Oleic acid biosynthesis in Plasmodium falciparum: characterization of the stearoyl-CoA desaturase and investigation as a potential therapeutic target.
BACKGROUND
Plasmodium falciparum parasitization of erythrocytes causes a substantial increase in the levels of intracellular fatty acids, notably oleic acid. How parasites acquire this monounsaturated fatty acid has remained enigmatic. Here, we report on the biochemical and enzymatic characterization of stearoyl-CoA desaturase (SCD) in P. falciparum.


RESULTS
Metabolic labeling experiments allowed us to demonstrate the production of oleic acid from stearic acid both in lysates of parasites incubated with [(14)C]-stearoyl-CoA and in parasite-infected erythrocytes labeled with [(14)C]-stearic acid. Optimal SCD activity was detected in schizonts, the stage of maximal membrane synthesis. This activity correlated with a late trophozoite stage-specific induction of PFE0555w transcripts. PFE0555w harbors a typical SCD signature. Similar to mammalian SCDs, this protein was found to be associated with the endoplasmic reticulum, as determined with PFE0555w-GFP tagged transgenic P. falciparum. Importantly, these parasites exhibited increased rates of stearic to oleic acid conversion, providing additional evidence that PFE0555w encodes the plasmodial SCD (PfSCD). These findings prompted us to assess the activity of sterculic acid analogues, known to be specific Delta9-desaturase inhibitors. Methyl sterculate inhibited the synthesis of oleic acid both with parasite lysates and infected erythrocytes, most likely by targeting PfSCD. This compound exhibited significant, rapid and irreversible antimalarial activity against asexual blood stages. This parasiticidal effect was antagonized by oleic acid.


CONCLUSIONS
Our study provides evidence that parasite-mediated fatty acid modification is important for blood-stage survival and provides a new strategy to develop a novel antimalarial therapeutic based on the inhibition of PfSCD.
Gratraud
Paul
P
Laboratoire de Dynamique des Interactions Membranaires Normales et Pathologiques, Universités de Montpellier II et I, CNRS, UMR 5235, case 107, Montpellier, France.
Huws
Enlli
E
Falkard
Brie
B
Adjalley
Sophie
S
Fidock
David A
DA
Berry
Laurence
L
Jacobs
William R
WR
Baird
Mark S
MS
Vial
Henri
H
Kremer
Laurent
L
D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D000962:Antimalarials / Q000737:chemistry / Q000627:therapeutic use*; D003521:Cyclopropanes / Q000737:chemistry; D004912:Erythrocytes / Q000469:parasitology; D004926:Escherichia coli / Q000378:metabolism; D005227:Fatty Acids / Q000737:chemistry; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D019301:Oleic Acid / Q000096:biosynthesis*; D010963:Plasmodium falciparum / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013230:Stearoyl-CoA Desaturase / Q000737:chemistry* / Q000627:therapeutic use*
D000962:Antimalarials; D003521:Cyclopropanes; D005227:Fatty Acids; D049452:Green Fluorescent Proteins; D019301:Oleic Acid; C021985:cyclopropene; D013230:Stearoyl-CoA Desaturase
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