CoA [m] + CoA [m] --> acetyl-CoA [m] + butyryl-CoA [m] round 9, step 4
MAR03163 butyryl-CoA [m] + FAD [m] --> crotonyl-CoA [m] + FADH2 [m] round 10, step 1
MAR03164 crotonyl-CoA [m] + H2O [m] --> (S)-3-hydroxybutyryl-CoA [m] round 10, step 2
MAR03166 (S)-3-hydroxybutyryl-CoA [m] + NAD+ [m] --> acetoacetyl-CoA [m] + H+ [m] + NADH [m] round 10, step 3
MAR03885 acetoacetyl-CoA [m] + CoA [m] <=> 2 acetyl-CoA [m] round 10, step 4
MAR00970 (4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoyl-CoA [m] + CoA [m] + H2O [m] + NAD+ [m] --> (5Z,8Z,11Z,14Z,17Z)-eicosapentaenoyl-CoA [m] + acetyl-CoA [m] + H+ [m] + NADH [m] round 1, all steps
MAR00923 (5Z,8Z,11Z,14Z,17Z)-eicosapentaenoyl-CoA [m] + CoA [m] + H2O [m] + NAD+ [m] --> (6Z,9Z,12Z,15Z)-octadecatetraenoyl-CoA [m] + acetyl-CoA [m] + H+ [m] + NADH [m] alternate version of round 2
MAR05365 (6Z,9Z,12Z,15Z)-octadecatetraenoyl-CoA [m] + CoA [m] + FAD [m] + H2O [m] + NAD+ [m] --> acetyl-CoA [m] + FADH2 [m] + H+ [m] + NADH [m] + 4,7,10,13-Hexadecatetraenoyl Coenzyme A [m] partially duplicates MAR05369
MAR00818 (6Z,9Z,12Z,15Z)-octadecatetraenoyl-CoA [m] + 5 CoA [m] + FAD [m] + 5 H2O [m] + 5 NAD+ [m] --> 5 acetyl-CoA [m] + FADH2 [m] + 5 H+ [m] + 5 NADH [m] + octanoyl-CoA [m] incorrect version of rounds 3-7, all steps
MAR03428 (5Z,8Z,11Z,14Z,17Z)-eicosapentaenoyl-CoA [m] + 9 CoA [m] + 4 FAD [m] + 9 H2O [m] + 9 NAD+ [m] --> 10 acetyl-CoA [m] + 4 FADH2 [m] + 9 H+ [m] + 9 NADH [m] rounds 2-10, all steps
MAR09719 (6Z,9Z,12Z,15Z)-octadecatetraenoyl-CoA [m] + 8 CoA [m] + 4 FAD [m] + 8 H2O [m] + 8 NAD+ [m] --> 9 acetyl-CoA [m] + 4 FADH2 [m] + 8 H+ [m] + 8 NADH [m] rounds 3-10, all steps
MAR03430 (4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoyl-CoA [m] + 10 CoA [m] + 4 FAD [m] + 10 H2O [m] + 10 NAD+ [m] --> 11 acetyl-CoA [m] + 4 FADH2 [m] + 10 H+ [m] + 10 NADH [m] all rounds, all steps

Expected feature/value/output:

At the moment, 5,8,11,14,17-Eicosapentenoyl Coenzyme A (MAM03284m) (5Z,8Z,11Z,14Z,17Z)-eicosapentaenoyl-CoA (MAM00103m) are different metabolites, but the changes proposed in #771 would remove MAM03284m and replace it with MAM00103m in all the reactions it currently participates in, so I'm not addressing that further in this issue.

I think it's clear that MAR00970, MAR03428, MAR09719, and MAR03430 are all duplicates of various subsets of the reactions between MAR05408 and MAR03885, so they should all be removed in favor of the more detailed series of reactions. MAR00818 is almost a duplicate of MAR05365 through MAR04984, except it incorrectly ends with octanoyl-CoA instead of 5-octenoyl-CoA (see #765 for a similar set of duplicates), so it should definitely be removed.

At first glance, MAR00923 just looks like an incorrect version of MAR05370, but I'm pretty sure it's supposed to represent the following (plausible, if slightly non-canonical) series of reactions:

  1. (5Z,8Z,11Z,14Z,17Z)-eicosapentaenoyl-CoA -> (2E,5Z,8Z,11Z,14Z,17Z)-eicosahexaenoyl-CoA (by ACADL or ACAD9)
  2. (2E,5Z,8Z,11Z,14Z,17Z)-eicosahexaenoyl-CoA -> (3Z,5Z,8Z,11Z,14Z,17Z)-eicosahexaenoyl-CoA (by ECI1 or ECI2)
  3. (3Z,5Z,8Z,11Z,14Z,17Z)-eicosahexaenoyl-CoA -> (2E,4E,8Z,11Z,14Z,17Z)-eicosahexaenoyl-CoA (by ECH1)
  4. (2E,4E,8Z,11Z,14Z,17Z)-eicosahexaenoyl-CoA -> (3E,8Z,11Z,14Z,17Z)-eicosapentaenoyl-CoA (by DECR1)
  5. (3E,8Z,11Z,14Z,17Z)-eicosapentaenoyl-CoA -> (2E,8Z,11Z,14Z,17Z)-eicosapentaenoyl-CoA (by ECI1 or ECI2)
  6. (2E,8Z,11Z,14Z,17Z)-eicosapentaenoyl-CoA -> 3-hydroxy-(8Z,11Z,14Z,17Z)-eicosatetraenoyl-CoA (by HADHA)
  7. 3-hydroxy-(8Z,11Z,14Z,17Z)-eicosatetraenoyl-CoA -> 3-oxo-(8Z,11Z,14Z,17Z)-eicosatetarenoyl-CoA (by HADHA)
  8. 3-oxo-(8Z,11Z,14Z,17Z)-eicosatetraenoyl-CoA -> (6Z,9Z,12Z,15Z)-octadecatetraenoyl-CoA (by HADHB)

So I don't think MAR00923 has to be removed, but its GPR should be changed to (ACADL or ACAD9) and (ECI1 or ECI2) and ECH1 and DECR1 and HADHA and HADHB.

MAR05365 represents one full round of beta-oxidation of beta-oxidation from (6Z,9Z,12Z,15Z)-octadecatetraenoyl-CoA to (4Z,7Z,10Z,13Z)-hexadecatetraenoyl CoA, but the first step in that process would be oxidation by ACADL or ACAD9 to form (2E,6Z,9Z,12Z,15Z)-octadecapentaenoyl-CoA, i.e. MAM03195m, which is a reactant in MAR05369, which produces (4Z,7Z,10Z,13Z)-hexadecatetraenoyl CoA. To resolve this partial redundancy, I propose that MAR05365 be edited to just represent the first step of this round of beta-oxidation, i.e. (6Z,9Z,12Z,15Z)-octadecatetraenoyl-CoA + FAD -> (2E,9Z,12Z,15Z)-octadecapentaenoyl-CoA + FADH2 with a GPR of ACADL or ACAD9.

Proposed changes: