Toxoplasma gondii serine hydrolases regulate parasite lipid mobilization during growth and replication within the host

Cell Chem Biol. 2021 Oct 21;28(10):1501-1513.e5. doi: 10.1016/j.chembiol.2021.05.001. Epub 2021 May 26.


The intracellular protozoan parasite Toxoplasma gondii must scavenge cholesterol and other lipids from the host to facilitate intracellular growth and replication. Enzymes responsible for neutral lipid synthesis have been identified but there is no evidence for enzymes that catalyze lipolysis of cholesterol esters and esterified lipids. Here, we characterize several T. gondii serine hydrolases with esterase and thioesterase activities that were previously thought to be depalmitoylating enzymes. We find they do not cleave palmitoyl thiol esters but rather hydrolyze short-chain lipid esters. Deletion of one of the hydrolases results in alterations in levels of multiple lipids species. We also identify small-molecule inhibitors of these hydrolases and show that treatment of parasites results in phenotypic defects reminiscent of parasites exposed to excess cholesterol or oleic acid. Together, these data characterize enzymes necessary for processing lipids critical for infection and highlight the potential for targeting parasite hydrolases for therapeutic applications.

Keywords: CDP-DAG; Plasmodium falciparum; Toxoplasma gondii; cholesterol; depalmitoylases; lipid metabolism; oleic acid; phosphatidic acid; serine hydrolases; α/β-hydrolase superfamily.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Catalytic Domain
  • Hydrolysis
  • Kinetics
  • Lipid Metabolism / physiology*
  • Phylogeny
  • Protozoan Proteins / classification
  • Protozoan Proteins / genetics
  • Protozoan Proteins / metabolism*
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / isolation & purification
  • Sequence Alignment
  • Serine Endopeptidases / classification
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / metabolism
  • Substrate Specificity
  • Toxoplasma / enzymology*
  • Toxoplasma / growth & development
  • Toxoplasma / physiology


  • Protozoan Proteins
  • Recombinant Proteins
  • Small Molecule Libraries
  • Serine Endopeptidases