SysBioChalmers / Human-GEM

The generic genome-scale metabolic model of Homo sapiens
https://sysbiochalmers.github.io/Human-GEM-guide/
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Reaction HMR_8759 should have the GPR FMO1 #257

Closed johan-gson closed 3 years ago

johan-gson commented 3 years ago

Description of the issue:

The GPR for HMR_8759

2 hypotaurine[c] + O2[c] => 2 taurine[c]

should be FMO1, possibly (FMO1 or FMO3), but I doubt the latter is the right choice. source: https://www.biorxiv.org/content/10.1101/750273v1.full This reaction forms a loop with HMR_3911

H+[c] + NADH[c] + taurine[c] <=> H2O[c] + hypotaurine[c] + NAD+[c]

which also is missing a GPR. I don't think this GPR is known, but googling says that it shows Michaelis-Menten behaviors and is thus probably facilitated by an enzyme. The problem is that this loop is a way to regenerate NAD+ for glycolysis, and replaces lactate production in ec models, since it is for free. Making HMR_3911 unidirectional would solve the issue, but I don't know if that is ok to do. But it seems that the direction from hypotaurine to taurine is what everybody is talking about.

I hereby confirm that I have:

haowang-bioinfo commented 3 years ago

@johan-gson thanks for the post.

Two questions:

  1. Which GPR rule do you suggest for HMR_8759, FMO1 or FMO1 or FMO3?
  2. Can you double check if there is any reference that can be associated with HMR_3911?
johan-gson commented 3 years ago

So, I think the GRP rule should simply be FMO1, because this is the main gene doing this reaction. In the preprint, they saw that FMO3 also catalyses this reaction, but at much lower rate, and FMO5 at really low rate.

As for the other reaction, it seems it is directed both ways. But it is problematic, I'm pretty sure that this does not replace lactate production. But I don't know if we can do anything about it right now.

johan-gson commented 3 years ago

And, I didn't find a GPR reference for HMR_3911

haowang-bioinfo commented 3 years ago

@johan-gson thanks for the clarification, will start a branch for this fix.

johan-gson commented 3 years ago

The more I look at this, the more confused I get. It may be valuable if you also looked through the preprint, it is not that long. What I wonder is if these two reactions should be replaced by one that uses NAPDH as cofactor. I'm not so sure what to do with this anymore :)

haowang-bioinfo commented 3 years ago

The preprint was recently published in Drug Metabolism and Disposition (32156684). Given the provided evidence demonstrating the catalysing role of FMO1 in the production of taurine from hypotaurine, a fixing branch was created for updating these changes.

@johan-gson as you suggested, HMR_3911 was also modified to irreversible in this branch, from which please test out the feasibility of the reaction direction change.

johan-gson commented 3 years ago

So, after some thinking, it is probably the reaction HMR_3911 that should have this GPR. And maybe we don't change anything else.

haowang-bioinfo commented 3 years ago

Yes, it does appear that the changes introduced in the paper should be applied to HMR_3911 according to the cofactor utilization.

haowang-bioinfo commented 3 years ago

But as illustrated in Fig3B and the Enzyme Assays section, the reactants are hypotaurine and NADH (or NADPH). However, this contradicts the equation of HMR_3911 and its external annotations: KEGG: R01681, MetaNetX: MNXR107116, Recon3D: r0381.

Therefore, the GPR changes probably should be applied to HMR_8759 and balanced as such: O2[c] + 2 hypotaurine[c] + NADH[c] + H+[c] ⇒ 2 taurine[c] + NAD+[c]

@johan-gson @JonathanRob what do you think?

johan-gson commented 3 years ago

I'm lost here now, I still don't from the evidence provided understand if NADH is really consumed, it just says it is a cofactor. Doesn't that mean that it is not consumed? My guess would be that the NADH should not be part of the reaction? But I'm not sure.

JonathanRob commented 3 years ago

This turned out to be a bit of an interesting case. From the paper abstract:

Despite the discovery in 1954 that the oxygenation of hypotaurine produces taurine, the identification of an enzyme catalyzing this reaction has remained elusive. In large part, this is due to the incorrect assignment, in 1962, of the enzyme as an NAD-dependent hypotaurine dehydrogenase.

So the dehydrogenase reaction (actually the reverse of HMR_3911 lacks evidence, and is actually a monooxygenase reaction, which I would assume has the (irreversible) stoichiometry:

O2 + hypotaurine + NADH + H+ --> taurine + NAD+ + H2O

So either HMR_3911 or HMR_8759 should be replaced with this equation, and the other removed. But I would suggest double checking the references for each reaction (also on Recon3D and VMH pages), to be sure that we're not missing something.

@Hao-Chalmers, your proposed reaction for HMR_8759 is unbalanced in protons.

@johan-gson cofactors can be changed by a reaction, the difference is that they are regenerated in a cycle (either with another reaction or within the same reaction). In this case, NADH is oxidized to NAD+, but can be reduced back to NADH by some other electron donor/enzyme elsewhere.

haowang-bioinfo commented 3 years ago

@JonathanRob thanks for the correction.

So the paper suggested such a reaction: O2 + hypotaurine + NADH + H+ => taurine + NAD+ + H2O, by which HMR_8759 should be modified.

While the other reaction HMR_3911: H+[c] + NADH[c] + taurine[c] <=> H2O[c] + hypotaurine[c] + NAD+[c], should be removed (or blocked), given the conclusion that its assignment to NAD-dependent hypotaurine dehydrogenase is incorrect.

~And the Oxidation of hypotaurine references (13979247, 7295801), which previously were associated to HMR_3911, should be moved to HMR_8759.~ For the references, retain the old ones to HMR_3911 unchanged, and add this new paper to HMR_8759.

JonathanRob commented 3 years ago

Since the newly proposed reaction is quite different from HMR_3911 and HMR_8759, I'm thinking that the correct approach may actually be to create a new reaction with the formula proposed above, and inactivate HMR_3911 and HMR_8759 (and eventually delete).

Again though, I would strongly suggest we first look into the databases/references associated with HMR_3911 and HMR_8759 to make sure that they really should be removed, since they are present in many other databases (MNX, Recon3D/VMH, BiGG, HMR2, etc.).

haowang-bioinfo commented 3 years ago

Since the newly proposed reaction is quite different from HMR_3911 and HMR_8759, I'm thinking that the correct approach may actually be to create a new reaction with the formula proposed above, and inactivate HMR_3911 and HMR_8759 (and eventually delete).

sounds good to me

Again though, I would strongly suggest we first look into the databases/references associated with HMR_3911 and HMR_8759 to make sure that they really should be removed, since they are present in many other databases (MNX, Recon3D/VMH, BiGG, HMR2, etc.).

Their common presence is a result copy/past between different data sources. Based on this new study, HMR_8759 should be modified and HMR_3911 should be removed. We can just block them first (ub = lb = 0), as we did before.