Stereochemistry of Phytanic Acid Metabolism

[Devlin-Moyer]

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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:

• [x] Rename MAM02746e, MAM02746c and MAM02746x to "(3R)-phytanic acid"
• [x] Bring back MAM03884e, MAM03884c and MAM03884x and rename them to "(3S)-phytanic acid"
• [x] Bring back MAR00659 and MAR01617 (exchange and [e] <-> [c] transport reactions for MAM03884)
• [x] Rename MAM02747c and MAM02747x to "(3R)-phytanoyl-CoA"
• [x] Replace MAM02746c with MAM03884c in MAR03388
• [x] Edit MAR03481 to be MAM02747c + MAM01371c + 2 MAM02040c -> MAM02746x + MAM01597c + MAM02039c + MAM01285c + MAM02751c, GPR: ENSG00000117528, references: PMID:24333844;PMID:33500543
• [x] Edit MAR06779 to be MAM03362c + MAM01371c + 2 MAM02040c -> MAM03384x + MAM01597c + MAM02039c + MAM01285c + MAM02751c, GPR: ENSG00000117528, references: PMID:24333844;PMID:33500543
• [x] Replace MAM02746x with MAM03884x in MAR03389
• [x] Rename MAM00655x to "(3R)-2-hydroxyphytanoyl-CoA"
• [x] Create a new metabolite to represent peroxisomal (2R)-pristanal
• [x] Replace (2S)-pristanal (MAM00564x) with the new (2R)-pristanal metabolite in MAR03486
• [x] Rename MAM02766e, MAM02766c, and MAM02766x to "(2S)-pristanic acid"
• [x] Bring back MAR03488 and MAM00077x, but replace MAM00564x with the new (2R)-pristanal metabolite in MAR03488
• [x] Replace MAM02766x with MAM00077x in MAR03493
• [x] Create MAM00077c and MAM00077e to represent cytosolic and extracellular (2R)-pristanic acid
• [x] Replace MAM02766c with MAM00077c in MAR03390
• [x] Create new reactions like MAR11966 and MAR11967 but with MAM00077c and MAM000077e instead of MAM02766c and MAM02766e

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]

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]

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]

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:

• [ ] Rename MAM02746e, MAM02746c and MAM02746x to "(3R)-phytanic acid"
• [ ] Rename MAM02747c and MAM02747x to "(3R)-phytanoyl-CoA"
• [ ] Rename MAM00655x to "(3R)-2-hydroxyphytanoyl-CoA"
• [ ] Create a new metabolite to represent peroxisomal (2R)-pristanal
• [ ] Replace (2S)-pristanal (MAM00564x) with the new (2R)-pristanal metabolite in MAR03486
• [ ] Bring back (2R,6S,10S)-pristanate (MAM00077x), MAR03488, and MAR03489 (they were removed in #519)
• [ ] Replace (2S)-pristanal (MAM00564x) with the new (2R)-pristanal metabolite in MAR03488
• [ ] Replace (2S)-pristanoyl-CoA (MAM00078x) with (2R)-pristanoyl-CoA (MAM00075x) in MAR03489
• [ ] Create new metabolites for extracellular and cytosolic (3S)-phytanic acid as well as an exchange reaction and [e] <-> [c] transport reaction
• [ ] Replace MAM02746c with the new cytosolic (3S)-phytanic acid metabolite in MAR03388
• [ ] Create a new [c] <-> [x] transport reaction for the existing (3S)-phytanoyl-CoA metabolites (MAM03362)
• [ ] Keep MAM03362c, MAM03362x, MAM03363x, MAR03384, and MAR03385 exactly as they are (i.e. instead of removing them, as initially proposed in this issue)
• [ ] Remove MAR03389 (currently converts phytanic acid (MAM02746x) to 3S-phytanoyl-CoA (MAM03362x); MAR03482 converts phytanic acid (MAM02746x) to phytanoyl-CoA (MAM02747x), so if we rename both of those to (3R)-phytanic acid and (3R)-phytanoyl-CoA, we only want to keep MAR03482)
• [ ] Remove MAR05186 and MAR05187 (I already proposed this in #775 since they duplicate MAR03486 + MAR03386 in addition to being ambiguous about stereochemistry)
• [ ] All changes proposed in #776

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]

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

[Christoff1993]

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.