What-if: Biosynthesis of deazaguanine

Sunday, 15 December 2019

What-if: Biosynthesis of deazaguanine

7-deazaguanine is an analogue of guanine that has a carbon instead of a nitrogen. This molecule that is not made in nature, but many substituted versions, namely queine, archaeosine nucleobase and their precursors. These are made via a different route. However, it would be very feasible to make via straightforward enzymology.

Derivatives and backbones

One thing that needs to be addressed is the difference between a molecule that is the precursor from which another is synthetically derived (i.e. a derivative) and a molecule that forms the backbone/skeleton of another, which differs by the presence of various substituents, but may have not have been made from the backbone molecule. This is the case of queine having a deazaguanine skeleton. In biochemistry this is quite common as the skeleton molecule will be unsubstituted, whereas polyketide or isoprenoids derivatives will have ketones, hydroxyls or methyls too many (for example, see wiki/Flavonoid).

The way queuosine, the nucleotide form of queine, is made is really disturbing. A complete guanosine has its ribose "merged" with the elimination of formic acid and acetayldehyde resulting in carbonyldeazaguanine. That is, it never goes through dezaguanine. So how can deazaguanine be made?

How can it be made?

The enzymes in the nucleotide biosynthesis pathways are very fast, which is not surprising given the high demand for their products. However, whne looking at the steps one can seem some steps that seem overly laborious. This is because, nucleotide biosynthesis is primordial: both the purine and the pyrimidine pathways used surprisingly simple compounds and many intermediate are able to form rudimentary base pairs. This is particularly true with the smaller ring of purines, which is synthesised first. First glycine forms an amide bond to an amino-derivatised ribose. Then a formyl is added. Then a side step happens and the aldheyde (from the formyl) attacks the original amine of the ribose. The nitrogen-7 of guanine is therefore derived from the nitrogen of the glycine.
However, what if the amino acid was not formyl-glycine, but aspartate semialdehyde? You'd end up with 7-deazaguanine!
Aspartate semialdehyde is a derivative of aspartate and is a precursor for lysine, the BCAAs, threonine and methionine. Actually, the one carbon longer version, glutamate semialdehyde, which is a precursor for arginine and proline, spontaneously cyclises with the same mechanism.

Why is it not made?

There are three major reasons.
  • It will alter the behaviour of RNA and DNA. The product of AIR synthetase is an early step. Assuming that the increased hydrophobicity of the growing nucleobase was not a problem it would be promiscuously pushed along resulting in deazainosine and then deazaadenosine and dezaguanosine. At some stage an enzyme will need to stop the latter two from being incorporated into DNA and RNA either stopping the production of their triphosphates forms or laboriously error-correcting DNA and RNA.
  • A 7-deazapurine is more hydrophobic than a purine, which already partitions more in octanol than in water, so it is less ideal than guanine.
  • There really ought to be a reason to make it and because it is cool is not really valid...


  1. Crippen, C. S., Lee, Y.-J., Hutinet, G., Shajahan, A., Sacher, J. C., Azadi, P., Crécy-Lagard, V. de, Weigele, P. R., and Szymanski, C. M. (2019) Deoxyinosine and 7-Deaza-2-Deoxyguanosine as Carriers of Genetic Information in the DNA of Campylobacter Viruses. J Virol. 10.1128/jvi.01111-19

    Hutinet, G., Kot, W., Cui, L., Hillebrand, R., Balamkundu, S., Gnanakalai, S., Neelakandan, R., Carstens, A. B., Lui, C. F., Tremblay, D., Jacobs-Sera, D., Sassanfar, M., Lee, Y.-J., Weigele, P., Moineau, S., Hatfull, G. F., Dedon, P. C., Hansen, L. H., and Crécy-Lagard, V. de (2019) 7-Deazaguanine modifications protect phage DNA from host restriction systems. Nat Commun. 10, 5442

    1. I believe all examples of deazaguanine-based compounds in nature have a deazaguanine scaffold, but with a substituent on the novel carbon and do not go through an unsubstituted nucleobase —generally through the rather funky queuosine route. Here I was idly speculating how a direct route would work.