Nicotinate Metabolism (R-HSA-196807)

[ukemi]

• Make mouse models : http://noctua.geneontology.org/editor/graph/gomodel:678073a900002053? (copied from fly with instances cleaned up);
• Make fly model

In fly:

• De novo synthesis from tryptophan appears not to be functional (no ortholog for human HAAO (3-hydroxyanthranilate 3,4-dioxygenase) and human QPRT (Nicotinate-nucleotide pyrophosphorylase) (PMID:38481042) and no quinolinic acid detected in fly)
• No ortholog in fly for human NAMPT (NAM to NMN reaction)
• fly has nicotinamide amidase (Naam) (Nam to NA), no ortholog in mammals

For the moment I made 3 separate models for NA, Nam and NR but we are thinking to merge them into one unique model.

• the mitochondrial NAD transporter is missing. I was wondering if it would be possible to add it to the human model (SLC25A51)Q9H1U9 the uniprot entry has all the publication links). Upstream of R-HSA-8955030?
• R-ALL-197220 (ChEBI:15763) should be replaced with the conjugate base CHEBI:57502.
• Should the output (ChEBI18304) of R-HSA-197235 be deamido-NAD zwitterion (CHEBI:14105) or deamido-NAD(2−) (CHEBI:58437). Fly model has the latter, but is the zwitterion more correct for Ph7.3?

I used Rhea reactions RHEA 22860 and RHEA 24384 to build the model and they both use CHEBI:58437. Do you think they made a mistake?

• @rozaru for one of your models (gomodel:678073a900000085 ), you have 2 activities occurring in the cytosol and one occurring in the cytoplasm. I assume that is because the enzyme is attached to the Golgi membrane. This is one of those cases where the reaction occurs in a different location that the localization of the protein and is one of the weaknesses of the GO-CAM. Just a heads up that in my model, I changed everything to cytosol.

This is an issue that I kept having problems with. Here the correct GO term is cytosol but in fly the experimental evidence is for cytoplasm. While looking for better evidence I kept the cytoplasm GO term. When I will make the model into production I will change it to cytosol. Sorry for the confusion.

[rozaru]

I am just adding the link to the ticket that we made with @sjm41 about the NAD metabolic process that we are trying to sort out.
geneontology/go-ontology#29050

[ukemi]

@deustp01 I think there might be a mistake in this pathway in Reactome? The blurb of R-HSA-197250 states that the reaction produces nicotinamide D-ribonucleotide (NMN), which would be CHEBI:14649 or maybe CHEBI:16171. However, the output of the reaction is nicotinate D-ribonucleotide (15763). If the output really is the amide, this would mean that the salvage pathways would not need feed into the 'de novo' pathway via nicotinate D-ribonucleotide with further processing to NAD via the activity of the synthase. Instead, the nicotinamide D-ribonucleotide (NMN) would be directly converted to NAD by the NMNAT paralogs. The MF for this reaction would be 'nicotinamide-nucleotide adenylyltransferase activity' (GO:0000309) and not 'nicotinate-nucleotide adenylyltransferase activity' (GO:0004515). This is consistent with the figure 2 in PMID:33028824](https://pubmed.ncbi.nlm.nih.gov/33028824/) and the studies presented in PMID: 34290089. There is also some evidence in PMID:38357931 that at least NADSYN1 is not important for salvage, you can take a look. Note this reaction, R-HSA-8939959, is the one from the amide. I think this should be injected into the salvage pathway after R-HSA-197250. The question now is whether the nuclear and mitochondrial paralogs can catalyze both reactions. At any rate, I think the amide one needs to be added to the pathway for NMNAT1 and NMNAT3.

I am still puzzled about the 'de novo' pathway in PMID:33028824](https://pubmed.ncbi.nlm.nih.gov/33028824/) as it shows the synthase acting on NAMN rather than NAAD. According to GO:0008795 it does act on the latter. So that leaves the question of how we go from NAMN to NAAD. Can the NMNAT paralogs also accept nicotinate D-ribonucleotide and catalyze the reaction shown in Reactome to NAAD?

I'd love to have you sanity check all of this. Note also @rozaru 's pathway (http://noctua.geneontology.org/editor/graph/gomodel:678073a900000085?)which can go through the acid/base because of the Naam enzyme that's not present in mammals. And her pathway has the fly NMNAT enzyme working on the acid. The authors of PMID:15310905 and PMID:14704851 state that the enzyme can work on the amide and the acid. https://enzyme.expasy.org/EC/2.7.7.1

[ukemi]

The definition of GO:0034354 'de novo' NAD biosynthetic process from tryptophan

"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."

is not correct. this pathway is downstream of the CATABOLISM of tryptophan through [CHEBI:77803] 2-ammonio-3-(3-oxoprop-1-enyl)but-2-enedioate(1-), which spontaneously forms quinolinate(2-)