-
Notifications
You must be signed in to change notification settings - Fork 41
New issue
Have a question about this project? Sign up for a free GitHub account to open an issue and contact its maintainers and the community.
By clicking “Sign up for GitHub”, you agree to our terms of service and privacy statement. We’ll occasionally send you account related emails.
Already on GitHub? Sign in to your account
Fix/removed beta-D-glucose and related reactions #307
Conversation
@pranasag interesting propose.
May I know what evidence makes these reactions unnecessary to the model? For example of reaction MAR07745, the catalytic gene ENSG00000143891 (GALM) is known to be expressed in kidney epithelium and many other tissues according to the Bgee database. |
Hi @Hao-Chalmers, By the way, I'm not sure why the YAML validation failed (says - reaction annotation not matching), I checked the changes introduced and these should be only related to removing 2 species and 5 reactions, as suggested. |
@pranasag thanks for quick response.
The failure of YAML validation is due to the inconsistency between model (in YAML) and annotation files ( |
@Hao-Chalmers my bad, I'll fix that in the next hours, thanks for the explanation! |
@pranasag no worries.
This probably means that the model should be expanded with a complete set of "beta-" version reactions, instead of removing them? |
I would argue for removal rather than expansion, as (indicated above) the mutarotational state of glucose does not influence the stoichiometry of the reaction. Moreover, to my knowledge, other popular GEMs (at least ones I'm working with) do not have such distinctions because of this reason. Added for the "do not have distinctions": (Please note that with the latest commit I also removed the gene |
Thanks for your help, @pranasag. I tend to agree with your logic, in that it doesn't really add anything meaningful to the model to have parallel reaction pathways for the different stereoisomers, since they don't produce anything different in the end (other than a few additional isomeric compounds). This is a bit similar to how we deal with lipid metabolism, where we don't try to model every possible combination of metabolites and reactions, but instead keep the most representative, common, or generic pathway form. Finally, having parallel reaction pathways can be problematic if simulations can seemingly compensate with the alternative pathway, when in reality, it may exhibit very poor efficiency. On the other hand, I share @Hao-Chalmers's concerns of removing content/information from the model unless really necessary. In this case, I would recommend removing the reactions as you suggest, @pranasag, except for the reaction transforming between the two glucose isomers (glucose and beta-glucose). This way, we still retain the information that this transformation can take place (and thus don't lose a gene association), but don't retain unnecessary components which are effectively a duplication of existing metabolites/reactions. I realize this creates a dead-end reaction and metabolite, but our approach with Human-GEM has been to allow dead-ends since they often contain valuable information and can easily be removed if not needed (e.g., for simulation). What do you think? |
Good one, @JonathanRob, thanks for jumping in! |
@pranasag on a side note, I'm wondering is this might be an artifact of several models being based on the same template. Similarly, I see that the stereoisomers exist in Recon3D with a reference to HMR2. |
@JonathanRob thanks for the clarification (this should be added to the Wiki as guidelines for future). Besides being a GEM, Human-GEM serves as a knowledgebase that allows dead-end reactions, which may be useful in other applications (e.g. integrative analysis). According to a previous issue #44, unnecessary reactions should be initially deleted |
Just to comment, @Hao-Chalmers, the "soft deletion" approach was developed before we had implemented the yaml workflow, when it was much harder to track and revert changes to the model (in particular deletion of components). Now that we have the convenient yaml-based workflow, I wouldn't see a need to use the soft deletion approach. |
@pranasag I wonder if you also notice more |
@Hao-Chalmers there's no extra metabolites for fructose and mannose, but for galactose, there's |
The reaction MAR08767 is associated with gene GALT (ENSG00000213930), which encode Galactose-1-phosphate uridylyltransferase (EC 2.7.7.12) that catalyzes the conversion of galactose-1-phosphate to glucose-1-phosphate in the Leloir pathway. According to UniProt, Rhea, MetaCyc and BRENDA, all the reactants and products are and only in alpha form. In addition, there is no literature found by searching Pubmed with key words In sum, there is no evidence supporting the change of alpha form in MAR08767. |
That's really a broad overview of literature, thanks @Hao-Chalmers. Correct me if I'm wrong -- your conclusion is to preserve the two forms of galactose-1-phosphate in the model. If that's so, then I'd appeal to what @JonathanRob said about having same end-products after the pathway branches to another metabolite species (being the same chemical thing), in this case, between the |
I'm not sure I fully understand what the consensus is at this point. Would this interpretation be correct, or did I misunderstand?
|
@JonathanRob even though I'd argue that the issue I see with the galactose pathway is very similar to the one for glycolysis (from the modelling perspective, while agreeing to the experimentally-relevant observations @Hao-Chalmers collected), maybe then let's stick to clearing up glycolysis at this time? |
@JonathanRob makes sense to me
@pranasag agree |
Revised implementation plan after GPR checking:
@pranasag @JonathanRob what do you think? |
Well done @Hao-Chalmers, sounds great! Also thanks for noticing |
Looks great, @Hao-Chalmers |
@pranasag how about restarting a new PR to implement the revised plan, this probably is easier than making amendments to the current one? Instead of pushing from a forked repo, I suggest making new PR directly to Human-GEM (you've assigned with write access), so that we can help in case there are issues raised by GitHub actions. |
Thanks @Hao-Chalmers, I'll make a branch, do the changes and submit a new PR then. |
@Hao-Chalmers what was the reason to keep |
@mihai-sysbio MAM01388c (beta-D-glucose) is part of the conversion reaction MAR07745, which we wanted to keep because it represents unique chemistry that is not duplicated elsewhere. Removing this would remove information (and a gene association) from the model. |
Main improvements in this PR:
Human-GEM had two definitions of cytosolic glucose and glucose-6-phosphate:
glucose[c]
andbeta-glucose[c]
(and respectively for the G6P). The conversion rxnbeta-D-glucose[c] <=> glucose[c]
(MAR07745
) and the reactions with the "beta-" glucose, ending withfructose-6-phosphate[c]
create unnecessarily alternative to glycolytic pathway fromglucose[c]
tofructose-6-phosphate[c]
, which has no added value to the model. Moreover, the "D-" and "unspecified" stereoisomer distinction is not there for any other sugar. Thus I suggest removing the respective metabolite species (MAM01388c
andMAM01389c
) and reactions (MAR07745
,MAR07746
,MAR07747
,MAR07748
,MAR07749
).I hereby confirm that I have:
develop
as a target branch