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SysBioChalmers / yeast-GEM

The consensus GEM for Saccharomyces cerevisiae
http://sysbiochalmers.github.io/yeast-GEM/
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add-rxn.prop: Hydrogen Sulfide Addition #300

Closed wtscott31 closed 2 years ago

wtscott31 commented 2 years ago

This is an enhancement to the model to properly account for the pathways responsible for the formation of hydrogen sulfide as well as other volatile sulfur compounds during fermentation (see source:https://academic.oup.com/femsyr/article/17/6/fox058/4056150)

Main improvements in this PR:

Try to be as clear as possible: Is it fixing/adding something in the model? Is it an additional test/function/dataset? PLEASE DELETE THIS LINE.

I hereby confirm that I have:

edkerk commented 2 years ago

Reviewing this PR, I realized that we did not have an intuitive and straightforward way to make such curations. To fix this, not just for here, but also for future usage, I wrote a function code/curateMetsRxnsGenes() that can take standardized TSV files as input, and adds the required metabolites, genes and/or reactions, with various warnings and error messages if something is going wrong. See the updated code/modelCuration/addSULnewRxn.m to see how this is run, and notice that the TSV files have some minor changes. This curateMetsRxnsGenes() will likely be incorporated in RAVEN in the near future, but for now is distributed with yeast-GEM.

Then, down to the actual model changes:

To do (@wtscott31) :

Note: the model was exported by using the branch from PR #301 and RAVEN from branch PR #396. Due to various generic model changes (identifiers suffices, sorting of entities etc.), it looks there were massive changes in the model files. Commit https://github.com/SysBioChalmers/yeast-GEM/pull/300/commits/031c9ce22e2326dc9de2df917293f91e5f36d533 is the best representative of real model changes related to sulfur metabolism.

wtscott31 commented 2 years ago

Gene YOL164W has been determined to regulate bacterially derived sulfatase, which is essential for converting sulfate esters to sulfates (see: https://www.yeastgenome.org/locus/S000005524). However, stoichiometry gets tricky when dealing with any known sulfate esters. Perhaps, the reactions are compound reactions with more than one step. Anyway, since this problem is hard to pin down, we can remove gene YOL164W for now.

On Mon, Mar 14, 2022 at 12:17 AM Eduard Kerkhoven @.***> wrote:

Reviewing this PR, I realized that we did not have an intuitive and straightforward way to make such curations. To fix this, not just for here, but also for future usage, I wrote a function code/curateMetsRxnsGenes() that can take standardized TSV files as input, and adds the required metabolites, genes and/or reactions, with various warnings and error messages if something is going wrong. See the updated code/modelCuration/addSULnewRxn.m https://github.com/SysBioChalmers/yeast-GEM/pull/300/files#diff-6c5cc77126e2912009441440379adda23c896c3cc00e8b7bee89629c6cdf3cb7 to see how this is run, and notice that the TSV files have some minor changes. This curateMetsRxnsGenes() will likely be incorporated in RAVEN in the near future, but for now is distributed with yeast-GEM.

Then, down to the actual model changes:

  • There were three transport reactions (cytoplasm <=> extracellular) that were called "exchange", this was corrected.
  • Three real exchange reactions were added, at the moment only allowing excretion.

To do @.*** https://github.com/wtscott31) :

Note: the model was exported by using the branch from PR #301 https://github.com/SysBioChalmers/yeast-GEM/pull/301 and RAVEN from branch PR #396 https://github.com/SysBioChalmers/RAVEN/pull/396. Due to various generic model changes (identifiers suffices, sorting of entities etc.), it looks there were massive changes in the model files. Commit 031c9ce https://github.com/SysBioChalmers/yeast-GEM/commit/031c9ce22e2326dc9de2df917293f91e5f36d533 is the best representative of real model changes related to sulfur metabolism.

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edkerk commented 2 years ago

Ok, because also in the article that you cite it shows BDS1 as involved in sulfate ester -> sulfate (Fig 1). But are none of the reactions that you propose to add an example of such a reaction?

wtscott31 commented 2 years ago

The only example metabolite mentioned in the article for that GPR is sodium dodecyl sulfate, but I cannot find any KEGG or MetaNetX reactions associated with sodium dodecyl sulfate. This would be helpful to avoid stoichiometry problems as it is a large molecule.

On Mon, Mar 14, 2022 at 3:34 PM Eduard Kerkhoven @.***> wrote:

Ok, because also in the article that you cite it shows BDS1 as involved in sulfate ester -> sulfate (Fig 1). But are none of the reactions that you propose to add an example of such a reaction?

— Reply to this email directly, view it on GitHub https://github.com/SysBioChalmers/yeast-GEM/pull/300#issuecomment-1066875466, or unsubscribe https://github.com/notifications/unsubscribe-auth/AISXXYQY4AOZZ65NH7LVYFDU75E5NANCNFSM5QJAQS7Q . Triage notifications on the go with GitHub Mobile for iOS https://apps.apple.com/app/apple-store/id1477376905?ct=notification-email&mt=8&pt=524675 or Android https://play.google.com/store/apps/details?id=com.github.android&referrer=utm_campaign%3Dnotification-email%26utm_medium%3Demail%26utm_source%3Dgithub.

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edkerk commented 2 years ago

With commit bbcc58f1c44817a4012e93c1f433c7780bad3524:

With commit ef8eaf63595f5bd20206718401a6b2497c57be52:

Remaining issues (@wtscott31):

wtscott31 commented 2 years ago

With commit bbcc58f:

With commit ef8eaf6:

  • Added a few additional metabolite identifiers (MetaNetX, BiGG, BioCyc).
  • Curated existing hydrogen sulfide metabolites for consistent identifiers.
  • Renamed 2-oxo-3-sulfanylpropanoate to more recognizable 3-mercaptopyruvate.

Remaining issues (@wtscott31):

  • [ ] The 3-mercaptopyruvate sulfurtransferase should be corrected. I noticed that dihydrolipoate disulfide (DHLA) was annotated with the KEGG ID for thioredoxin disulfide. Inspecting the cited reference, it seems to refer to Mikami et al. 2011, which suggests that both DHLA and thioredoxin are required in mice. Thioredoxin is currently not part of the 3-mercaptopyruvate sulfurtransferase reaction. Should DHLA (and dihydrolipoate disulfide) be replaced with oxidized & reduced thioredoxin?

If you look at the reference Huang et al. 2017, Fig. 1 ((https://academic.oup.com/femsyr/article/17/6/fox058/4056150) TUM1 gene associated reaction is a required part of sulphur metabolism. It is also cited here:(https://pathway.yeastgenome.org/YEAST/NEW-IMAGE?object=TUM1). I think we should include (1b) [3-mercaptopyruvate sulfurtransferase]-S-sulfanyl-L-cysteine + reduced thioredoxin = hydrogen sulfide + [3-mercaptopyruvate sulfurtransferase]-L-cysteine + oxidized thioredoxin [RN:R12690] for 3-mercaptopyruvate sulfurtransferase instead of the current one.

  • [ ] If DHLA should be kept in the reaction above, it does not seems to be recycled: it should also be produced in another reaction, otherwise this pathway is blocked.

See answer above.

  • [ ] Related to that, there does not seem to be a purpose for the dihydrolipoate-diphosphate reaction: it produces dihydrolipoyl-AMP that is not consumed elsewhere. Considering that this is a reaction without gene association, it should be left out.

Yes, it should be left out. See answer above.

edkerk commented 2 years ago

I think we should include (1b) [3-mercaptopyruvate sulfurtransferase]-S-sulfanyl-L-cysteine + reduced thioredoxin = hydrogen sulfide + [3-mercaptopyruvate sulfurtransferase]-L-cysteine + oxidized thioredoxin [RN:R12690] for 3-mercaptopyruvate sulfurtransferase instead of the current one.

That would only be a half-reaction, where the [3-mercatopyruvate sulfurtransferase]- metabolite is the actual gene associated to this reaction. Instead I've now included the whole reaction: TRX1 + 3-mercaptopyruvate --> TRX1 disulphide + pyruvate + hydrogen sulfide.

wtscott31 commented 2 years ago

I think that reaction should be acceptable then.