Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation (R-HSA-1474151)

[ukemi]

Make Mouse models:
http://noctua.geneontology.org/editor/graph/gomodel:67369e7600004836?
http://noctua.geneontology.org/editor/graph/gomodel:67369e7600005945?

[ukemi]

I have modeled the regulation of Gch1 differently than the reactome pathway. I have phenylalanine and BH4 regulating the inhibitory activity of GPCR.

[deustp01]

In response, I will take your work on tetrahydrobiopterin (R-HSA-1474151) in the getting-rid-of-molecular events, clean up the molecular events you noted as my next project to fix chemistry / align with RHEA and UniProt.

[ukemi]

Are R-HSA-1497784 and R-HSA-1497796 really part of this pathway? Not that I know where else to put them. I suspect they would be omitted in GO-CAMs.

[deustp01]

I'm working through thr BH4 pathway noe and will see if these reactions can be fitted into NO metabolism instead.

[ukemi]

I don't know how much you want to revise the pathway, but it looks like there is a bit missing wrt possible paths to BH4. See Figure 2 in PMID:37251335. Also see PMID:12893295 and PMID:2597161.

[deustp01]

It is a mess! see "tetrahydrobiopterin notes" Google Doc in the "pathways done" folder. I'll look next to see if your references help fill gaps or otherwise make sense of stuff I don't understand. I am also trying to understand how much of the discussion of interconnections with NO metabolism is based on real evidence form plausible systems and how much is a wishful attempt to tie folate metabolism to a hot topic.

[ukemi]

Thanks @deustp01. One thing that might be helpful is to look at the pathways that I distilled from Reactome for mouse (linked above). There are a lot of references to the NOS linkage, but where does one thing end and another begin. There are certainly other things downstream that are not in this pathway. I don't have the pathway through BH3 because I wasn't sure how it fit in.

[deustp01]

The mess is even worse. We currently annotate R-HSA-1497794 as catalyzed by DHFR. Wrong. DHFR acts on folates, not their smaller cousins pterins. The correct human enzyme is QDPR and it looks to me like the RHEA reaction should be RHEA:32249 (6R)-L-erythro-6,7-dihydrobiopterin [CHEBI:43120] + NADPH + H(+) => (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin [CHEBI:59560] + NADP(+). (I've added this information to the entry for the reaction in the "tetrabiopterin notes" document linked two comments above.)

If I am now right, Figure 2 of the Cronin et al. paper PMID:37251335, which shows DHFR catalyzing this reaction, is also wrong. Perhaps @sjm41 has some independent chemistry expertise that he could apply here? I'm in over my head.

[ukemi]

There is genetic evidence that it can also be Dhfr (PMID:19666465 and PMID: 21402147).

[deustp01]

PMID: 21402147

And indeed we cite this reference for the DHFR-enabled reaction, so the Reactome error was to provide folate inputs and outputs instead of the correct pterin ones. More than that, we manually inferred the human reaction by homology from mouse.

[ukemi]

It looks like the inputs and outputs are correct when you look at the upstream enzyme. But the activity isn't 'dihydrofolate reductase activity', right? It should be '7,8-dihydrobiopterin reductase activity', which we don't have.

[deustp01]

'7,8-dihydrobiopterin reductase activity', which we don't have

So we have to go to a parental term, GO:0016646 oxidoreductase activity, acting on the CH-NH group of donors, NAD or NADP as acceptor?

[ukemi]

I think so, or request the term.

[deustp01]

RHEA reaction should be RHEA:32249

Wrong - RHEA is for the 6,7 positions and we need 7,8 - same problem as with GO MF term

[sjm41]

https://www.uniprot.org/uniprotkb/P09417/entry says that QDPR catalyses:
Rhea 17865
5,6,7,8-tetrahydropteridine + NADP+ = 6,7-dihydropteridine + NADPH + H+
EC:1.5.1.34

= GO:0004155 6,7-dihydropteridine reductase activity

But that's no good if you really need a 7,8 reductase.....