| Summary: | Summary The translation process, central to life, is tightly connected to the one‐carbon (1‐C) metabolism via a plethora of macromolecule modifications and specific effectors. Using manual genome annotations and putting together a variety of experimental studies, we explore here the possible reasons of this critical interaction, likely to have originated during the earliest steps of the birth of the first cells. Methionine, S‐adenosylmethionine and tetrahydrofolate dominate this interaction. Yet, 1‐C metabolism is unlikely to be a simple frozen accident of primaeval conditions. Reactive 1‐C species (ROCS) are buffered by the translation machinery in a way tightly associated with the metabolism of iron–sulfur clusters, zinc and potassium availability, possibly coupling carbon metabolism to nitrogen metabolism. In this process, the highly modified position 34 of tRNA molecules plays a critical role. Overall, this metabolic integration may serve both as a protection against the deleterious formation of excess carbon under various growth transitions or environmental unbalanced conditions and as a regulator of zinc homeostasis, while regulating input of prosthetic groups into nascent proteins. This knowledge should be taken into account in metabolic engineering.
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