NAD, NADH, NADPH processes logical definitions inconsistencies

[balhoff]

There are several inconsistencies in the relations used:

• NAD metabolic process == 'metabolic process' and ('has primary input or output' some NAD) FOLLOWS PATTERN
• NADH metabolic process == 'metabolic process' and ('has participant' some 'NADH(2-)')
• NADH oxidation == 'metabolic process' and ('has input' some 'NADH(2-)') and ('has output' some 'NAD(1-)')
• NADH regeneration == 'metabolic process' and ('has input' some 'NAD(1-)') and ('has output' some 'NADH(2-)')
• NADPH oxidation == 'metabolic process' and ('has input' some 'NADPH(4-)') and ('has output' some 'NADP(3-)')
• NADPH regeneration == 'metabolic process' and ('has input' some 'NADP(3-)') and ('has output' some 'NADPH(4-)')

@pgaudet @ukemi is this on purpose? Noticed this due to inferences in this PR: #24276

[balhoff]

More specifically, should NADH metabolic process follow the design pattern? It's the one causing the inference in the PR. The others are a little different given that they have inputs and outputs. Should they be "primary" inputs and outputs?

[deustp01]

• 'has primary input or output' some NAD

Not sure what is meant here by "NAD". All the other relations use forms with correct pH 7.3 charge states, while this one appears not to. Is that because it's intended to be a higher-level grouping term (in which case, as is clear from the lower-level terms in all the other relations, there is no single correct charge state)?

[deustp01]

More specifically, should NADH metabolic process follow the design pattern?

What is "metabolic process" intended to mean here? If it's specifically the de novo synthesis of NADH then NADH(2-) is a primary output. If it's something broader, including synthesis and breakdown and oxidation / reduction interconversions, then all that covers all these cases is participant. @ukemi @hdrabkin

[balhoff]

@deustp01 we are using 'has primary input or output' for something more specific than 'has participant' in the design pattern for metabolic processes, and then under that catabolic processes use 'has primary input' and synthesis processes use 'has primary output'.

It seems to me that the oxidation and regeneration processes should use "primary" relations rather than just 'has input' and output.

[ukemi]

This has been a long term discussion. At one point I think we had concluded that not every reaction that uses NAD+ NADH(-2) should be considered a type of metabolism of of these molecules. But clearly in some processes these are the primary players in the process from a biochemistry point of view. As @deustp01 points out, the formation of these molecules is certainly a class where they are the primary output. But is oxidation/reduction coupled to every reaction that uses these (detailed biochemistry aside where they clearly are) or are these processes reserved for special cases where the objective of these processes is to use the molecules are used in very specific ways? For example the NADH that is made in the TCA cycle is special, it is a major player in a downstream process. Maybe this doesn't hold water. I know we have discussed this before.

[balhoff]

I looked at reasoning changes from switching to "primary" relations for oxidation/regeneration. By doing that they go back under "metabolism" but they lose some subclasses. I think we need a discussion of what the intention is for the meaning.

[balhoff]

We merged #24288 prematurely. I reverted the second commit (about oxidation/regeneration) in #24291, so that we can resolve this later.

[cmungall]

We have over a thousand annotations to http://amigo.geneontology.org/amigo/term/GO:0006734, hopefully we all know what the inclusion and exclusion criteria are for this class, otherwise we will have inconsistent annotation

Shouldn't grouping classes like this have a do-not-annotate? Why would someone ever directly annotate to this?

It seems most annotations stem from a handful of rat publications http://amigo.geneontology.org/amigo/reference/PMID:12351438

seems a more specific term covering the concept of NADH shuttle was what the curator was after

[deustp01]

While we're resolving, here's a related inconsistency:

GO:0006734 NADH metabolic process has the definition "The chemical reactions and pathways involving reduced nicotinamide adenine dinucleotide (NADH), a coenzyme present in most living cells and derived from the B vitamin nicotinic acid." but GO:0006739 NADP metabolic process has the definition "The chemical reactions and pathways involving nicotinamide-adenine dinucleotide phosphate, a coenzyme involved in many redox and biosynthetic reactions; metabolism may be of either the oxidized form, NADP, or the reduced form, NADPH. I can't think of any good biochemical reason to be interested in NAD metabolism only when it's reduced, while NADP metabolism is of interest whether it's reduced or not.

And GO:0006734 (NAD) and GO:0006739 (NADP) should probably be sibling terms, not distant cousins (i.e., the NAD term should be much closer to the NADP term in the hierarchy.