Branched-chain amino acid metabolism controls membrane phospholipid structure in Staphylococcus aureus

J Biol Chem. 2021 Nov;297(5):101255. doi: 10.1016/j.jbc.2021.101255. Epub 2021 Sep 28.


Branched-chain amino acids (primarily isoleucine) are important regulators of virulence and are converted to precursor molecules used to initiate fatty acid synthesis in Staphylococcus aureus. Defining how bacteria control their membrane phospholipid composition is key to understanding their adaptation to different environments. Here, we used mass tracing experiments to show that extracellular isoleucine is preferentially metabolized by the branched-chain ketoacid dehydrogenase complex, in contrast to valine, which is not efficiently converted to isobutyryl-CoA. This selectivity creates a ratio of anteiso:iso C5-CoAs that matches the anteiso:iso ratio in membrane phospholipids, indicating indiscriminate utilization of these precursors by the initiation condensing enzyme FabH. Lipidomics analysis showed that removal of isoleucine and leucine from the medium led to the replacement of phospholipid molecular species containing anteiso/iso 17- and 19-carbon fatty acids with 18- and 20-carbon straight-chain fatty acids. This compositional change is driven by an increase in the acetyl-CoA:C5-CoA ratio, enhancing the utilization of acetyl-CoA by FabH. The acyl carrier protein (ACP) pool normally consists of odd carbon acyl-ACP intermediates, but when branched-chain amino acids are absent from the environment, there was a large increase in even carbon acyl-ACP pathway intermediates. The high substrate selectivity of PlsC ensures that, in the presence or the absence of extracellular Ile/Leu, the 2-position is occupied by a branched-chain 15-carbon fatty acid. These metabolomic measurements show how the metabolism of isoleucine and leucine, rather than the selectivity of FabH, control the structure of membrane phospholipids.

Keywords: Staphylococcus aureus; branched-chain amino acids; fatty acid; fatty acid synthesis; phospholipids.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyl Carrier Protein / genetics
  • Acyl Carrier Protein / metabolism
  • Amino Acids, Branched-Chain / genetics
  • Amino Acids, Branched-Chain / metabolism*
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Phospholipids / genetics
  • Phospholipids / metabolism*
  • Staphylococcus aureus / genetics
  • Staphylococcus aureus / metabolism*


  • Acyl Carrier Protein
  • Amino Acids, Branched-Chain
  • Bacterial Proteins
  • Phospholipids