The nicotinamide biosynthetic pathway is a by-product of the RNA world

Many of the biosynthetic pathways, especially those leading to the coenzymes, must have originated very early, perhaps before enzymes were available to catalyze their synthesis. While a number of enzymatic reactions in metabolism are known to proceed nonenzymatically, there are no examples of entire metabolic sequences that can be achieved in this manner. The most primitive pathway for nicotinic acid biosynthesis is the reaction of aspartic acid with dihydroxyacetone phosphate. We report here that nicotinic acid (NAc) and its metabolic precursor, quinolinic acid (QA), are produced in yields as high as 7% in a six-step nonenzymatic sequence from aspartic acid and dihydroxyacetone phosphate (DHAP). The biosynthesis of ribose phosphate could have produced DHAP and other three carbon compounds. Aspartic acid could have been available from prebiotic synthesis or from the ribozyme synthesis of pyrimidines. These results suggest that NAD could have originated in the RNA world and that the nonenzymatic biosynthesis of the cofactor nicotinamide could have been an inevitable consequence of life based on carbohydrates and amino acids. The enzymes of the modern pathway were later added in any order.