[Go] 'binding issues' item listed on the GO Consortium meetingagenda
D'Eustachio, Peter
Peter.D'Eustachio at nyumc.org
Tue Mar 24 05:51:46 PDT 2009
One a quibble. The fix is needed in ChEBI, not in GO. Just as there
should be one resource of, e.g., human proteins that others point to
(rather than also a freestanding RGD resource and perhaps a freestanding
resource for other databases that sometimes want to cross-reference a
human protein for their own local reasons), there should be a single
definitive resource of small (non-encoded) molecules that we all point
to. If I'm trying to describe a reaction, practically, I'm not going to
double my work by determining both how ChEBI describes the non-encoded
participant molecules and also how GO handles them.
Another quibble. Jim's reference to "physiological pH" gets at a key,
unsolvable ambiguity. Whose physiology? That of a human stomach (pH ~
2), that of the same human's blood (pH a bit above 7), that of some
yeast growing anaerobically, that of a prokaryote growing in a mineral
vent?
-----Original Message-----
From: go-bounces at genome.stanford.edu
[mailto:go-bounces at genome.stanford.edu] On Behalf Of Chris Mungall
Sent: Monday, March 23, 2009 7:20 PM
To: Jim Hu
Cc: GO LIST
Subject: Re: [Go] 'binding issues' item listed on the GO Consortium
meetingagenda
On Mar 23, 2009, at 3:55 PM, Jim Hu wrote:
> Hi all,
>
> I think this particular case should be ok as long as we have some
> way of handling the is_conjugate_acid and is_conjugate_base
> relationships. "phosphoenolpyruvic acid" and "phosphoenolpyruvate"
> interconvert in water, and very few papers will be able to
> distinguish which form is the actual ligand. I think that this
> means that curators would correct to annotate to either, and
> reasoners will have to know that annotations to one are equivalent
> to annotations to the other. Note that the conjugate acid/base
> business here actually understates the chemical heterogeneity, as
> the phosphate group in PEP is treated in ChEBI as if it doesn't
> titrate. My colleagues point out that this doesn't even touch on
> things like Mg-ATP vs ATP; adenylate kinase uses one of each!
Ah OK, now we're getting to the nitty gritty stuff. As I said, I think
CHEBI and chemical entities present specific dfificulties that aren't
present in other col 16 use cases.
> For most annotation, we don't care which form is used, as long as
> they meet some criterion for being chemically "the same". For me,
> that would be having the same covalent structure and considering
> titratable groups that dissociate easily in water as noncovalently
> bound. So, for annotation, I suppose I'd prefer a single term that
> merged "phosphoenolpyruvic acid" and "phosphoenolpyruvate"
I agree. Or rather, more specifically, to avoid confusion, I think
CHEBI should include a term that is the is_a parent of both
"phosphoenolpyruvic acid" and "phosphoenolpyruvate"
I'm not sure what we would call this term.
> But ChEBI isn't set up that way. In principle, I suppose we could
> make a ChEBI slim for GO that only has the dominant form at
> physiological pH?
I don't think a slim helps here. We want a new term.
We could in principle make an application ontology (similar to a slim)
which has our own terms in it such as GOCHEM:1234 ! PEP, and then
define these as unions of existing CHEBI terms. On a theoretical level
there is absolutely nothing wrong with this, but on a practical level
I think there is a lot to be said for keeping things simple and using
only pre-existing CHEBI terms, and engaging CHEBI in a dialog.
Note that Mike Bada took this approach (of making new on-the-fly terms
that were the union of existing CHEBI IDs) when defining GO terms in
the BP x CHEBI cross-product:
http://wiki.geneontology.org/index.php/XP:biological_process_xp_chebi#CH
EBI_terms
> Or we could ask the ChEBI people to change?
We can certainly ask.
> Did that make sense?
To me, but IANAC
> The functional parentage relationship is fundamentally very
> different, and true path does emphatically not apply. The
> functional parent of PEP (both forms) is acrylate/acrylic acid,
> which lacks the phosphate. The covalent structure is different.
> Some examples that might fall under what Harold is thinking about
> might be: dUTP vs dTTP for DNA polymerase, or Isoleucine vs Valine
> for aminoacyl-tRNA synthetases. In both cases, the single methyl
> group can only provide a small amount of difference in binding
> energy - which still gives a difference in affinity on the order of
> 100-fold. Misincorporation in the absence of proofreading is
> evidence that these alternate substrates can bind, but I don't think
> I would annotate valine binding to Ile-aaRS or dUTP binding to DNA
> polymerase.
>
> Would people annotate azaC binding to reverse transcriptase? I
> wouldn't, but perhaps some would?
>
> Jim
>
>
> On Mar 23, 2009, at 4:25 PM, Harold Drabkin wrote:
>
>> From one of Jim's earlier comments, I think a big problem is
>> parentage: if Chebi has a relationship between, say glucose-6
>> phosphate and glucose (child parent or something) , and we have a
>> protein that binds glucose-6-phosphate, we don't want to imply any
>> binding to glucose ( it might, but it might not). Chebi may have
>> relationships between, for example, for ATP, ADP, and AMP, but a
>> protein may bind very specifically to one of them. And I suppose
>> there are many cases where a protein can bind related chemicals
>> with different non-zero affinities, so that if one annotated
>> binding to one there may be a good chance it would bind another.
>> Should there be a rule in how one interprets the annotation line so
>> as to not read any relationships among things in the target
>> ontology to the actual single term designated as the target for the
>> GO annotation? (hope this is clear).fcc
>>
>> Harold
>>
>>
>>
>> Chris Mungall wrote:
>>> I have added this example to the col16 page:
>>>
http://wiki.geneontology.org/index.php/Annotation_Cross_Products#Binding
>>>
>>> I think the use of CHEBI in annotation-time cross-products poses
>>> specific problems
>>>
>>> * It's often not clear (to me anyway) which CHEBI term to use.
>>> Jim's example (linked to in the above page) has "PEP binding".
>>> CHEBI has two terms in which PEP is a RELATED synonym:
>>> "phosphoenolpyruvic acid" and "phosphoenolpyruvate". neither of
>>> these are defined in the traditional OBO sense. It's not clear if
>>> the InChi strings count as they are under RELATED synonym too.
>>>
>>> (Jim/Debbie - since you provided this example can you comment on
>>> this, I'm too lazy to read the PMID, thanks!)
>>>
>>> * Many CHEBI terms do not have is_a parents. It's extremely
>>> important for there to be correct is_a parentage. For example, if
>>> the post-composed term is "phosphoenolpyruvic acid binding" then
>>> this can be inferred to be a subtype of GO:0042301 ! phosphate
>>> binding, based on is_a parentage in CHEBI.
>>>
>>> * CHEBI has other relations, but their semantics are unclear
>>>
>>> This gives me reason for caution. However, I am optimistic - CHEBI
>>> are willing to fix these things in their ontology.
>>>
>>> In particular I would propose the following guidelines for use of
>>> CHEBI in annotation time cross-products
>>>
>>> * The CHEBI term *should* preferably have a definition. The GO
>>> annotator who uses a CHEBI ID in col 16 should propose a
>>> definition on the CHEBI tracker
>>> * The CHEBI term *must* have is_a ancestry to CHEBI:24431 !
>>> molecular structure. If a GO annotator wishes to use a CHEBI ID in
>>> col 16, and there is no such ancestry, the annotator should send a
>>> request on the CHEBI tracker
>>> * The CHEBI term *should* have the correct synonym assignment. For
>>> example, if the GO curator thinks the correct post-composed term
>>> is "PEP binding" then PEP *must* be either an EXACT synonym or a
>>> primary term name.
>>>
>>> On Mar 18, 2009, at 7:53 AM, Jim Hu wrote:
>>>
>>>> Hi Pascale,
>>>>
>>>> I think this is also potentially related to the discussion of
>>>> whether/how the cross-product system can/should be used for post-
>>>> composition of binding annotations.
>>>>
>>>> Jim
>>>>
>>>> On Mar 18, 2009, at 8:46 AM, Pascale Gaudet wrote:
>>>>
>>>>> Hi Emily,
>>>>>
>>>>> I am attaching the summary Debby Siegele put together about some
>>>>> of the issues we've been having with substrate binding. (This
>>>>> was sent to the ref genome list).
>>>>>
>>>>> Pascale
>>>>>
>>>>> Emily Dimmer wrote:
>>>>>>
>>>>>> Hi,
>>>>>>
>>>>>> I noticed that the GO Consortium meeting agenda for Monday 30th
>>>>>> March has a item entitled 'binding issues'. However there is no
>>>>>> indication of who added this topic.Could someone please give a
>>>>>> bit more detail about why this item has been added?
>>>>>>
>>>>>> I do agree that it is an area that is probably worth discussing
>>>>>> (particularly with regards ISSing 'protein binding'
>>>>>> annotations). Its just that I feel that agenda items which deal
>>>>>> with annotation issues are more easily resolved when the
>>>>>> meeting participants have had advanced notice as to the
>>>>>> background of the discussion topic, so to be able to review
>>>>>> their database's annotation sets/collect their thoughts!
>>>>>>
>>>>>> Thanks,
>>>>>> Emily
>>>>>>
>>>>>>
>>>>>>
>>>>>>
------------------------------------------------------------------
>>>>>> Emily Dimmer Ph.D.
>>>>>> GOA Coordinator
>>>>>> EMBL-EBI
>>>>>> Wellcome Trust Genome Campus
>>>>>> Hinxton
>>>>>> Cambridge CB10 1SD, U.K.
>>>>>> Tel: +44 1223 494654
>>>>>> Fax: +44 1223 494468
>>>>>> email: edimmer at ebi.ac.uk
>>>>>> URL: http://www.ebi.ac.uk/goa
>>>>>>
>>>>>> _______________________________________________
>>>>>> Go mailing list
>>>>>> Go at geneontology.org
>>>>>> http://fafner.stanford.edu/mailman/listinfo/go
>>>>>>
>>>>>>
>>>>> <
>>>>> BindingTermDocumentation
>>>>> .doc>_______________________________________________
>>>>> Go mailing list
>>>>> Go at geneontology.org
>>>>> http://fafner.stanford.edu/mailman/listinfo/go
>>>>
>>>> =====================================
>>>> Jim Hu
>>>> Associate Professor
>>>> Dept. of Biochemistry and Biophysics
>>>> 2128 TAMU
>>>> Texas A&M Univ.
>>>> College Station, TX 77843-2128
>>>> 979-862-4054
>>>>
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