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Source ontology files for the Gene Ontology
http://geneontology.org/page/download-ontology
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alcohol dehydrogenase/aldo-keto reductase hierarchy #28532

Open sjm41 opened 2 months ago

sjm41 commented 2 months ago

We currently have this arrangement:

oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor
    |_alcohol dehydrogenase [NAD(P)+] activity (GO:0018455) [EC:1.1.1.71, RHEA:10736]
        |_alcohol dehydrogenase (NAD+) activity (GO:0004022) [EC:1.1.1.1, RHEA:10740]
            |_[SEVERAL CHILDREN]
    |_aldo-keto reductase (NADPH) activity (GO:0004033) [no EC/RHEA]
        |_alcohol dehydrogenase (NADP+) activity (GO:0008106) [EC:1.1.1.2, RHEA:15937] aka "aldehyde reductase"
            |_[SEVERAL CHILDREN]
        |_carbonyl reductase (NADPH) activity (GO:0004090) [EC:1.1.1.184, RHEA:19257] aka "ketone reductase"

Note that all the reactions above are 'alcohol dehydrogenase' reactions - 'alcohol dehydrogenase' and 'Aldo/keto reductase' describe the same reaction though from opposite directions, and use either NAD or NADP as the acceptor.

Anyway, there are a few parentage and xref issues with the current hierarchy:

id: GO:0004022 name: alcohol dehydrogenase (NAD+) activity namespace: molecular_function def: "Catalysis of the reaction: an alcohol + NAD+ = an aldehyde or ketone + NADH + H+." [EC:1.1.1.1] xref: EC:1.1.1.1 xref: MetaCyc:ALCOHOL-DEHYDROG-GENERIC-RXN xref: RHEA:10740 xref: UM-BBD_reactionID:r0022 xref: UM-BBD_reactionID:r0603 is_a: GO:0018455 ! alcohol dehydrogenase [NAD(P)+] activity

EC 1.1.1.1 alcohol dehydrogenase a primary alcohol + NAD(+) = an aldehyde + H(+) + NADH a secondary alcohol + NAD(+) = a ketone + H(+) + NADH Mapped to: RHEA:10736 a primary alcohol + NAD+ = an aldehyde + H+ + NADH Mapped to: RHEA:10740 a secondary alcohol + NAD+ = a ketone + H+ + NADH

Tasks:

id: GO:0018455 name: alcohol dehydrogenase [NAD(P)+] activity namespace: molecular_function def: "Catalysis of the reaction: an alcohol + NAD(P)+ = an aldehyde + NAD(P)H + H+." [EC:1.1.1.71] xref: EC:1.1.1.71 xref: MetaCyc:ALCOHOL-DEHYDROGENASE-NADP+-RXN xref: RHEA:10736 xref: UM-BBD_reactionID:r0172 is_a: GO:0016616 ! oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor

EC:1.1.1.71 alcohol dehydrogenase [NAD(P)(+)] a primary alcohol + NAD(+) = an aldehyde + H(+) + NADH a primary alcohol + NADP(+) = an aldehyde + H(+) + NADPH Reduces aliphatic aldehydes of chain length from C2 to C14, with greatest activity on C4, C6 and C8 aldehydes. Also reduces retinal to retinol.

Issue: This is a grouping term in GO, but it's definition (and EC xref) are more specific than its children - i.e. it is specific for primary alcohols/aldehydes, while its child (GO:0004022 - see above) also includes secondary alcohols/ketones. If we stick with the current definition, then we'll need to do some complicated/awkward rearranging of term relationships.

I think the simplest/better solution here is to:

Also:

id: GO:0004033 name: aldo-keto reductase (NADPH) activity namespace: molecular_function def: "Catalysis of the reaction: an alcohol + NADP+ = an aldehyde or a ketone + NADPH + H+." [GOC:ai] is_a: GO:0016616 ! oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor property_value: term_tracker_item "https://github.com/geneontology/go-ontology/issues/27180" xsd:anyURI

Tasks:

id: GO:0008106 name: alcohol dehydrogenase (NADP+) activity namespace: molecular_function def: "Catalysis of the reaction: an alcohol + NADP+ = an aldehyde + NADPH + H+." [EC:1.1.1.2] xref: EC:1.1.1.2 xref: MetaCyc:ALCOHOL-DEHYDROGENASE-NADPORNOP+-RXN xref: RHEA:15937 is_a: GO:0004033 ! aldo-keto reductase (NADPH) activity property_value: term_tracker_item "https://github.com/geneontology/go-ontology/issues/28183" xsd:anyURI

EC:1.1.1.2 alcohol dehydrogenase (NADP(+)) a primary alcohol + NADP(+) = an aldehyde + H(+) + NADPH Some members of this group oxidize only primary alcohols; others act also on secondary alcohols.

If we implement the above, the hierarchy becomes:

oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor (GO:0016616) [EC:1.1.1.-]
    |_alcohol dehydrogenase [NAD(P)+] activity (GO:0018455) [EC:1.1.1.71]
        |_alcohol dehydrogenase (NAD+) activity (GO:0004022) [EC:1.1.1.1, RHEA:10740, RHEA:10736]
            |_[SEVERAL CHILDREN]
        |_aldo-keto reductase (NADPH) activity (GO:0004033) [no EC]
            |_alcohol dehydrogenase (NADP+) activity (GO:0008106) [EC:1.1.1.2, RHEA:15937]
                |_[SEVERAL CHILDREN]
            |_carbonyl reductase (NADPH) activity (GO:0004090) [EC:1.1.1.184, RHEA:19257]

What do you think @pgaudet ?

pgaudet commented 2 months ago

Just a question: if we broaden the def of GO:0018455 definition to include secondary alcohols/ketones, thenshould we also change the term name?

sjm41 commented 1 month ago

if we broaden the def of GO:0018455 definition to include secondary alcohols/ketones, then should we also change the term name?

I don't think so. Since the current GO:0018455 term name is "alcohol dehydrogenase [NAD(P)+] activity") rather than "primary alcohol dehydrogenase [NAD(P)+] activity", the implication is that it describes an activity that works with both primary and secondary alcohols. Similarly, the name of the "GO:0004022 alcohol dehydrogenase (NAD+) activity" child term, which is already defined as working on both primary and secondary alcohols, just says "alcohol dehydrogenase".

pgaudet commented 3 weeks ago

Hi @sjm41

My question about the changing the term label was about the aldo-keto versus alcohol distinction than about the primary/ secondary – intuitively an aldo-keto should not be is_a alcohol, although I did see what you wrote about these being the same reactions, in opposite directions.

Looking more closely, we could consider obsoleting aldo-keto reductase (NADPH) activity since it has no xrefs and seems to have been misused.

For example the protein name of https://www.uniprot.org/uniprotkb/P42330/entry is Aldo-keto reductase family 1 member C3, and is annotated to EC:1.1.1.357, which is missing from GO.

So we could take advantage of this re-organization to get rid of aldo-keto reductase (NADPH) activity (GO:0004033) since that has no mappings. What do you think?

Thanks, Pascale

sjm41 commented 3 weeks ago

So we could take advantage of this re-organization to get rid of aldo-keto reductase (NADPH) activity (GO:0004033) since that has no mappings. What do you think?

Yes, that looks good to me. Though I see there are 23 direct EXP annotations to GO:0004033 that would need to be reviewed.

Obsoleting GO:0004033 (and doing the other tasks above) would lead to this simpler and more logical arrangement:

oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor (GO:0016616) [EC:1.1.1.-]
    |_alcohol dehydrogenase [NAD(P)+] activity (GO:0018455) [EC:1.1.1.71]
        |_alcohol dehydrogenase (NAD+) activity (GO:0004022) [EC:1.1.1.1, RHEA:10740, RHEA:10736]
            |_[SEVERAL CHILDREN]
        |_alcohol dehydrogenase (NADP+) activity (GO:0008106) [EC:1.1.1.2, RHEA:15937]
            |_carbonyl reductase (NADPH) activity (GO:0004090) [EC:1.1.1.184, RHEA:19257]
            |_[SEVERAL OTHER CHILDREN]
sjm41 commented 3 weeks ago

@pgaudet Let me know if I should go ahead and make the other (non-obsoletion) changes proposed above.

deustp01 commented 3 weeks ago

I see there are 23 direct EXP annotations to GO:0004033

Reactome is responsible for 7 of those and it looks like all could be patched with terms in the proposed simplified hierarchy.

pgaudet commented 3 weeks ago

yes yes

I had this on my list to discuss with you tomorrow, but please go ahead and get started.

sjm41 commented 3 weeks ago

OK, I've done the 'easy' edits and we can discuss the final bits tomorrow.