Catalytic prebiotic origins of coenzymes

To understand the origin of life, demonstrating the organic chemistry that produced the first biomolecules is necessary. This is a goal of prebiotic chemistry: to reveal the chemical processes that led to nascent biology on early Earth. Enzymes are life’s principal catalysts, but their structures are of such overwhelming complexity that it is unimaginable how they self-assembled on early Earth. There was probably an intermediary phase comprising of simpler catalysts that preceded enzymes. However, the functional range of these simple catalysts was likely limited in the same way that enzyme catalysis is restricted by a lack in diversity of the twenty amino acids. Despite billions of years of evolution, enzymes still require low-molecular weight ‘helper’ molecules called ‘coenzymes’ to expand their catalytic repertoire. This strongly suggests that early catalysts also depended on coenzymes, so chemical pathways to coenzymes need to be found. A major hypothesis for the origin of life is that biomolecules necessary for the first cell were produced from hydrogen cyanide. The chemistry emanating from cyanide produces an array of complex products: ribonucleotides, peptides, and lipids. This reaction network initially lacked pathways for coenzyme formation until we very recently produced the catalytic core of coenzyme A. However, coenzyme A alone is not enough for onward progression towards metabolic networks. We need more coenzymes, and we think thiamine is one of them. Thiamine pyrophosphate is one of nature’s most unique and essential coenzymes. It reverses the natural polarity (‘umpolung’) of organic molecules to allow otherwise impossible biochemical reactions to proceed. Our aim is to demonstrate prebiotic syntheses of thiamine precursors (‘proto-thiamines’) using cyanide chemistry. These syntheses will feature organocatalysis for selective bond formations, dehydration reactions in water, and reaction cascades to rapidly generate structural complexity. Upcycling of waste is of enormous benefit in environments with limited resources, so we will convert by-products of proto-thiamine syntheses into amino acids in ways that sidestep the challenges associated with biomimetic reductive aminations. The production of thiamines through shared pathways already producing essential biomolecules would greatly support an origin of life starting from cyanide. It will motivate the exploration of catalytic prebiotic umpolung chemistry, and increase the possibilities of simple chemical ensembles undergoing rapid expansion towards reaction networks under catalytic control. This proposal will have broad appeal: origins of life researchers will reconsider coenzymes as plausible prebiotic substrates; geochemists will constrain environmental boundaries of life’s earliest habitat; enzymologists will be informed of prebiotic pathways for coenzymes that preceded extant biosynthetic processes. Our approach for the rapid onset of molecular complexity in water fits well with the EPSRC’s priority for sustainable green chemistry sought by synthetic and industrial chemists that are cheap, atom-efficient, and scalable. By recreating ancient predecessors of intermediary metabolism, we will contribute towards the bottom-up approach to synthetic biology. This is recognised by the UK government as one of the great new technologies in science. As the international quest to discover life beyond our planet intensifies, our findings will inform physicists and astronomers on key biosignatures to search for across the solar system. Finally, the question of life’s origin holds unique appeal for people of all ages and backgrounds, each of whom bring their own perspectives on our beginnings. An insight into the origins of life enriches our understanding of our shared ancestry and deepens our connection to the natural world.