The rTCA cycle (also known as the reverse Krebs cycle) is a central anabolic biochemical pathway whose origins are proposed to trace back to geochemistry, long before the advent of enzymes, RNA or cells, and whose imprint still remains intimately embedded in the structure of core metabolism. If it existed, a primordial version of the rTCA cycle would necessarily have been catalyzed by naturally occurring minerals at the earliest stage of the transition from geochemistry to biochemistry. Here we report non-enzymatic promotion of multiple reactions of the rTCA cycle in consecutive sequence, whereby 6 of its 11 reactions are promoted by Zn2+, Cr3+ and Fe0 in an acidic aqueous solution. Two distinct three-reaction sequences can be achieved under a common set of conditions. Selectivity is observed for reduction reactions producing rTCA cycle intermediates compared to those leading off-cycle. Reductive amination of ketoacids to furnish amino acids is observed under similar conditions. The emerging reaction network supports the feasibility of primitive anabolism in an acidic, metal-rich reducing environment.

The biochemistry of all living organisms uses complex, enzyme-catalyzed metabolic reaction networks. Yet, at life's origins, enzymes had not yet evolved. Therefore, it has been postulated that non-enzymatic metabolic pathways predated their enzymatic counterparts. In this account article, we describe our recent work to evaluate whether two ancient carbon fixation pathways, the rTCA (reductive tricarboxylic acid) cycle and the reductive AcCoA (Wood-Ljungdahl) pathway, could have operated without enzymes and therefore have originated as prebiotic chemistry. We also describe the discovery of an Fe 2+-promoted complex reaction network that may represent a prebiotic predecessor to the TCA and glyoxylate cycles. The collective results support the idea that most central metabolic pathways could have roots in prebiotic chemistry.