A connection between two ancient and essential cellular processes, iron-sulfur protein biogenesis and fatty acid synthesis, in Escherichia coli

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, we demonstrated that [Fe-S] and FA biosynthesis pathways are coordinated processes, driven by a physical interaction between ACP and the ISC [Fe-S] biogenesis machinery. Using bacterial two-hybrid assays, co-purification, and biochemical analyses, we demonstrated a molecular interaction between ACP and IscS, the ISC machinery cysteine desulfurase that provides sulfur for [Fe-S] cluster formation. Structural modeling and directed mutagenesis pinpointed the ACP-binding site in a region of IscS shared for interactions with other components of the ISC [Fe-S] biogenesis system, mainly Fdx and CyaY. At the cellular level, ACP depletion was found to disrupt ISC-dependent [Fe-S] cluster biogenesis, diminishing the activity of key [Fe-S]-dependent regulators (IscR, FNR, and NsrR) and enzymes (aconitase and biotin synthase). Moreover, FASII inhibition by triclosan, which perturbs ACP species homeostasis, also compromised the assembly of the [Fe-S]-dependent FNR regulator. Our findings underscore a functional link between [Fe-S] cluster biogenesis and fatty acid metabolism, with far-reaching unexplored intricacies of metabolic coordination and cellular homeostasis. Comparison with eukaryotic systems highlights a strong evolutionary driving force toward a link between [Fe-S] cluster and fatty acid biosynthesis in all living systems.IMPORTANCECellular functions rely on interconnected metabolic pathways; however, many regulatory links remain unexplored. Iron-sulfur [Fe-S] clusters are cofactors of proteins driving fundamental cellular processes, from respiration to gene regulation. Our study uncovers a direct connection between [Fe-S] cluster biogenesis and fatty acid biosynthesis. We demonstrate the molecular connection between these two essential cellular processes to lie within the interaction between the acyl carrier protein (ACP), a shuttle of fatty acid biosynthetic intermediates, and IscS, the source of sulfur for [Fe-S] cluster assembly. Intriguingly, similar interactions between ACP and [Fe-S] building cysteine desulfurase have been observed in yeast and human models; however, these mechanisms rest on different molecular determinants. This points out the existence of a strong evolutive driving force toward establishing a link between [Fe-S] cluster and fatty acid biosynthesis in all living systems, with far-reaching implications for metabolic coordination and cellular homeostasis.