NAD(P) metabolic process terms

[sjm41]

We currently have this arrangement:

NAD metabolic process
|__NAD biosynthetic process
|__NAD catabolic process
|__NADH metabolic process
    |__NADH oxidation
    |__NADH regeneration

NADP metabolic process
|__NADP biosynthetic process
|__NADP catabolic process
|__NADPH oxidation
|__NADPH regeneration

And here are the terms:

id: GO:0019674
name: NAD metabolic process
def: "The chemical reactions and pathways involving nicotinamide adenine dinucleotide (NAD), a coenzyme present in most living cells and derived from the B vitamin nicotinic acid." [GOC:jl, ISBN:0618254153]
intersection_of: GO:0008152 ! metabolic process
intersection_of: has_primary_input_or_output CHEBI:13389 ! NAD
property_value: term_tracker_item "#21577" xsd:anyURI
property_value: term_tracker_item "#23467" xsd:anyURI

id: GO:0009435
name: NAD biosynthetic process
def: "The chemical reactions and pathways resulting in the formation of nicotinamide adenine dinucleotide, a coenzyme present in most living cells and derived from the B vitamin nicotinic acid; biosynthesis may be of either the oxidized form, NAD, or the reduced form, NADH." [GOC:jl, ISBN:0618254153]
intersection_of: GO:0009058 ! biosynthetic process
intersection_of: has_primary_output CHEBI:13389 ! NAD
property_value: term_tracker_item "#21577" xsd:anyURI

id: GO:0019677
name: NAD catabolic process
def: "The chemical reactions and pathways resulting in the breakdown of nicotinamide adenine dinucleotide, a coenzyme present in most living cells and derived from the B vitamin nicotinic acid; catabolism may be of either the oxidized form, NAD, or the reduced form, NADH." [GOC:jl, ISBN:0618254153]
intersection_of: GO:0009056 ! catabolic process
intersection_of: has_primary_input CHEBI:13389 ! NAD
property_value: term_tracker_item "#21577" xsd:anyURI

id: GO:0006734 (28 direct EXP annotations)
name: NADH metabolic process
def: "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." [GOC:jl, ISBN:0618254153]
intersection_of: GO:0008152 ! metabolic process
intersection_of: has_primary_input_or_output CHEBI:57945 ! NADH(2-)

id: GO:0006116 (25 direct EXP annotations)
name: NADH oxidation
def: "A metabolic process that results in the oxidation of reduced nicotinamide adenine dinucleotide, NADH, to the oxidized form, NAD+." [GOC:ai]
intersection_of: GO:0008152 ! metabolic process
intersection_of: has_primary_input CHEBI:57945 ! NADH(2-)
intersection_of: has_primary_output CHEBI:57540 ! NAD(1-)
property_value: term_tracker_item "#21577" xsd:anyURI

id: GO:0006735 (9 direct EXP annotations)
name: NADH regeneration
def: "A metabolic process that generates a pool of NADH by the reduction of NAD+." [GOC:mah]
intersection_of: GO:0008152 ! metabolic process
intersection_of: has_output CHEBI:57945 ! NADH(2-)
intersection_of: has_primary_input CHEBI:57540 ! NAD(1-)
intersection_of: has_primary_output CHEBI:57945 ! NADH(2-)

---

id: GO:0006739
name: NADP metabolic process
def: "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." [GOC:mah]
intersection_of: GO:0008152 ! metabolic process
intersection_of: has_primary_input_or_output CHEBI:58349 ! NADP(3-)
property_value: term_tracker_item "#23467" xsd:anyURI

id: GO:0006741
name: NADP biosynthetic process
def: "The chemical reactions and pathways resulting in the formation of nicotinamide-adenine dinucleotide phosphate, a coenzyme involved in many redox and biosynthetic reactions; biosynthesis may be of either the oxidized form, NADP, or the reduced form, NADPH." [GOC:mah]
intersection_of: GO:0009058 ! biosynthetic process
intersection_of: has_primary_output CHEBI:58349 ! NADP(3-)

id: GO:0006742
name: NADP catabolic process
def: "The chemical reactions and pathways resulting in the breakdown of nicotinamide-adenine dinucleotide phosphate, a coenzyme involved in many redox and biosynthetic reactions; catabolism may be of either the oxidized form, NADP, or the reduced form, NADPH." [GOC:mah]
intersection_of: GO:0009056 ! catabolic process
intersection_of: has_primary_input CHEBI:58349 ! NADP(3-)

id: GO:0070995 (16 direct EXP annotations)
name: NADPH oxidation
def: "A metabolic process that results in the oxidation of reduced nicotinamide adenine dinucleotide, NADPH, to the oxidized form, NADP." [GOC:BHF, GOC:mah]
is_a: GO:0006739 ! NADP metabolic process
intersection_of: GO:0008152 ! metabolic process
intersection_of: has_primary_input CHEBI:57783 ! NADPH(4-)
intersection_of: has_primary_output CHEBI:58349 ! NADP(3-)

id: GO:0006740 (24 direct EXP annotations)
name: NADPH regeneration
def: "A metabolic process that generates a pool of NADPH by the reduction of NADP+." [GOC:mah]
is_a: GO:0006091 ! generation of precursor metabolites and energy
is_a: GO:0006739 ! NADP metabolic process
intersection_of: GO:0008152 ! metabolic process
intersection_of: has_primary_input CHEBI:58349 ! NADP(3-)
intersection_of: has_primary_output CHEBI:57783 ! NADPH(4-)

---

I think there are several issues to address here:

• In all these defs, "the oxidized form" should be reported as 'NAD+' or ''NADP+' rather than just 'NAD' or 'NADP'.

• For the 'NAD metabolic process' term def, should add "metabolism may be of either the oxidized form, NAD+, or the reduced form, NADH." to match the defs of the child 'NAD biosynthetic/catabolic process' terms as well as the def of the equivalent 'NADP metabolic process' term.

• Implementing the point above would make the "NADH metabolic process" term redundant, so it should be obsoleted (or rather merged into the parent 'NAD metabolic process' term). Doing so would also then match how the NADP branch is already organised.

• As alluded to in malate-aspartate shuttle parentage #27924, "NADH oxidation" and "NADPH oxidation" are just inevitable consequences of these factors acting as co-enzymes for oxidoreductase enzymes - I can't see any utility in having these terms (as defined), since they could be applied to any oxidoreductase reaction using NAD(P)H and operating in the reductase direction. Suggest these two terms are obsoleted.

• Change the primary_input/output chemical on the NAD metabolic/biosynthesis/catabolic terms from 'CHEBI:13389 ! NAD' to 'CHEBI:57540 ! NAD(1-)' to be consistent with how this is reported in the other terms mentioned above. (This was meant to be fixed in Change logical definition of 'GO:0019674 NAD metabolic process #23467, but doesn't look like it actually happened.)

• The LD of the 'NADH regeneration' term has the same CHEBI as both 'has_output' and 'has_primary_output' - remove the former.

• The 'NADPH regeneration' term appears to have a "is_a: GO:0006739 ! NADP metabolic process" relation that is redundant with the LD - need to check and remove if so.

I found PMID:28648096 is a good general review of NAD(H) and NADP(H) biology, including synthetic pathways.

@rozaru @deustp01 @ukemi

See also ticket #24279

[rozaru]

The NAD biosynthetic process branch will need some updating too.

NAD biosynthetic process
    |__'de novo' NAD biosynthetic process
    |   |__'de novo' NAD biosynthetic process from aspartate
    |   |__'de novo' NAD biosynthetic process from tryptophan(+ regulatory terms)
    |__NAD biosynthesis via nicotinamide riboside salvage pathway
    |__NAD salvage

This is how the GO terms fits into the various pathways known to make NAD.

There are various issues:

1. term definitions needs to be updated
2. some Xref to MetacCyc are missing
3. misplaced terms

---

For the parent:

GO:0009435 NAD biosynthetic process
def: "The chemical reactions and pathways resulting in the formation of nicotinamide adenine dinucleotide, a coenzyme present in most living cells and derived from the B vitamin nicotinic acid; biosynthesis may be of either the oxidized form, NAD, or the reduced form, NADH."

• the definition is too restrictive and doesn’t mention the alternative routes
• vitamin B3 would be the correct term and this term normally includes various forms including nicotinamide and nicotinic acid (nicotinate)

Proposal 1:

def:"The chemical reactions and pathways resulting in the formation of nicotinamide adenine dinucleotide (NAD), a coenzyme present in most living cells; biosynthesis may be of either the oxidized form, NAD, or the reduced form, NADH."

Proposal 2:

def:"The chemical reactions and pathways resulting in the formation of nicotinamide adenine dinucleotide (NAD), a coenzyme present in most living cells and is derived from various sources including vitamin B3; biosynthesis may be of either the oxidized form, NAD, or the reduced form, NADH."

---

For these 2 terms:

GO:0034628 'de novo' NAD biosynthetic process from aspartate
def: "The chemical reactions and pathways resulting in the formation of nicotinamide adenine dinucleotide (NAD), beginning with the synthesis of aspartate from simpler precursors; biosynthesis may be of either the oxidized form, NAD, or the reduced form, NADH."

GO:0034354 'de novo' NAD biosynthetic process from tryptophan
def: "The chemical reactions and pathways resulting in the formation of nicotinamide adenine dinucleotide (NAD), beginning with the synthesis of tryptophan from simpler precursors; biosynthesis may be of either the oxidized form, NAD, or the reduced form, NADH."

• both definitions “beginning with the synthesis of aspartate/tryptophane”. This is incorrect as it is their catabolism that provides the precursor quinolinate for NAD biosynthesis
• normally it's L-aspartate and L-tryptophan

Proposal:

GO:0034628 'de novo' NAD biosynthetic process from L-aspartate
def: "The chemical reactions and pathways resulting in the formation of nicotinamide adenine dinucleotide (NAD), beginning with the catabolism of L-aspartate into the precursor quinolinate; biosynthesis may be of either the oxidized form, NAD, or the reduced form, NADH."

GO:0034354 'de novo' NAD biosynthetic process from L-tryptophan
def: "The chemical reactions and pathways resulting in the formation of nicotinamide adenine dinucleotide (NAD), beginning with the catabolism of L-tryptophan into the precursor quinolinate; biosynthesis may be of either the oxidized form, NAD, or the reduced form, NADH."

---

For these terms:

GO:0034355 NAD salvage
def: "Any process that generates nicotinamide adenine dinucleotide (NAD) from derivatives of it, without de novo synthesis; salvage is usually from the degradation products nicotinic acid (Na) and nicotinamide (Nam)."

• “from the degradation products...” it’s probably true but they are mostly acquired from the diet
• the term name may be updated
• In the literature, the production of NAD from nicotinate (nicotinic acid) is called the Preiss-Handler pathway, some authors include it in the salvage pathway other not. For the moment the NAD salvage GO term includes it.

Proposal:

GO:0034355 NAD salvage biosynthetic process
Def: Any process that generates nicotinamide adenine dinucleotide (NAD) from vitamin B3 derivatives including nicotinic acid (NA) and nicotinamide (NAM), without de novo synthesis. NAD can also be produced from beta-nicotinamide D-ribonucleotide (NMN) or beta-nicotinamide D-riboside (NR).

GO:0034356 NAD biosynthesis via nicotinamide riboside salvage pathway
def: "The chemical reactions and pathways resulting in the formation of nicotinamide adenine dinucleotide (NAD) from the vitamin precursor nicotinamide riboside."

• it should be a child of GO:0034355 NAD salvage
• Should this term be kept or merged to NAD salvage?
• If the term is kept the name and the definition will need to be updated and the other compounds would need their own GO term

[pgaudet]

Hi @rozaru

Maybe GO:0034355 NAD biosynthetic process by/via (the) salvage pathway sounds less GO-speak?

[rozaru]

@pgaudet
I like your suggestion "NAD biosynthetic process via the salvage pathway", it works better.

[ukemi]

@tberardini , the proposal is to implement the above changes with the NADP branch of GO as well. I thought it would be good to check with you since IIRC (I might be wrong) NADP is the more prominent metabolite in plants than it is in animals.