The proposed experiments would contribute significantly to our understanding of prebiotic chemistry and solve long standing challenges in the field. For example, 1) the generation of alpha-keto…

This is a $1,490,825 grant awarded by a U.S. government civilian agency to Furman University, a private non-profit liberal arts institution located in Greenville, South Carolina. The grant, titled "Prebiotic Origins and Protometabolic Roles of Alpha-Keto Acids," is focused on conducting research to advance the understanding of prebiotic chemistry and the origins of metabolism. The proposed experiments aim to explore autocatalytic pathways, reductive carboxylation, and nucleobase synthesis, which could significantly impact current theories on the evolutionary origins of fundamental biological processes. This grant is not set-aside and represents a direct research collaboration between the government agency and the university, with the goal of advancing scientific knowledge in the field of astrobiology. Furman University has a robust research portfolio, including numerous grants from the National Science Foundation and the National Institutes of Health, which emphasize undergraduate research experiences and interdisciplinary scientific exploration.

The proposed experiments would contribute significantly to our understanding of prebiotic chemistry and solve long standing challenges in the field. For example, 1) the generation of alpha-keto acids from glyoxylate-activated carboxylic acids in aim i would be the first demonstration of an autocatalytic pathway within a productive and sustainable prebiotic chemical system. The discovery of a productive autocatalytic chemical system has been a goal of the field of prebiotic chemistry for half a century, and the identification of one that provides the primary source material for an alpha-keto acid protometabolism would have a substantial effect on current thinking about the origins of metabolism. 2) the proposed synthesis of alpha-keto acids from carboxylic acids in aim II would be the first demonstration of a prebiotically plausible reductive carboxylation. This reaction type underpins multiple fundamental anabolic pathways in modern biology and the discovery of a prebiotic analog would significantly impact our understanding of its evolutionary origins. 3) the identification of a reaction pathway that converts a dead-end product (as some in the field have considered diketopiperazines) to readily available alpha-keto acid sources in aim III would greatly increase the plausibility of hypothesized protometabolic pathways based on these building blocks. 4) the development of sustainable activation and oxidative pathways from alpha-amino and alpha-hydroxy acids would naturally lead to the emergence of transamination pathways reflective of what is observed in biology. 5) the possibility of synthesizing purines starting from hydantoins (which are easily accessed from alphaamino and alpha-keto acids) will complement the demonstrated pyrimidine synthesis from hydantoins and presents a novel paradigm of accessing nucleobases that can become part of a replicating system with potential feedback opportunities. The demonstration of sustainable prebiotic sources of alpha-keto acids and the exploration of their reaction landscapes offers an alternative to the (form)aldehyde-based chemistries that have dominated origins of life endeavors and suggests that a demonstration of a transition from prebiotic to plausible early biotic protometabolic systems may finally become experimentally tractable. Thus, the research paradigm based on alpha-keto acids is directly relevant to exobiology in "determining what chemical systems could have served as precursors of metabolic and replicating systems on earth and elsewhere, including alternatives to the current dnarna- protein basis for life", and could add a new dimension to the strategies of NASA-astrobiology in its endeavor to study the origin, evolution, and distribution of life in the universe.