Mechanistic binding insights for 1-deoxy-D-Xylulose-5-Phosphate synthase, the enzyme catalyzing the first reaction of isoprenoid biosynthesis in the malaria-causing protists, Plasmodium falciparum and Plasmodium vivax

Protein Expr Purif. 2016 Apr;120:16-27. doi: 10.1016/j.pep.2015.12.003. Epub 2015 Dec 15.


We have successfully truncated and recombinantly-expressed 1-deoxy-D-xylulose-5-phosphate synthase (DXS) from both Plasmodium vivax and Plasmodium falciparum. We elucidated the order of substrate binding for both of these ThDP-dependent enzymes using steady-state kinetic analyses, dead-end inhibition, and intrinsic tryptophan fluorescence titrations. Both enzymes adhere to a random sequential mechanism with respect to binding of both substrates: pyruvate and D-glyceraldehyde-3-phosphate. These findings are in contrast to other ThDP-dependent enzymes, which exhibit classical ordered and/or ping-pong kinetic mechanisms. A better understanding of the kinetic mechanism for these two Plasmodial enzymes could aid in the development of novel DXS-specific inhibitors that might prove useful in treatment of malaria.

Keywords: 1-Deoxy-d-xylulose-5-phosphate synthase; Isoprenoids; Malaria; Methylerythritol phosphate pathway; Plasmodium falciparum; Plasmodium vivax.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Catalytic Domain
  • Cloning, Molecular
  • Glyceraldehyde 3-Phosphate / metabolism
  • Kinetics
  • Molecular Sequence Data
  • Plasmodium falciparum / enzymology*
  • Plasmodium vivax / enzymology*
  • Protozoan Proteins / metabolism*
  • Pyruvic Acid / metabolism
  • Recombinant Proteins / metabolism
  • Sequence Alignment
  • Transferases / metabolism*


  • Protozoan Proteins
  • Recombinant Proteins
  • Glyceraldehyde 3-Phosphate
  • Pyruvic Acid
  • Transferases
  • deoxyxylulose-5-phosphate synthase