handling terms for xenobiotic role and removing drug role

[krchristie]

As discussed at a couple GO Editors Calls in April, presented at the April 7, 2020 Annotation call, and summarized at the GOC meeting on 5/13/20, here is the plan to move forwards with the terms relating to the ChEBI roles for drug and xenobiotic.

The plan is summarized in the bullet points below and shown in more detail in the table showing the summary of my analysis of the drug & xenobiotic terms in the ontology and their usage in annotations.

• MF terms ("drug binding" & 2 xenobiotic transporter activity terms) - will be made OBSOLETE as it doesn't make sense to describe a molecular function based on the context a chemical is being used in. Annotations will need to be reviewed and transferred to an appropriate MF term based on chemical specificity if possible.
• BP terms (transport terms, metabolic terms, response terms) - "drug" terms will be merged into the corresponding "xenobiotic" terms if one exists, or renamed from "drug" to "xenobiotic" if not.
• regulation BP terms - There only a few of these all variations of "regulation of response to drug", so we will request for these to be reviewed and then decide if they should be converted to "xenobiotic" terms or Obsoleted.

[krchristie]

email from @RLovering (5/14/20)

Hi Karen

Sorry I couldn’t find the appropriate ticket for drug binding and the other binding discussions. But I just wanted to point out the problem Shirin is having with annotating the target of transporters (see example below)

While I agreed that in this example below you would argue that by it would be easier to annotate if only 1 ‘activity’ needed to be associated with the gene to capture this role. My issue is that ‘organic cation’ is a very uninformative term to be used to classify these chemicals. The direct parent in ChEBI https://www.ebi.ac.uk/chebi/chebiOntology.do?chebiId=CHEBI:641 for this chemical is pyridinium ion. So possibly pyridinium ion/pyridine transport and transporter activity would be useful.

Example: Paper 26376205 where the authors describe 1‐methyl‐4‐phenylpyridinium (MPP) as a xenobiotic (and by ChEBI as a xenobiotic metabolite + organic cation; MPP is actually a metabolite of the pro-drug MPTP) Transport of MPP was captured using the following terms GO:0042908 xenobiotic transport (BP) GO:0015695 organic cation transport (BP) GO:0015101 organic cation transmembrane transporter activity (MF) GO:0042910 xenobiotic transmembrane transporter activity (MF)

Based on the ChEBI record for MPP, the following terms can also be added as ChEBI describes MPP as a neurotoxin. (I have not got round to including these terms) GO:1901998 toxin transport (BP) GO:0019534 toxin transmembrane transporter activity (MF)

Shirin has mostly been annotating MPP to these 6 terms, however looking back at this paper Shirin only added in xenobiotic transport as the authors described MPP as one. To remain consistent (whilst annotating other papers) Shirin continued to use xenobiotic transport terms to describe MPP transport.

Please would you add this example to the relevant ticket and also let us know your thoughts on this.

Kind regards, Shirin and Ruth

[krchristie]

While I agreed that in this example below you would argue that by it would be easier to annotate if only 1 ‘activity’ needed to be associated with the gene to capture this role. My issue is that ‘organic cation’ is a very uninformative term to be used to classify these chemicals. The direct parent in ChEBI https://www.ebi.ac.uk/chebi/chebiOntology.do?chebiId=CHEBI:641 for this chemical is pyridinium ion. So possibly pyridinium ion/pyridine transport and transporter activity would be useful.

@RLovering - Your suggestion to have new terms for pyridinium ion/pyridine transport and transporter activity seem like a good idea, at least the MF term. I'm not completely up on current thought as to whether an "X transport" term in BP is considered redundant with an "X transporter activity" term in MF. Please go ahead and submit a ticket with the new term request(s).

Example: Paper 26376205 where the authors describe 1‐methyl‐4‐phenylpyridinium (MPP) as a xenobiotic (and by ChEBI as a xenobiotic metabolite + organic cation; MPP is actually a metabolite of the pro-drug MPTP) Transport of MPP was captured using the following terms GO:0042908 xenobiotic transport (BP) GO:0015695 organic cation transport (BP) GO:0015101 organic cation transmembrane transporter activity (MF) GO:0042910 xenobiotic transmembrane transporter activity (MF) Based on the ChEBI record for MPP, the following terms can also be added as ChEBI describes MPP as a neurotoxin. (I have not got round to including these terms) GO:1901998 toxin transport (BP) GO:0019534 toxin transmembrane transporter activity (MF) Shirin has mostly been annotating MPP to these 6 terms, however looking back at this paper Shirin only added in xenobiotic transport as the authors described MPP as one. To remain consistent (whilst annotating other papers) Shirin continued to use xenobiotic transport terms to describe MPP transport.

As you pointed out, "toxin" is also a ChEBI role. I suspect we will deal with it similarly to xenobiotic, which would mean obsoleting the MF term for toxin transmembrane transporter activity, like the 2 xenobiotic transmembrane transporter terms are slated for obsoletion.

I would suggest not making any further annotations to these MF terms and instead use a chemically-based transporter term, requesting a new one if there isn't anything specific enough.

[RLovering]

Hi Karen will you be creating a spreadsheet for us to see all the annotations we need to revise. It looks like there are around 160 although many are too the more specific terms https://www.ebi.ac.uk/QuickGO/annotations?goId=GO:0042910&goUsageRelationships=is_a,part_of,occurs_in&goUsage=descendants&evidenceCode=ECO:0000269,ECO:0000304,ECO:0000303,ECO:0000305&evidenceCodeUsage=descendants If you download the AE information associated with these you should see the 30 ChEBI IDs that have been included with these annotations. Would you be able to use these to preempt the new terms that are going to be required. https://www.ebi.ac.uk/QuickGO/annotations?extension=has_input(ChEBI&goId=GO:0042910&goUsageRelationships=is_a,part_of,occurs_in&goUsage=descendants Thanks Ruth

[krchristie]

@RLovering - Yes, I will be creating spreadsheets, but it will probably be a few weeks before I have time since I'm only about 50% on ontology development and I need to spend some time on annotation to balance the time I've just spent on ontology development. I created this ticket to write up the decisions and plan while it was fresh in my mind so I would remember everything when I get back to it.

I would recommend not starting to review these annotations yet. The two I have tried to do so far suggest that there may be some issues about what kinds of terms we really want in the ontology and the next meeting of the ontology editors group isn't until 5/31.

That's a good idea to look at the ChEBI IDs used in extensions. I'll take a look at them. Thanks for the suggestion.

[krchristie]

Summary of obsoletions & merges

Obsoletions

• drug binding -- obsoletion email & announcement ticket -- annotation review spreadsheet created -- remove direct SubClass Of relationships from child terms ofdrug binding
• endogenous drug catabolic process -- obsoletion email & announcement ticket (0 annotations)
• 2 xenobiotic transmembrane transporter MF terms -- xenobiotic transmembrane transporter activity -- ATPase-coupled xenobiotic transmembrane transporter activity -- obsoletion email & announcement ticket -- annotation review spreadsheet created -- remove Equivalence axioms or direct SubClass Of relationships referring to a xenobiotic term from child terms

Merges

• drug transport into xenobiotic transport
• drug transmembrane transport into xenobiotic transmembrane transport
• drug metabolic process into xenobiotic metabolic process
• drug catabolic process into xenobiotic catabolic process
• exogenous drug catabolic process into xenobiotic catabolic process
• response to drug into response to xenobiotic
• cellular response to drug into cellular response to xenobiotic

rename

• drug export to xenobiotic export

review annotations & decide

• regulation of response to drug
• negative regulation of response to drug
• positive regulation of response to drug
• regulation of cellular response to drug
• negative regulation of cellular response to drug
• positive regulation of cellular response to drug

[krchristie]

For discussion at ontology editors call on 6/22/2020

Proposed instructions for review of regulation of response to drug terms

As described in handling terms for xenobiotic role and removing drug role #19460, we would like to review the small number of annotations to the various "regulation of response to drug" terms in order to determine if there is a need for "regulation of response to xenobiotic" terms or if these terms should be obsoleted.

Please check if these annotations

• meet current standards for regulation terms (the sole experimental MGI annotation did not meet this criterion)
• represent a process sufficiently general to merit annotating to a high level grouping term for "[pos/neg/-] regulation of [cellular] response to xenobiotic", or if some more specific regulation term would be better.

Here is the annotation review spreadsheet: Ticket-#### Review annotations to regulation of response to drug (GO:2001023, GO:2001024, GO:2001025, GO:2001038, GO:2001039, GO:2001040)

[krchristie]

For discussion at ontology editors call on 6/22/2020

Proposed instructions for review of xenobiotic transmembrane transporter MF terms

As described in the ticket: handling terms for xenobiotic role and removing drug role #19460, we have decided to obsolete the terms ATPase-coupled xenobiotic transmembrane transporter activity and xenobiotic transmembrane transporter activity since referring to the role of xenobiotic does not provide a meaningful functional description of what kind of binding is occurring. We request that groups that have used these terms review their annotations and annotate to a chemically meaningful term instead, if possible.

=> What is current thought as to whether an "X transport" term in BP is considered redundant with an "X transporter activity" term in MF?

Here is the annotation review spreadsheet: Ticket-#### Review annotations to xenobiotic transmembrane transporters (GO:0042910, GO:0008559)

Checks for obsoletion for:xenobiotic transmembrane transporter activity

1. Annotation Usage Table of annotations to xx by contributor:

2. Ontology usage

• used in 5 Equivalent To relationships
• used in 7 SubClass Of relationships
• used 5 term replaced by relationships: -- GO_0015238 -- GO_0015239 -- GO_0015559 -- GO_0015564 -- GO_0090484

3. Subset usage:

• goslim_metagenomics

4. External mappings

• InterPro: multiple
• Unirule: multiple

Checks for obsoletion for:ATPase-coupled xenobiotic transmembrane transporter activity

1. Annotation Usage Table of annotations to xx by contributor:

2. Ontology usage

• used 2 term replaced by relationships: -- GO_0005226 -- GO_0008560
• database_xrefs -- EC:7.6.2.2 -- MetaCyc:3.6.3.44-RXN -- Reactome:R-HSA-1467457 -- Reactome:R-HSA-2161506 -- Reactome:R-HSA-2161538

3. Subset usage:

• none

4. External mappings

• InterPro: at least InterPro:IPR030244
• Unirule: at least UniRule:UR000046410

5. Notification:

Obsoletion email template: SUBJECT: Proposal to obsolete "drug binding" (GO:0008144)

BODY: Dear all, The proposal has been made to obsolete: "drug binding" (GO:0008144). The reason for obsoletion is that it is not meaningful to describe a molecular function by what role a compound is involved in.

There are 236 experimental, 5 author statement, & 326 sequence-based annotations to this term (see table).

There are 2 mappings to this term:

• InterPro:IPR000335
• Rfam:RF02912

This term is included in the subset: goslim_pir

Any comments can be added to the issue: https://github.com/geneontology/go-ontology/issues/19480.

We are opening a comment period for this proposed obsoletion. We’d like to proceed and obsolete this term on July 14th. Unless objections are received by July 14, 2020, we will assume that you agree to this change.

[deustp01]

Here is the annotation review spreadsheet: Ticket-#### Review annotations to xenobiotic transmembrane transporters (GO:0042910, GO:0008559)

Reactome cases fixed - changes will become public with September 2020 release.

[RLovering]

Hi

As mentioned previously we need to know whether an "X transport" term in BP is going to be considered redundant with an "X transporter activity" term in MF. Shirin has requested the GO term pyridinium ion transport and pyridinium ion transmembrane transporter activity https://github.com/geneontology/go-ontology/issues/19642#issuecomment-647419435

Several issues we need help with:

1. The problem is that in ChEBI the pyridinium ion is not a child of pyridine or pyridines. It is not clear to us whether we should use the pyridine or pyridines as the chemical in the GO term as these are neutral, or the ion term. In ChEBI the chemical 1-methyl-4-phenylpyridinium (MPP) is a child of pyridinium ion but is not a child of pyridine or pyridines. Should acidic chemicals be child terms in ChEBI of the neutral chemicals they are related too?

2. Many of the chemicals we are looking at have multiple parents eg pentamidine https://www.ebi.ac.uk/chebi/chebiOntology.do?chebiId=CHEBI:45081 has multiple parents, few of which have transport or transporter activity terms in GO. Should we request a selection of the parent terms as both BP and MF terms, or just the more specific terms as BP and MF. Alternatively should we look at the MF for O15245 SLC22A1 (which transports pentamidine) and use the existing GO terms and just add the ChEBI ID to these. Currently SLC22A1 has the following GO MF terms associated with it: monoamine transmembrane transporter activity (but pentamidine is not a monoamine) organic cation transmembrane transporter activity (but pentamidine is not a organic cation) quaternary ammonium group transmembrane transporter activity (but pentamidine is not a quaternary ammonium group) Note for MPP there are at least 5 transporters identified that transport this molecule)

Please look at the ChEBI ontology for pentamidine and advise what GO terms would be best to enable us to capture role of SLC22A1 in transport for both BP and MF terms.

3. Finally we are assuming that although many drugs are not 'normal' that GO will capture the role of proteins in metabolising and transporting these chemicals. Please confirm.

@pgaudet

Thanks Ruth and Shirin

[ShirinSaverimuttu]

Hi,

To add to the issue regarding pentamidine, we also have amisulpride https://www.ebi.ac.uk/chebi/chebiOntology.do?chebiId=CHEBI:64045 which has multiple parents. Having multiple parents makes consistent annotation difficult. To capture amisulpride transport the ChEBI ontology describes amisulpride as an aromatic amide which is an amide. Based on this we can use 'GO:0042887 amide transmembrane transporter activity'. Amisulpride is also described as an aromatic amine in ChEBI. However, in the ChEBI ontology aromatic amine is not an amine. If Amisulpride is not an amine then we are unable to use 'GO:0005275 amine transmembrane transporter activity'.

Thank you Shirin & Ruth

[ValWood]

I prefer to keep substrate-specific processes because in recent overhaul it was decided that process would capture the axis of classification for organelle/ import export etc.

We have substrate and mechanisms in MF, and we specify substrate+ destination + directionality in the process term.

This works well because sometimes we know that a transporter is importing into an organelle but we don't know which https://www.pombase.org/reference/PMID:29529046 (for example)

Substrate-specific transport processes also provide a superclass to group high and low affinity transporters, and regulatory pathways under a common term.

I'm not quite sure how we could describe transmembrane transport fully without these terms. To me they are not at all equivalent to the function terms that describe individual transporters.

This indicates the different detail we have been able to capture so far for zinc transport (process)https://www.pombase.org/term/GO:0071577

It is completely orthogonal to the information under function https://www.pombase.org/term/GO:0005385

It might seems like a duplication, but without it you can't get all of the information for iron transport, zinc transport etc.

v

[ValWood]

iron transport might illustrate better: https://www.pombase.org/term/GO:0005381 https://www.pombase.org/term/GO:0034755

[ValWood]

Has this

As mentioned previously we need to know whether an "X transport" term in BP is going to be considered redundant with an "X transporter activity" term in MF.

been under discussion somewhere? If so I will move this to the correct ticket. As far as I knew there was no (current) discussion to remove transmembrane transport processes.

[RLovering]

Hi Karen I have removed the BP term requested above and I have reviewed all the MF terms UCL has used in annotations, listed in the spreadsheet attached. However I have not removed the xenobiotic transporter activity, instead I created a new MF annotation. It was very challenging because the drugs/chemicals don't fall within chemical domains that are represented in the MF or BP ontology. Best Ruth

[krchristie]

Summary of obsoletions & merges (re-posting comment from Jun 18, 2020 to make it easier for me to find summary)

Obsoletions

• drug binding - https://github.com/geneontology/go-ontology/issues/19480 - completed 7/6/21 -- obsoletion email & announcement ticket -- annotation review spreadsheet created -- remove direct SubClass Of relationships from child terms ofdrug binding
• endogenous drug catabolic process -- obsoletion email & announcement ticket (0 annotations) - https://github.com/geneontology/go-ontology/issues/21819 - deadline: 7/19/21
• 2 xenobiotic transmembrane transporter MF terms -- xenobiotic transmembrane transporter activity -- ATPase-coupled xenobiotic transmembrane transporter activity -- obsoletion email & announcement ticket -- annotation review spreadsheet created -- remove Equivalence axioms or direct SubClass Of relationships referring to a xenobiotic term from child terms

Merges

• drug transport into xenobiotic transport - completed 7/7/21
• drug catabolic process into xenobiotic catabolic process - completed 7/7/21
• exogenous drug catabolic process into xenobiotic catabolic process - completed 7/7/21
• drug metabolic process into xenobiotic metabolic process - completed 7/7/21
• response to drug into response to xenobiotic - completed 7/8/21
• cellular response to drug into cellular response to xenobiotic - completed 7/8/21

rename

• drug export to xenobiotic export - completed 7/8/21
• drug transmembrane transport to xenobiotic transmembrane transport (correction from original, rename not merge) - completed 7/8/21

refinement of GO definition of a xenobiotic - 7/8/21

• Updated multiple definitions which used this phrase: a xenobiotic compound, a compound foreign to living organisms. Used of chemical compounds, e.g. a xenobiotic chemical, such as a pesticide.
• to this phrase which was already present in one definition: A xenobiotic is a compound foreign to the organim exposed to it. It may be synthesized by another organism (like ampicilin) or it can be a synthetic chemical.

review annotations & decide

• regulation of response to drug
• negative regulation of response to drug
• positive regulation of response to drug
• regulation of cellular response to drug
• negative regulation of cellular response to drug
• positive regulation of cellular response to drug

[pgaudet]

I think regulation of response to drug and the children you mention can be obsoleted, and rehoused under more informative processes. There are only 29 EXP annotations - I made a review spreadsheet: https://docs.google.com/spreadsheets/d/1R0FApD21Enxphge9wvTzzpQQJKwMJpkfA_UjzOynOQQ/edit#gid=0

Thanks, Pascale

[pgaudet]

I also fixed or disputed the UniProt annotations.