Protometabolic Reduction of NAD(+) with α-Keto Acids

[Image: see text] Deciphering the origins of the chemistry that supports life has frequently centered on determining prebiotically plausible paths that produce the molecules found in biology. What has been less investigated is how the energy released from the breakdown of foodstuff is coupled to the persistence of the protocell. To gain better insight into how such coupled chemistry could have emerged prebiotically, we probed the reactivity of the ribodinucleotide NAD(+) with small organic molecules that were previously identified as potential constituents of protometabolism. We find that NAD(+) is readily reduced nonenzymatically by α-keto acids, such as pyruvate and oxaloacetate, during oxidative decarboxylation. In the presence of FAD and a terminal electron acceptor, the consumption of α-keto acids by NAD(+) initiates a plausible prebiotic electron transport chain. The observed reactivity suggests that components of the RNA world were capable of initiating the chemistry needed to capture the energy released from catabolism to drive anabolism.