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