Protein folds and catalytic strategies at the origin of biological CO2 fixation

Biological carbon fixation is the basis of all ecosystems. Out of the seven known pathways organisms use to fix CO2, the acetyl-CoA pathway is assumed to be the most ancient. Its enzymes bear primordial traits, including carbon-metal bonds and an abundance of transition metal clusters. Ancient traits can also be reflected in structural folds adopted by the enzymes and the catalytic strategies they employ. Here I show that the most common catalytic strategies used to accelerate reactions in the acetyl-CoA pathway are cofactor-aided catalysis, electrostatic interactions and general acid/base catalysis. Enzymes of the acetyl-CoA pathway are replete with Rossman folds, TIM barrel folds, and alpha-beta plaits. These topologies evolved before the divergence of bacteria and archaea, along with five other catalytic folds of the acetyl-CoA pathway. Rossmann folds and TIM barrels likely underwent rapid diversification early in the history of life. In contrast, over half of the folds in the pathway are weakly diversified folds that emerged only once in the history of life, at the origin of biological CO2 fixation. Ancient metabolic pathways point to enzymes with conserved structural cores, which uncover topologies and catalytic strategies employed at the onset of metabolism.