Periodic Reporting for period 2 - MetabolismOrigins (On the chemical origins of biological metabolism)
Reporting period: 2023-06-01 to 2024-11-30
It has long been assumed that biological metabolism must have been an invention of life since its many reactions are catalyzed by enzymes, complex proteins that did not exist at life’s origins. However, my group and others have recently discovered that transition metals can mediate much of life’s most central metabolic pathways in the absence of enzymes. In contrast to popular ideas about the origin of life that focus only on genetics, this realization suggests a radically different vision in which biological metabolism arose from geochemical reaction networks, before enzymes or life itself, and created the molecules of genetics in the process.
With this proposal, I wish to find out how much of core biological metabolism might have emerged without enzymes and whether it could have given rise to genetics. I propose an experimental research program to identify conditions that would trigger the spontaneous emergence of metal-catalyzed versions of the biosynthetic pathways for sugar phosphates, amino acids and ribonucleotides.
This metabolism-guided approach to prebiotic chemistry will furnish deep understanding of how and why life’s biochemistry emerged and explain why it operates the way that it does today, rooted in fundamental principles of catalysis and organic chemistry.
With this proposal, I wish to find out how much of core biological metabolism might have emerged without enzymes and whether it could have given rise to genetics. I propose an experimental research program to identify conditions that would trigger the spontaneous emergence of metal-catalyzed versions of the biosynthetic pathways for sugar phosphates, amino acids and ribonucleotides.
This metabolism-guided approach to prebiotic chemistry will furnish deep understanding of how and why life’s biochemistry emerged and explain why it operates the way that it does today, rooted in fundamental principles of catalysis and organic chemistry.
We have started to examine the nonenzymatic metal-promoted analogs of amino acid synthesis (reductive amination and transamination), sugar phosphate synthesis, ribonucleotide biosynthesis, and catalytic properties of ribonucleotide-derived coenzymes and other coenzymes. Progress has been more rapid than anticipated. This work has already resulted in 11 publications.
In the first half of the project we shave shown that several nonenzymatic analogs of metabolic pathways are viable, including amino acid synthesis through reductive amination and transamination, pyrimidine nucleobase biosynthesis and parts of gluconeogenesis, substantially increasing the available evidence for the nonenzymatic origin of core metabolism. We have also shown that the three most important coenzymes in metabolism can all perform their biological jobs nonenzymatically when they are in the presence of specific metal ions (Fe3+ and Al3+). This implicates at least one of those metals at the origin of metabolism. Moving forward, we aim to learn more about how amino acids and ribonucleotides might interact with each other through catalysis.