FabF and FadM Cooperate to Recycle Fatty Acids and Rescue Δ plsX Lethality in Staphylococcus aureus
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Phospholipids are essential components of most cell membranes. In Staphylococcus aureus , PlsX acyltransferase is considered indispensable for initiating phospholipid synthesis, unless exogenous fatty acids (FAs) are available for a bypass route. We report that S. aureus can capture internal FAs sources that overcome PlsX essentiality via gain-of-function mutations in two alleles: Δ pls X suppression by a FabF mutation, as mimicked by a FabF antibiotic inhibitor, suggests that FabF stalling causes FA release. Suppressor mutations in FadM, a bifunctional acyl-CoA thioesterase and ACP-binding protein, appear to retain only ACP-binding activity. The fabF and fadM suppressors compensate PlsX forward, but not reverse activity. Remarkably, fabF suppressors emerge only if fadM is present, indicative of FabF-FadM cooperation. We propose that increased ACP binding in FadM suppressor mutants facilitates FA release from FabF-acyl-ACP intermediates. A FabF-FadM relay leading to FA release may contribute to homeostasis between FASII and phospholipid synthesis pathways.
Importance
Phospholipids are vital cell membrane components. The Staphylococcus aureus PlsX enzyme uses acyl-ACP, the product of fatty acid (FA) synthesis (FASII), to initiate phospholipid production. Despite its central role, PlsX can be substituted by exogenous FAs whose phosphorylation yields the same product. We discovered that without FA supplementation, mutants arise that rescue growth, indicating that internal FAs are released. Mutations occurred in either FabF, a FASII enzyme, or in FadM, a little characterized protein. Our analyses give evidence that FabF and FadM proteins cooperate, and stimulate FA availability when either protein is mutated. We propose that in normal conditions, FadM acts as an “overflow valve” by releasing FAs from the FabF intermediate, which prevents buildup of FASII intermediates, and ensures FA-phospholipid balance.
