NADH and FADH2 redox reactions are built deep into our biochemistry. For example, pyridine nucleotides are involved in >500 enzymatic reactions. When we look at the structure of deamido-NAD+, it is strikingly symmetrical:

NAD, with nicotinic

The same is true for FAD, a two-headed monster of a nucleotide flavin mononucleotide

in which we can recognize the two heads, belonging to xanthosine (a purine nucleotide) and alpha-ribazole 5'-phosphate, the latter of which is produced from flavin in the course of B12 synthesis:

xanthosine alpha-ribazole 5'-phosphate

The phosphoribose can be swapped between alpha-ribazole 5'-phosphate and nicotinic acid.

Given such enticing hints, it is tempting to speculate that one or more of these nucleotides might be so fundamental because it was actually part of some ancient RNA primary sequence, giving RNA containing this code the power to do serious catalytic chemistry with acid and amide groups, powerful options for redox and methyltransferase activity and more.

I know this is a hard question to answer, but is there any evidence that weighs in, or could weigh in, on whether this happened? For example, if these functional groups are too unstable in regard to intramolecular reactions on a strand of RNA, or if there is no way to envision a potential base pair that would be reliably distinguished from the known base pairings. Or if RNA editing sometimes creates them in some organism. Or if aptamers made from these subunits show improved catalytic possibilities. (That doesn't seem so easy to look up, since many papers look for aptamers binding these as prosthetic groups, rather than incorporating them) It would be useful simply to have a notion of what evidence for such an idea would look like.

  • $\begingroup$ Have you searched the literature relating to thoughts on the adenine nucleotide components of NAD and FAD? I am not familiar with this myself, but it clearly must be extensive. My own thoughts on the subject (probably off-topic here) do not include your suggestion of these having been "bases". Nicotinamide and flavin do not look remotely like the bases, have no obvious "pair", and are essentially later oxidising agents to the likely more ancient Fe–S electron redox centres. If they arose to supply the redox function which ribozymes lack, how might they bind to the latter? $\endgroup$ – David Mar 1 at 20:51
  • $\begingroup$ Your thoughts shouldn't be off topic - if you can make a good case for late evolution of NADH and FADH2, then it would rule out the idea. But to my eye, nicotinamide and 5,6-dimethylbenzimidazole don't seem any more different from purines and pyrimidines than those two are from each other. (I'm not claiming to know what they would base pair with) $\endgroup$ – Mike Serfas Mar 2 at 0:35
  • $\begingroup$ There are NAD capped RNAs [1,2] but that's not what you are asking, right? $\endgroup$ – WYSIWYG Mar 2 at 9:20
  • $\begingroup$ There are two reasons that I think this question off-topic. The first is that although you have asked for chemical arguments, answers are likely to be matters of opinion. The second is that it does not really conform to the question and answer format of this site, but is more to the discouraged type "I have this idea, am I right?". The way I see of resolving this (because I find the topic interesting) is given in the following comment. $\endgroup$ – David Mar 2 at 11:18
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    $\begingroup$ Mike. I'd like to discuss this sort of question, but I have been rather busy over the last few months and am only just re-engaging with the list again in a small way. I am still quite busy and have some other questions here that I need to tidy up loose ends on. I would prefer to wait until I have time to do some reading in this area and then post a question that I feel can generate some good answers. (The great thing about being a scientist is that you never retire. It's just that there comes a time when people aren't paying you any more.) $\endgroup$ – David Mar 2 at 17:26

There are naturally occurring RNAs that contain a NAD "cap" at 5' end (Bird et al., 2018; Wang et al., 2019).

I could not find any papers on natural RNAs with nicotinamide or flavin as a regular base. However, a study with synthetic oligonucleotides reports that NAD containing oligonucleotides can form stable triplex structures (Göckel & Richert,2015).

There are two studies from 1970s that explore base pairing potential of flavin. Raszka and Kaplan (1974) report that FMN can hydrogen-bond with AMP but not other nucleotides. They further explore this finding to show that FAD can form intramolecular hydrogen bonds. Scarbrough et al (1976) show that flavin containing nucleotides can form stacking interaction in addition to base pairing kind of hydrogen bonds. (Compare D-X bonds) enter image description here

More recently, Julius et al. (2020) have shown that NAD and FAD can act as co-factors of primase to initiate DNA replication.

Overall, it seems plausible for FAD and NAD to be a part of nucleotide chains (more plausibly for RNA as they are already known to contain a variety of unusual bases). However, I cannot comment if they really did play such a role during cellular evolution.


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