In Memoriam: Dan Tawfik

The biochemist Dan Tawfik passed away in May 2021 at age sixty-five and yet the height of his powers. Dan’s scientific research focused on proteins and, in particular, on enzyme evolution. Recently he had begun working on the most difficult challenge in biochemical evolution: reconstructing the metabolic pathways that may have led to the emergence of the first functional proteins.

Energy Conservation via Thioesters in a Non-Enzymatic Metabolism-like Reaction Network

<p><b>Life’s catabolic processes capture chemical energy from the oxidative breakdown of metabolites. In the catabolic pathways at the core of biochemistry, the oxidation of </b>α-<b>ketoacids or aldehydes is coupled to the synthesis of thioesters, whose energy-releasing hydrolysis is in turn coupled to the production of adenosine 5’-triphosphate (ATP). How these processes became linked before life emerged, and thus how the framework for modern bioenergetics was established, is a major problem for understanding the origins of biochemistry. The structure of biochemical networks suggests that the intermediary role of thioesters in biological energy flows, and their central role in biosynthesis, is a consequence of their entry into metabolism at the earliest stage of biochemical evolution. However, how thioesters could have become embedded within a metabolic network before the advent of enzymes remains unclear. Here we demonstrate non-enzymatic oxidant- or light-driven thioester synthesis from biological </b>α-<b>ketoacids and show it can be integrated within an iron-promoted metabolism-like reaction network. The thioesters obtained are those predicted to be pivotal in computational reconstructions of primitive biochemical networks (acetyl, malonyl, malyl and succinyl thioesters), demonstrating a rare convergence between top-down and bottom-up approaches to the origins of metabolism. The diversity and simplicity of conditions that form thioesters from core metabolites suggests the energetic link between thioester synthesis and catabolism was in place at the earliest stage of prebiotic chemistry, constraining the path for the later evolution of life’s phosphorus-based energy currencies.</b></p>

Energy Conservation via Thioesters in a Non-Enzymatic Metabolism-like Reaction Network

<p><b>Life’s catabolic processes capture chemical energy from the oxidative breakdown of metabolites. In the catabolic pathways at the core of biochemistry, the oxidation of </b>α-<b>ketoacids or aldehydes is coupled to the synthesis of thioesters, whose energy-releasing hydrolysis is in turn coupled to the production of adenosine 5’-triphosphate (ATP). How these processes became linked before life emerged, and thus how the framework for modern bioenergetics was established, is a major problem for understanding the origins of biochemistry. The structure of biochemical networks suggests that the intermediary role of thioesters in biological energy flows, and their central role in biosynthesis, is a consequence of their entry into metabolism at the earliest stage of biochemical evolution. However, how thioesters could have become embedded within a metabolic network before the advent of enzymes remains unclear. Here we demonstrate non-enzymatic oxidant- or light-driven thioester synthesis from biological </b>α-<b>ketoacids and show it can be integrated within an iron-promoted metabolism-like reaction network. The thioesters obtained are those predicted to be pivotal in computational reconstructions of primitive biochemical networks (acetyl, malonyl, malyl and succinyl thioesters), demonstrating a rare convergence between top-down and bottom-up approaches to the origins of metabolism. The diversity and simplicity of conditions that form thioesters from core metabolites suggests the energetic link between thioester synthesis and catabolism was in place at the earliest stage of prebiotic chemistry, constraining the path for the later evolution of life’s phosphorus-based energy currencies.</b></p>

Autocatalytic chemical networks preceded proteins and RNA in evolution

Modern cells embody metabolic networks containing thousands of elements and form autocatalytic molecule sets that produce copies of themselves. How the first self-sustaining metabolic networks arose at life’ s origin is a major open question. Autocatalytic molecule sets smaller than metabolic networks were proposed as transitory intermediates at the origin of life, but evidence for their role in prebiotic evolution is lacking. Here we identify reflexively autocatalytic food-generated networks (RAFs)—self-sustaining networks that collectively catalyze all their reactions—embedded within microbial metabolism. RAFs in the metabolism of ancient anaerobic autotrophs that live from H2 and CO2 generate amino acids and bases, the monomeric components of protein and RNA, and acetyl-CoA, but amino acids and bases do not generate metabolic RAFs, indicating that small-molecule catalysis preceded polymers in biochemical evolution. RAFs uncover intermediate stages in the origin of metabolic networks, narrowing the gaps between early-Earth chemistry and life.