Of all the plausible prebiotic source molecules, cyanide and aldehydes are considered the simplest and widely prevalent. The reactions of cyanide and simple aldehydes, in the context of prebiotic…

This is a $911,716 grant award from the National Aeronautics and Space Administration (NASA) to the Scripps Research Institute, a nonprofit biomedical research organization based in La Jolla, California. The grant is focused on investigating the role of cyanide and aldehydes in prebiotic chemistry and the development of proto-metabolic pathways, which are key objectives under NASA's Exobiology research emphasis. Specifically, the research aims to systematically explore cyanide-mediated systems chemistry reactions involving simple aldehydes and alpha-hydroxy keto acids, with the goal of identifying self-sustaining reaction pathways that could transform into early metabolic cycles. This work builds on the organization's previous experience conducting government-funded research in areas such as catalysis, purification systems, and organic synthesis. The grant does not appear to have any set-aside designation.

Of all the plausible prebiotic source molecules, cyanide and aldehydes are considered the simplest and widely prevalent. The reactions of cyanide and simple aldehydes, in the context of prebiotic chemistry, are proposed to have played a major role in accumulating important prebiologically relevant building blocks (nucleobases, sugars, hydroxy acids, fatty acids and amino acids). However, further chemistries of the thus produced primordial building blocks are usually dealt separately , in isolation from the very prebiotic molecular source molecules they were produced from, which is highly unrealistic. Systems chemistry is an important concept that has to be reckoned with in prebiotic chemistry, especially given the heterogeneous product distribution that results in almost all of the prebiotic reactions (for example the formose reaction and HCN polymerization to name a few). We hypothesize that under systems chemistry scenarios the source prebiotic molecules (such as cyanide and formaldehyde) would also interact with their respective reaction products, and lead to productive primordial reaction pathways. Specifically, we hypothesize that the transformations of simple aldehydes and alpha-hydroxy keto acids by their interaction with cyanide (in the presence and absence of amino compounds) would lead to alternative and extant biogenic molecules. We propose to systematically investigate the scope of this cyanide mediated systems chemistry with a view to developing an inventory of systems chemistry reactions (such as the reactions in a reductive citric acid cycle) that can become self-sustaining given a continuous supply of prebiotic source molecules. This would set the stage for systems chemistry to transform into proto-metabolic pathways. We have promising preliminary results that lend credence to the cyanide mediated systems chemistry hypothesis and approach. We have discovered that cyanide interacts with many small molecules (such as formaldehyde and glyoxylate), gets incorporated and hydrolyzed to yield a suite of hydroxy acids that are constituents of some of the metabolic cycles of extant biology. Moreover, based on the potential to transform such hydroxy acids to keto acids, we propose that interaction of these keto acids with cyanide would open up opportunities (such as reductive chemistries) that were not possible previously in a prebiotic context. Based on this hypothesis, we have developed an efficient conversion of an alpha-keto acid (oxala acetate) to its corresponding alpha hydroxy acid (malate) under potentially prebiotic conditions. This observation also opens up a novel reductive amination process that could convert selected alpha-keto acids to the corresponding alpha-amino acids. The demonstration of many of the key steps of the reductive citric acid cycle, that so far has eluded experimental demonstration, would become possible by employing this cyanide mediated chemical transformation repetitively. This proposal addresses the prebiotic evolution research emphasis of exobiolgy, specifically relating to the major objective in determining what chemical systems could have served as precursors of metabolic systems on earth and/or elsewhere. This proposal also experimentally models a type of early environment on the earth in which organic chemical synthesis could occur in the context of protometabolic pathways.