Although the building blocks of the modern genomic material found in today’s living systems are well defined, and some level of mastery behind their synthesis and replication has been achieved, the constituents of these building blocks are not generated in isolation. Indeed, the formation of nucleobases from simple precursors can be achieved by the formamide condensation, which is known to deliver a complex mixture of products, including amino acids. In addition, electric-discharge Miller-Urey type ‘Beilstein’ synthesis is also suspected to produce nucleobases alongside some amino acids. So could we imagine a scenario where the synthesis of nucleic acids and proteins might have been intertwined together before life got started? 

So, why have we not studied these reactions before (or more)?  The resulting product mixtures of multi-component dehydrations reaction are analytically challenging. Most of the ‘real’ work behind studying such complex chemical systems, comes from being able to properly characterize all the different compounds in solution. This is because the synthetic procedures are relatively straight-forward, all done in a one-pot fashion with no extra purification steps, catalysts, or activating agents.  In our laboratory we have taken advantage of cutting-edge technologies in chromatography and high-resolution mass-spectrometry to help us in the deconvolution process of messy mixtures. This allowed us to look for differences across many products and their relative concentration, as well as identifying new ones. Validation through chemical standards and tandem mass-spectrometry can also be challenging, but it does represent an unequivocal assignment of a compound, which is necessary due to the complexity of the product mixtures. Assessing what is the chemical environment under certain conditions, means that a clear overview of the product distribution is necessary to understand how they relate to each other in a dynamic environment. 

We decided to investigate the co-reactivity of amino acids (Glycine) and nucleotide building blocks (P-ribose and a nucleobase) under simple dehydration conditions (at 90 °C for 5 h). Our results showed that adding glycine to the reaction, has a stereo-selective effect on the glycosidic bond formation. This confirmed that the presence of other organic compounds in the reaction mixture, species suspected to be present in prebiotic broths, have the capacity to direct the isomeric distribution of the resulting nucleotides in a dehydration reaction. As well, exchange of nucleobases within and between nucleoside and nucleotide compounds indicated a dynamic environment of early-forming nucleic acid monomers.

We are excited since an agnostic approach to generating simple chemical messes / soups within well-defined experimental environments looks like to be an extremely fruitful area to push the field, and remove assumptions, bias, and explore for new phenomenon beyond prebiotic synthesis.

This post was co-authored with Stephanie Colón-Santos, a PhD student in my laboratory.

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