7 replies to this topic

[recon]

This is mostly just my hypothesis but from Katsyuba 2017 I see that both the de novo and the salvage pathways use one same enzyme.

[1]
In the de novo pathway,
NA —> NAMN —> NAAD —> NAD+
The change from NAMN to NAAD is catalysed by NMNAT.

In the salvage pathway,
NR —> NMN —> NAD+
The change from NMN to NAD+ is catalysed by NMNAT.

So, for those taking NR having a shorter route to NAD+, we shouldn’t take NA at the same time?
If NMNAT is limited, then wouldn’t engaging it through the de novo pathway by taking NA be taking away the needed NMNAT for NR?

I’ve always thought that taking NA will help increase NAD+ level because it uses another pathway.


Reference:
[1]
Modulating NAD(+) metabolism, from bench to bedside.
Katsyuba E, et al. EMBO J. 2017 Sep 15;36(18):2670-2683. doi: 10.15252/embj.201797135. Epub 2017 Aug 7.
https://www.ncbi.nlm...ubmed/28784597/

Edited by recon, 11 November 2017 - 03:49 AM.

[Michael]

I don't think that's likely ... if NNAD competes with NMN for NMAT, all that happens is that one precursor is used to generate NAD instead of the other: you get NAD either way. There's nothing 'special' about NAD derived from one precursor vs. another.

 

The only exception would be if the enzymatic activity of NMAT were much lower for NNAD than NMN, in which case there's a possibility of the slower conversion leading to reduced overall NAD synthesis when both are present than if NMN were present alone. I'm not aware of any evidence to that effect, but I've not looked into it and don't know if the question has even been investigated.

[recon]

I don't think that's likely ... if NNAD competes with NMN for NMAT, all that happens is that one precursor is used to generate NAD instead of the other: you get NAD either way. There's nothing 'special' about NAD derived from one precursor vs. another.

The only exception would be if the enzymatic activity of NMAT were much lower for NNAD than NMN, in which case there's a possibility of the slower conversion leading to reduced overall NAD synthesis when both are present than if NMN were present alone. I'm not aware of any evidence to that effect, but I've not looked into it and don't know if the question has even been investigated.

While there may not be evidence that NMNAT activity for NAMN is slower than that for NMN, there is more steps for NAMN to become NAD+ (NAMN —> NAAD —> NAD+) than NMN (NMN —> NAD+). That’s technically equivalent.

I’m worried that the longer (and thus slower) pathway from the de novo pathway will allow more activity by CD73 for reverse catalysis of NMN back to NR. Plus, I hypothesise that the over abundance of the pool of NMN that is accumulating but not acted upon by NMNAT may either downregulate the NRK to reduce the continuous addition of NMN or upregulate NMNAT for elimination or both.

Edited by recon, 11 November 2017 - 09:02 PM.

[Michael]

I see... You know, that's a good point. We'd again want to know the K_Ms of all the reactions involved, but on its face that does seem biochemically plausible.

 

I wonder if the huge and unexplained jump in NAAD following NR administration in Trammel-Brenner PMID 27721479 isn't possibly tied in with this womehow. Certainly, if NR-derived NMN were hogging all the NMAT, you wouldn't expect a concomitant spike in NAAD.

[recon]

That’s really interesting, Michael. I’ll look up Trammel-Brenner PMID 27721479 to see what’s all that about.

For now, you’re right that if NMNAT is being hogged by NMN in the salvage pathway, then theoretically NAAD from the de novo pathway shouldn’t see a spike.

More hypotheses can be inferred and I’ll take a look at the literature to see if I can disprove any of these:

1. Increase in NMN following administration of NR upregulates NMNAT that also helps in NAMN to NAAD.

2. Increase in NAD+ somehow reverse catalyse back into NAAD via some sort of a reverse de novo pathway. From a PM with LenaW, I was reiterated the basic idea that enzyme works both ways provided that the active binding sites remain the same. So it could be possible that NAD+ can somehow back-catalyse into NAAD.

3. Increase in NAD+ downregulates NADS that turns NAAD into NAD+ in order to stop accumulation.

4. NMNAT preferentially catalyses NAMN into NAAD instead of NMN to NAD+. We’d need to know the rate of reactions for this.

5. Involvement of extra genes, proteins or enzymes I have yet to learn.

6. More or all of the above.

[able]

 

 

While there may not be evidence that NMNAT activity for NAMN is slower than that for NMN, there is more steps for NAMN to become NAD+ (NAMN —> NAAD —> NAD+) than NMN (NMN —> NAD+). That’s technically equivalent.

I’m worried that the longer (and thus slower) pathway from the de novo pathway will allow more activity by CD73 for reverse catalysis of NMN back to NR. Plus, I hypothesise that the over abundance of the pool of NMN that is accumulating but not acted upon by NMNAT may either downregulate the NRK to reduce the continuous addition of NMN or upregulate NMNAT for elimination or both.

 

 

I guess in theory, a lot of NA and NMN may run into a bottleneck, but I don't quite understand WHY you suppose NA could hog all the NMNAT, or why it could be a rate-limiting factor, other than the fact both NA and NMN use that enzyme.

 

The Trammel paper shows in figure 5g that NA is pretty much all gone from the liver within about 1 hour or so.

 

So at least this first step in the  NA de novo pathway, using NMNAT, doesn't seem slow or rate limited.

[recon]

While there may not be evidence that NMNAT activity for NAMN is slower than that for NMN, there is more steps for NAMN to become NAD+ (NAMN —> NAAD —> NAD+) than NMN (NMN —> NAD+). That’s technically equivalent.

I’m worried that the longer (and thus slower) pathway from the de novo pathway will allow more activity by CD73 for reverse catalysis of NMN back to NR. Plus, I hypothesise that the over abundance of the pool of NMN that is accumulating but not acted upon by NMNAT may either downregulate the NRK to reduce the continuous addition of NMN or upregulate NMNAT for elimination or both.

I guess in theory, a lot of NA and NMN may run into a bottleneck, but I don't quite understand WHY you suppose NA could hog all the NMNAT, or why it could be a rate-limiting factor, other than the fact both NA and NMN use that enzyme.

The Trammel paper shows in figure 5g that NA is pretty much all gone from the liver within about 1 hour or so.

So at least this first step in the NA de novo pathway, using NMNAT, doesn't seem slow or rate limited.

I haven’t taken a look at the paper yet since I’m running backlog on papers presented to me, but I believe that the Trammel paper compares individual administration of NR or NA. If so, then it’s irrelevant in this case on how fast NA is gone. What I want to know is during coadministration with NR, whereby the same NMNAT is used, will NA’s use of NMNAT affects NR’s given that bottlenecking one or the other via the other pathway using the same rate-limiter may downregulate something.

The fact that NA is gone within the hour may mean that it is converted into NAMN by NAPRT. Now, NAMN requires NMNAT to convert into NAAD. NMNAT is also required for converting NMN auto NAD+ if NR or NMN is taken.

My hypothesis is then that since both of these require NMNAT at the same time, will that give CD73 time to reverse catalyse NMN back to NR?

So I may not be understanding what you’ve brought up but I don’t see any conflict to my case here.

PS: Using NMNAT is not the first step of the de novo pathway for NA. NA is first converted to NAMN via NAPRT. That may be where your case detracted.

[recon]

Oh. After reading your statement again, you may be asking why do I think NA is the “culprit” to hogging NMNAT given that both NMN and NA uses them.

If that’s the case, no I don’t. I don’t think NA or NMN in particular is hogging the NMNAT. It may be NA more than NMN, or NMN more than NA, or even equally, and I cannot find out unless I know the rate of reactions for each of them.

However,
1) given that NMN can be reverse catalysed back to NR via CD73, I therefore hypothesise that even if the NMNAT is equally used, we're possibly slowing down NMN to NAD+ and allowing more time for CD73 to work. So eventually, some NMN will become NAD+ and some will become NR back, while all of NA will eventually become NAAD and still have one more step to go.

2) given that NR is much much more expensive and NA is trivially cheaper, NA is technically making NR less effacious in this sense if I am right. It could be true that NR is hogging the NMNAT that NA uses but then NAMN have no reverse catalysis so it’ll become NAAD eventually anyways while NMN from NR will turn back by time.

Edited by recon, 12 November 2017 - 09:52 PM.