What's special about the purine scaffold?

Question

Purine is a remarkable substance, given Nature has chosen it as the scaffold for two nucleobases from DNA/RNA: adenine (A) and guanine (G). Its structure also appears in several other substances of biological interest, by substitution on the fused ring system, like these examples shown in Wikipedia:

The base ring system has 4 nitrogen atoms and 5 carbon atoms. Then I wonder, it's not hard to imagine isomers or at least similar compounds just by changing the positions of the nitrogen atoms around the rings, with a few constraints. The five-membered ring needs at least one N to maintain aromaticity in the pyrrole ring. It's better to have this N at the position where a glycosidic bond is expected, if we want to incorporate it in some kind of nucleic acid. Along the edge connecting the two fused cycles, it's better to have C, to avoid N atoms with four bonds. So we are left with the following template:

We can distribute the remaining 3 N and 3 C atoms among the 6 free positions in $6!/((6-3)! \cdot 3!) = 20$ different ways.

So my question is, what's special in purine, that caused its scaffold to be picked among all the other possibilities?

Answer 1

It is important to remember that the purine scaffold is one of the most fundamental organic structures in all lifeforms. From an evolutionary standpoint, this means that there must have been a simple, effective way for this scaffold to be prepared in the pre-biotic earth. After all, the first organisms to contain purine scaffolds did not have "access" to complex enzymes, proteins, etc.

Take a look at the molecular formula for adenine, a simple purine derivative. C₅H₅N₅. We could rewrite this as (HCN)₅. As the molecular formula alone might lead you to conclude, adenine can be made from only one chemical: hydrogen cyanide. Interestingly, hydrogen cyanide was a very abundant chemical in the earth's primordial atmosphere. Roy et al.¹ replicated the atmospheric conditions of the primordial earth and found that substantial quantities of adenine could be produced! The mechanism for this reaction is quite beautiful, and I will include Peter Jacobi's rendition of it below. The mechanism for the formation of adenine also explains why other constitutional isomers are not produced. We must consider the alternating nature involved in these nucleophilic-electrophilic interactions (e.g. two nitrogen atoms will never "decide" to couple).

So, to conclude, the purine substructure is "special" because it not only has the unique ability to hydrogen bond and form a base pair for DNA replication but was also incredibly easy to synthesize in the primordial earth's atmosphere. Although life forms do not use HCN to synthesize the purine substructure anymore, its synthesis is still incredibly simple.

¹ Roy, D.; Najafian, K.; Schleyer, P. V. R. Proc. Natl. Acad. Sci USA 2007, 104, 17272-17277.