Pinpointing Conditions for a Metabolic Origin of Life: Underlying Mechanisms and the Role of Coenzymes.

Famously found written on the blackboard of physicist Richard Feynman after his death was the phrase, "What I cannot create, I do not understand." From this perspective, recreating the origin of life in the lab is a necessary condition for achieving a deep theoretical understanding of biology. The "metabolism-first" hypothesis is one of the leading frameworks for the origin of life. A complex self-organized reaction network is thought to have been driven into existence as a chemical path of least resistance to release free energy in the environment that could otherwise not be dissipated, rerouting energy from planetary processes to organic chemistry. To increase in complexity, the reaction network, initially under catalysis provided by its geochemical environment, must have produced organic catalysts that pruned the existing flux through the network or expanded it in new directions. This boot-strapping process would gradually lessen the dependence on the initial catalytic environment and allow the reaction network to persist using catalysts of its own making. Eventually, this process leads to the seemingly inseparable interdependence at the heart of biology between catalysts (coenzymes, enzymes, genes) and the metabolic pathways that synthesize them. Experimentally, the primary challenge is to recreate the conditions where such a network emerged. However, the near infinite number of microenvironments and sources of energy available on the early Earth or elsewhere poses an enormous combinatorial challenge. To constrain the search, our lab has been surveying conditions where the reactions making up the core of some of the most ancient chemolithoautotrophic metabolisms, which consist of only a small number of repeating chemical mechanisms, occur nonenzymatically. To give a fresh viewpoint in the first part of this account, we have organized the results of our search (along with important results from other laboratories) by reaction mechanism, rather than by pathway. We expect that identifying a common set of conditions for each type of reaction mechanism will help pinpoint the conditions for the emergence of a self-organized reaction network resembling core metabolism. Many of the reaction mechanisms were found to occur in a wide variety of nonenzymatic conditions. Others, such as carboxylate phosphorylation and C-C bond formation from CO