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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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Stereochemistry of Phytanic Acid Metabolism #773

Closed Devlin-Moyer closed 5 months ago

Devlin-Moyer commented 9 months ago

Current behavior:

Human-GEM's representation of the stereochemistry of phytanic acid metabolites is inconsistent: some metabolites clearly specifically represent the (3S) enantiomers, while others seem to represent racemic mixtures of the (3S) and (3R) enantiomers:

Metabolite/Reaction unspecified/racemic version S enantiomer
phytanic acid MAM02746 doesn't exist
phytanoyl-CoA MAM02747 MAM03362
2-hydroxyphytanoyl-CoA MAM00655 MAM03363
pristanal doesn't exist MAM00564
pristanic acid MAM02766 doesn't exist
pristanoyl-CoA MAM03884 MAM00078
phytanic acid [c] -> phytanoyl-CoA [c] MAR03480 MAR03388
phytanic acid [c] -> phytanic acid [x] MAR03478 doesn't exist
phytanoyl-CoA [c] -> phytanoyl-CoA [x] MAR06779 and MAR03481 doesn't exist
phytanic acid [x] -> phytanoyl-CoA [x] MAR03482 MAR03389
phytanoyl-CoA [x] -> 2-hydroxyphytanoyl-CoA [x] MAR03484 MAR03384
2-hydroxyphytanoyl-CoA [x] -> pristanal [x] MAR03486 MAR03385
pristanal [x] -> pristanic acid [x] MAR03386 doesn't exist
pristanic acid [x] -> pristanoyl-CoA [x] MAR05183 MAR03387

Expected feature/value/output:

Apparently, most people's diets contain both (3S) and (3R)-phytanic acid, and while the enzymes responsible for the alpha-oxidation of phytanic acid (i.e. the enzymes responsible for the reactions mentioned in this issue) work with either enantiomer, the enzymes responsible for the beta-oxidation of pristanoyl-CoA only recognize (2S)-pristanoyl-CoA, so people who are born with defective AMACR (the enzyme responsible for converting (2R)-pristanoyl-CoA into (2S)-pristanoyl-CoA) can only fully metabolize (3S)-phytanic acid and accumulate (2R)-pristanic acid in their blood (source). In order to properly reflect this, I think the unspecified/racemic phytanic acid metabolites should be edited to instead represent the (3R)-enantiomers, and the reactions involving these two sets of metabolites should be fully separated from each other up until MAR03491, which already represents the isomerization of (2R)-pristanoyl-CoA and (2S)-pristanoyl-CoA by AMACR:

Metabolite/Reaction (S) version (R) version
phytanic acid MAM03884 MAM02746
phytanoyl-CoA MAM03362 MAM02747
2-hydroxyphytanoyl-CoA MAM03363 MAM00655
pristanal MAM00564 need to make a new one
pristanic acid MAM02766 MAM00077
pristanoyl-CoA MAM00078 MAM00075
<-> phytanic acid [e] MAR00659 MAR09037
phytanic acid [e] -> phytanic acid [c] MAR01617 MAR00440
phytanic acid [c] -> phytanoyl-CoA [c] MAR03388 MAR03480
phytanoyl-CoA [c] -> phytanoyl-CoA [x] MAR06779 MAR03481
phytanic acid [x] -> phytanoyl-CoA [x] MAR03389 MAR03482
phytanoyl-CoA [x] -> 2-hydroxyphytanoyl-CoA [x] MAR03384 MAR03484
2-hydroxyphytanoyl-CoA [x] -> pristanal [x] MAR03385 MAR03486
pristanal [x] -> pristanic acid [x] MAR03386 MAR03488
pristanic acid [x] -> pristanoyl-CoA [x] MAR03387 MAR03493

I noticed that #646 removed the MAM03884 metabolites and all associated reactions for being duplicates of the MAM02746 metabolites, since both sets represent(ed) phytanic acid. I'm proposing to bring back the MAM03884 metabolites and reactions so that they can represent (3R)-phytanic acid, so that we can edit the MAM02746 metabolites and reactions to specifically represent (3S)-phytanic acid.

MAR03481 and MAR06779 both represent transport of phytanoyl-CoA from the cytosol into peroxisomes, but only MAR06779 correctly represents that this is an ATP-dependent process mediated by ABCD3 (source). Since they both use the racemic phytanoyl-CoA metabolite (MAM02747), and there is no equivalent reaction using (2S)-phytanoyl-CoA (MAM03362), I'm proposing to edit both reactions so that they both represent ATP-dependent import, but one uses (2S)-phytanoyl-CoA and the other uses (2R)-phytanoyl-CoA. Also it turns out that ABCD3 probably removes the CoA from its substrates just before it transports them across the peroxisomal membrane (source), so I'm also accounting for that in my proposed changes.

Proposed changes:

These changes don't address the existence of Pristanoyl Coenzyme A (MAM03887) in addition to (2S)-pristanoyl-CoA (MAM00078) and (2R)-pristanoyl-CoA (MAM00075); that's taken care of in #776

haowang-bioinfo commented 9 months ago

3(S)-Phytanoyl-CoA (MAM03362c and MAM03362x) and 3(S)-2-Hydroxyphytanoyl-CoA (MAM03363x) seem to be entirely redundant with phytanoyl-CoA (MAM02747c and MAM02747x) and 2-hydroxyphytanoyl-CoA (MAM00655x)

@Devlin-Moyer if you have more evidence demonstrating that 3(S)-Phytanoyl-CoA (MAM03362c and MAM03362x) and 3(S)-2-Hydroxyphytanoyl-CoA (MAM03363x) are the same?

@Christoff1993 if you can help to double check this?

Devlin-Moyer commented 9 months ago

sorry I may not have written that super clearly; 3(S)-Phytanoyl-CoA (MAM03362) is the same as phytanoyl-CoA (MAM02747), and 3(S)-2-Hydroxyphytanoyl-CoA (MAM03363) is the same as 2-hydroxyphytanoyl-CoA (MAM00655)

Devlin-Moyer commented 9 months ago

I just came across this paper that mentions that people's diets usually consist of a racemic mixture of (3S)- and (3R)-phytanic acid, and while the enzymes responsible for the alpha-oxidation of phytanic acid to pristanal recognize either enantiomer, ACOX2 and ACOX3 (the enzymes responsible for the first step of beta-oxidation of pristanic acid) only act on 2S-pristanoyl-CoA, so people born with defective AMACR (the enzyme responsible for converting 2R-pristanoyl-CoA into 2S-pristanoyl-CoA) accumulate 2R-pristanic acid in their blood.

At the moment, it seems like MAM02746, MAM02747, and MAM00655x represent racemic phytanic acid, phytanoyl-CoA, and 2-hydroxyphytanoyl-CoA, and no metabolites that are currently present in Human-GEM specifically represent the 3R enantiomers. The stereochemistry gets even more confusing with the metabolites representing pristanal, pristanic acid, and pristanoyl-CoA; 2S-pristanal (MAM00564x) becomes (racemic?) pristanic acid (MAM02766x) in MAR03386, which can become 2S-pristanoyl-CoA (MAM00078x) in MAR03387, 2R-pristanoyl-CoA (MAM00075x) in MAR03493, or (racemic?) pristanoyl-CoA (MAM03887x) in MAR05183. The changes I proposed in the initial comment would basically remove any semblance of stereospecificity in this pathway; if we instead wanted to represent each enantiomer with a separate metabolite, we should:

This would create two fully distinct series of metabolites and reactions for representing each pair of enantiomers that converge at MAR03491, which already interconverts (2R)-pristanoyl-CoA (MAM00075x) and (2S)-pristanoyl-CoA (MAM00078x):

Reaction ID using S-enantiomers ID using R-enantiomers
Exchange of phytanic acid new MAR09037
Transport of phytanic acid from [e] to [c] new MAR00440
Transport of phytanic acid from [c] to [x] not sure if necessary MAR03478
Phytanic acid to phytanoyl-CoA in [c] MAR03388 MAR06779
Transport of phytanoyl-CoA from [c] to [x] new MAR03481
Phytanic acid to phytanoyl-CoA in [x] not sure if necessary MAR03482
Phytanoyl-CoA to 2-hydroxyphytanoyl-CoA MAR03384 MAR03484
2-hydroxyphytanoyl-CoA to pristanal MAR03385 MAR03486
Pristanal to pristanic acid MAR03386 MAR03488
Pristanic acid to pristanoyl-CoA MAR03387 MAR03489
Metabolite S-enantiomer R-enantiomer
Phytanic acid new MAM02746
Phytanoyl-CoA MAM03362 MAM02747
2-Hydroxyphytanoyl-CoA MAM03363 MAM00655
Pristanal MAM00564 new
Pristanic acid MAM02766 MAM00077
Pristanoyl-CoA MAM00078 MAM00075
Devlin-Moyer commented 9 months ago

I edited the proposed changes to try and accurately reflect the stereochemistry that's relevant to these reactions

Christoff1993 commented 8 months ago

I have checked the reasoning and citations, and everything seems comprehensive and sound: all the indicated ambiguities do indeed exist and the proposed changes will solve them. I have no disagreements/additional suggestions.