Independently developed iron-sulphur/thioester- and phosphate-driven chemical reactions would have set up two distinct reaction networks prior to coupling in a proto-metabolic system supporting a minimal organisation closure. Each chemical system assisted initially by simple catalysts and then by more complex cofactors would have provided the precursors of the small metabolites and monomer units along with their respective polymers through dehydrating template-independent assemblies. For example, acylation reactions mediated by activated thioester groups produced peptides, fatty acids and polyhydroxyalkanoates, while phosphorylation reactions by phosphorylating agents allowed the synthesis of polysaccharides, polyribonucleotides and polyphosphates. Here, we address how these independent chemical systems might fit together and shaped a proto-metabolic system, focusing specifically on cofactors as molecular fossils of metabolism. As a result, the proposed overview suggests that non-coded peptides capable of binding a variety of ligands, but in particular with a redox active versatility and/or group transfer potential could have facilitated the chemical connections that led to a minimal closure with a proto-metabolism. Later developments would have made it possible to establish a cellular organisation with more complex and interdependent metabolic pathways. Copyright © 2021 Elsevier B.V. All rights reserved.