Apicoplast fatty acid synthesis is essential for organelle biogenesis and parasite survival in Toxoplasma gondii.
Apicomplexan parasites are the cause of numerous important human diseases including malaria and AIDS-associated opportunistic infections. Drug treatment for these diseases is not satisfactory and is threatened by resistance. The discovery of the apicoplast, a chloroplast-like organelle, presents drug targets unique to these parasites. The apicoplast-localized fatty acid synthesis (FAS II) pathway, a metabolic process fundamentally divergent from the analogous FAS I pathway in humans, represents one such target. However, the specific biological roles of apicoplast FAS II remain elusive. Furthermore, the parasite genome encodes additional and potentially redundant pathways for the synthesis of fatty acids. We have constructed a conditional null mutant of acyl carrier protein, a central component of the FAS II pathway in Toxoplasma gondii. Loss of FAS II severely compromises parasite growth in culture. We show FAS II to be required for the activation of pyruvate dehydrogenase, an important source of the metabolic precursor acetyl-CoA. Interestingly, acyl carrier protein knockout also leads to defects in apicoplast biogenesis and a consequent loss of the organelle. Most importantly, in vivo knockdown of apicoplast FAS II in a mouse model results in cure from a lethal challenge infection. In conclusion, our study demonstrates a direct link between apicoplast FAS II functions and parasite survival and pathogenesis. Our genetic model also offers a platform to dissect the integration of the apicoplast into parasite metabolism, especially its postulated interaction with the mitochondrion.
Mazumdar
Jolly
J
Department of Cellular Biology and Center for Tropical and Emerging Global Diseases, University of Georgia, Paul D. Coverdell Center, 500 D. W. Brooks Drive, Athens, 30602, USA.
H Wilson
Emma
E
Masek
Kate
K
A Hunter
Christopher
C
Striepen
Boris
B
D000085:Acetates / Q000378:metabolism; D000123:Acetyltransferases / Q000378:metabolism; D000213:Acyl Carrier Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002250:Carbon Radioisotopes; D002736:Chloroplasts / Q000378:metabolism*; D054889:Fatty Acid Synthase, Type II; D005227:Fatty Acids / Q000096:biosynthesis*; D005786:Gene Expression Regulation / Q000187:drug effects; D018390:Gene Targeting; D006801:Humans; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism; D050505:Mutant Proteins / Q000302:isolation & purification; D010271:Parasites / Q000166:cytology* / Q000254:growth & development / Q000378:metabolism* / Q000472:pathogenicity; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D013752:Tetracycline / Q000494:pharmacology; D014122:Toxoplasma / Q000166:cytology* / Q000254:growth & development / Q000378:metabolism* / Q000472:pathogenicity; D014774:Virulence
D000085:Acetates; D000213:Acyl Carrier Protein; D002250:Carbon Radioisotopes; D005227:Fatty Acids; D009097:Multienzyme Complexes; D050505:Mutant Proteins; D011768:Pyruvate Dehydrogenase Complex; D000123:Acetyltransferases; D054889:Fatty Acid Synthase, Type II; D013752:Tetracycline