Spontaneous Emergence of S‐Adenosylmethionine and the Evolution of Methylation

S ‐Adenosylmethionine (SAM) is an essential methylation cofactor. The origins of SAM methylation are complex, seemingly demanding the simultaneous emergence of an enzyme that makes SAM and enzyme(s) that utilize it. We report that both ATP and adenosine spontaneously react with methionine to yield SAM, thus suggesting that SAM could have emerged by chance. SAM methylation thus exemplifies how metabolites and pathways can co‐emerge through the gradual recruitment of individual enzymes in reverse order.