Abstract
BackgroundThe balanced synthesis of membrane phospholipids, fatty acids and cell wall constituents is a vital facet of bacterial physiology, but there is little known about the biochemical control points that coordinate these activities in Gram-positive bacteria. In Escherichia coli, the glycerol-phosphate acyltransferase (PlsB) plays a key role in coordinating fatty acid and phospholipid synthesis, but pathogens like Staphylococcus aureus have a different acyltransferase (PlsY), and the headgroup of the major membrane phospholipid, phosphatidylglycerol (PtdGro), is used as a precursor for lipoteichoic acid synthesis.ResultsThe PlsY acyltransferase in S. aureus was switched off by depriving strain PDJ28 (ΔgpsA) of the required glycerol supplement. Removal of glycerol from the growth medium led to the rapid cessation of phospholipid synthesis. However, the continued utilization of the headgroup caused a reduction in PtdGro coupled with the accumulation of CDP-diacylglycerol and phosphatidic acid. PtdGro was further decreased by its stimulated conversion to cardiolipin. Although acyl-acyl carrier protein (ACP) and malonyl-CoA accumulated, fatty acid synthesis continued at a reduced level leading to the intracellular accumulation of unusually long-chain free fatty acids.ConclusionsThe cessation of new phospholipid synthesis led to an imbalance in membrane compositional homeostasis. PtdGro biosynthesis was not coupled to headgroup turnover leading to the accumulation of pathway intermediates. The synthesis of cardiolipin significantly increased revealing a stress response to liberate glycerol-phosphate for PtdGro synthesis. Acyl-ACP accumulation correlated with a decrease in fatty acid synthesis; however, the coupling was not tight leading to the accumulation of intracellular fatty acids.
Highlights
The balanced synthesis of membrane phospholipids, fatty acids and cell wall constituents is a vital facet of bacterial physiology, but there is little known about the biochemical control points that coordinate these activities in Gram-positive bacteria
Expression of the genes responsible for phosphatidic acid biosynthesis in Bacillus subtilis and S. aureus is controlled by FapR [15], which releases from its DNA binding sites within the regulons multiple promoters when bound to malonylCoA [16,17]
Due to the lack of glycerolPO4, PtdGro cannot be resynthesized from DAG due to the requirement of PtdGro synthase for glycerol-PO4 leading to the accumulation of the Phosphatidic acid (PtdOH) and CDPDAG intermediates
Summary
The balanced synthesis of membrane phospholipids, fatty acids and cell wall constituents is a vital facet of bacterial physiology, but there is little known about the biochemical control points that coordinate these activities in Gram-positive bacteria. Long-chain acyl-ACPs act as potent feedback inhibitors of FASII by blocking the initiation of new acyl chains at the FabH step [10,11] and slowing the elongation of acyl chains by inhibiting acetyl-CoA carboxylase [12] It is not clear whether this regulatory model for membrane lipid homeostasis in E. coli can be extended to Gram-positive bacteria. These organisms do not have a PlsB acyltransferase, but rather use a novel activated acyl donor, acyl-phosphate (acyl-PO4), produced by PlsX from the acyl-ACP end-products of FASII, and have a unique glycerol-PO4 acyltransferase, PlsY, which only uses acyl-PO4 [13]. The transcriptional regulation of lipid synthesis is understood in considerable detail, much less is known about the biochemical regulation of FASII or the coupling of fatty acid and phospholipid synthesis
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