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SysBioChalmers / Human-GEM

The generic genome-scale metabolic model of Homo sapiens
https://sysbiochalmers.github.io/Human-GEM-guide/
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Mitochondrial Beta-Oxidation Reactions That Reduce O2 to H2O2 #791

Open Devlin-Moyer opened 10 months ago

Devlin-Moyer commented 10 months ago

Current behavior:

While working on #634, I noticed a few mitochondrial reactions in which an acyl-CoA was oxidized to a 2-trans-enoyl-CoA (the first step of beta-oxidation) that reduce O2 to H2O2. As discussed in #607 and #639, the enzymes responsible for catalyzing these reactions reduce their FAD cofactors before eventually reducing ubiquinone to ubiquinol (in mitochondria) or reducing O2 to H2O2 (in peroxisomes), and we decided to edit all of these reactions to reduce FAD to FADH2 and have separate reactions for redox between FAD and ubiquinone or O2. This is a list of all mitochondrial reactions currently in Human-GEM that reduce O2 to H2O2:

ID Reaction Notes
MAR01253 20-CoA-20-oxo-LTB4 [m] + O2 [m] --> (18E)-20-oxo-20-CoA-LTB4 [m] + H2O2 [m] not mentioned in other issues
MAR01270 10,11-dihydro-LTB4-CoA [m] + O2 [m] --> 5(S),12(R)-dihydroxy-eicosa-2,8-trans-6,14-cis-tetraenoyl-CoA [m] + H2O2 [m] not mentioned in other issues
MAR03997 O2 [m] + Cis-6-Dodecenoyl Coenzyme A [m] --> H2O2 [m] + trans,cis-lauro-2,6-dienoyl-CoA [m] not mentioned in other issues
MAR03456 (4Z,7Z,10Z)-hexadecatrienoyl-CoA [m] + O2 [m] --> (2E,4Z,7Z,10Z)-hexadecatetraenoyl-CoA [m] + H2O2 [m] mentioned in #761, but proposed changes don’t affect it
MAR01161 5-oxo-12(R)-hydroxy-eicosa-(8E,10E,14Z)-trienoyl-CoA [m] + O2 [m] --> 5-oxo-12(R)-hydroxy-eicosa-(2E,8E,10E,14Z)-tetraenoyl-CoA [m] + H2O2 [m] mentioned in #749, but proposed changes don’t affect it
MAR01204 5-oxo-12(S)-hydroxy-eicosa-(8E,10E,14Z)-trienoyl-CoA [m] + O2 [m] --> 5-oxo-12(S)-hydroxy-eicosa-(2E,8E,10E,14Z)-tetraenoyl-CoA [m] + H2O2 [m] mentioned in #749, but proposed changes don’t affect it
MAR01175 8(R)-hydroxy-hexadeca-(4E,6E,10Z)-trienoate [m] + O2 [m] --> 8(R)-hydroxy-hexadeca-(2E,4E,6E,10Z)-tetraenoate [m] + H2O2 [m] mentioned in #749, but proposed changes wouldn’t address the oxygen/peroxide problem
MAR01180 6(R)-hydroxy-tetradeca-(4E,8Z)-dienoate [m] + O2 [m] --> 6(R)-hydroxy-tetradeca-(2E,4E,8Z)-trienoate [m] + H2O2 [m] mentioned in #749, but proposed changes wouldn’t address the oxygen/peroxide problem
MAR01217 8(S)-hydroxy-hexadeca-(4E,6E,10Z)-trienoate [m] + O2 [m] --> 8(S)-hydroxy-hexadeca-(2E,4E,6E,10Z)-tetraenoate [m] + H2O2 [m] mentioned in #749, but proposed changes wouldn’t address the oxygen/peroxide problem
MAR01223 6(S)-hydroxy-tetradeca-(4E,8Z)-dienoate [m] + O2 [m] --> 6(S)-hydroxy-tetradeca-(2E,4E,8Z)-trienoate [m] + H2O2 [m] mentioned in #749, but proposed changes wouldn’t address the oxygen/peroxide problem
MAR06433 11-carboxy-alpha-tocotrienol [m] + ATP [m] + CoA [m] + 2 H2O [m] + NAD+ [m] + O2 [m] --> 9-carboxy-alpha-tocotrienol [m] + acetyl-CoA [m] + AMP [m] + 2 H+ [m] + H2O2 [m] + NADH [m] + PPi [m] mentioned in #738, but proposed changes wouldn’t address the oxygen/peroxide problem
MAR06435 7-carboxy-alpha-tocotrienol [m] + ATP [m] + CoA [m] + 2 H2O [m] + O2 [m] --> 5-carboxy-alpha-chromanol [m] + acetyl-CoA [m] + AMP [m] + H+ [m] + H2O2 [m] + PPi [m] mentioned in #738, but proposed changes wouldn’t address the oxygen/peroxide problem
MAR06482 13-carboxy-alpha-tocopherol [m] + ATP [m] + CoA [m] + 2 H2O [m] + NAD+ [m] + O2 [m] --> 11-carboxy-alpha-chromanol [m] + AMP [m] + 2 H+ [m] + H2O2 [m] + NADH [m] + PPi [m] + propanoyl-CoA [m] mentioned in #738, but proposed changes wouldn’t address the oxygen/peroxide problem
MAR06484 11-carboxy-alpha-chromanol [m] + ATP [m] + CoA [m] + 2 H2O [m] + NAD+ [m] + O2 [m] --> 9-carboxy-alpha-chromanol [m] + acetyl-CoA [m] + AMP [m] + 2 H+ [m] + H2O2 [m] + NADH [m] + PPi [m] mentioned in #738, but proposed changes wouldn’t address the oxygen/peroxide problem
MAR06486 9-carboxy-alpha-chromanol [m] + ATP [m] + CoA [m] + 2 H2O [m] + NAD+ [m] + O2 [m] --> 7-carboxy-alpha-chromanol [m] + AMP [m] + 2 H+ [m] + H2O2 [m] + NADH [m] + PPi [m] + propanoyl-CoA [m] mentioned in #738, but proposed changes wouldn’t address the oxygen/peroxide problem
MAR06488 7-carboxy-alpha-chromanol [m] + ATP [m] + CoA [m] + 2 H2O [m] + NAD+ [m] + O2 [m] --> 5-carboxy-alpha-chromanol [m] + acetyl-CoA [m] + AMP [m] + 2 H+ [m] + H2O2 [m] + NADH [m] + PPi [m] mentioned in #738, but proposed changes wouldn’t address the oxygen/peroxide problem
MAR06436 5-carboxy-alpha-chromanol [m] + ATP [m] + CoA [m] + 2 H2O [m] + NAD+ [m] + O2 [m] --> 3-carboxy-alpha-chromanol [m] + AMP [m] + 2 H+ [m] + H2O2 [m] + NADH [m] + PPi [m] + propanoyl-CoA [m] mentioned in #738, but proposed changes wouldn’t address the oxygen/peroxide problem
MAR06448 11-carboxy-gamma-tocotrienol [m] + ATP [m] + CoA [m] + 2 H2O [m] + NAD+ [m] + O2 [m] --> 9-carboxy-gamma-tocotrienol [m] + acetyl-CoA [m] + AMP [m] + 2 H+ [m] + H2O2 [m] + NADH [m] + PPi [m] mentioned in #738, but proposed changes wouldn’t address the oxygen/peroxide problem
MAR06451 7-carboxy-gamma-tocotrienol [m] + ATP [m] + CoA [m] + 2 H2O [m] + O2 [m] --> 5-carboxy-gamma-chromanol [m] + acetyl-CoA [m] + AMP [m] + H+ [m] + H2O2 [m] + PPi [m] mentioned in #738, but proposed changes wouldn’t address the oxygen/peroxide problem
MAR06453 5-carboxy-gamma-chromanol [m] + ATP [m] + CoA [m] + 2 H2O [m] + NAD+ [m] + O2 [m] --> AMP [m] + gamma-carboxyethyl-hydroxychroman [m] + 2 H+ [m] + H2O2 [m] + NADH [m] + PPi [m] + propanoyl-CoA [m] mentioned in #738, but proposed changes wouldn’t address the oxygen/peroxide problem
MAR06470 13-carboxy-gamma-tocopherol [m] + ATP [m] + CoA [m] + 2 H2O [m] + NAD+ [m] + O2 [m] --> 11-carboxy-gamma-chromanol [m] + AMP [m] + 2 H+ [m] + H2O2 [m] + NADH [m] + PPi [m] + propanoyl-CoA [m] mentioned in #738, but proposed changes wouldn’t address the oxygen/peroxide problem
MAR06471 11-carboxy-gamma-chromanol [m] + ATP [m] + CoA [m] + 2 H2O [m] + NAD+ [m] + O2 [m] --> 9-carboxy-gamma-chromanol [m] + acetyl-CoA [m] + AMP [m] + 2 H+ [m] + H2O2 [m] + NADH [m] + PPi [m] mentioned in #738, but proposed changes wouldn’t address the oxygen/peroxide problem
MAR06472 9-carboxy-gamma-chromanol [m] + ATP [m] + CoA [m] + 2 H2O [m] + NAD+ [m] + O2 [m] --> 7-carboxy-gamma-chromanol [m] + AMP [m] + 2 H+ [m] + H2O2 [m] + NADH [m] + PPi [m] + propanoyl-CoA [m] mentioned in #738, but proposed changes wouldn’t address the oxygen/peroxide problem
MAR06473 7-carboxy-gamma-chromanol [m] + ATP [m] + CoA [m] + 2 H2O [m] + NAD+ [m] + O2 [m] --> 5-carboxy-gamma-chromanol [m] + acetyl-CoA [m] + AMP [m] + 2 H+ [m] + H2O2 [m] + NADH [m] + PPi [m] mentioned in #738, but proposed changes wouldn’t address the oxygen/peroxide problem
MAR00799 5 CoA [m] + gamma-linolenoyl-CoA [m] + 5 H2O [m] + 5 NAD+ [m] + 2 O2 [m] --> 5 acetyl-CoA [m] + 5 H+ [m] + 2 H2O2 [m] + 5 NADH [m] + octanoyl-CoA [m] proposed to be removed in #763
MAR03366 arachidonyl-CoA [m] + O2 [m] --> 2-trans-cis,cis,cis,cis-4,8,11,14-eicosapentaenoyl-CoA [m] + H2O2 [m] proposed to be removed in #737
MAR03371 cis,cis-myristo-5,8-dienoyl-CoA [m] + O2 [m] --> H2O2 [m] + trans-2-cis,cis-5,8-tetradecatrienoyl-CoA [m] proposed to be removed in #737
MAR04003 4-cis-decenoyl-CoA [m] + O2 [m] --> 2-trans-4-cis-decadienoyl-CoA [m] + H2O2 [m] proposed to be removed in #737
MAR00965 (4Z,7Z,10Z,13Z,16Z)-docosapentaenoyl-CoA [m] + CoA [m] + H2O [m] + NAD+ [m] + O2 [m] --> (5Z,8Z,11Z,14Z,17Z)-eicosapentaenoyl-CoA [m] + acetyl-CoA [m] + H+ [m] + H2O2 [m] + NADH [m] removed in #794

MAR02134, MAR02136, MAR04189, and MAR04755 also reduce mitochondrial oxygen to H2O2, but none of them are beta-oxidation reactions (i.e. they're associated with other enzymes that may actually directly reduce oxygen to H2O2), so I'm not addressing them here.

There are other problems with many of these reactions, which I address in other issues (hence the "Notes" column), but I figured it might be nice to have a single issue that addresses this specific problem in every reaction that has it.

Proposed changes:

Replace oxygen (MAR02630m) with FAD (MAM01802m) and hydrogen peroxide (MAM02041m) with FADH2 (MAM01803m) in: