Apicoplast fatty acid synthesis is essential for organelle biogenesis and parasite survival in Toxoplasma gondii

被引:179
作者
Mazumdar, Jolly
Wilson, Emma H.
Masek, Kate
Hunter, Christopher A.
Striepen, Boris
机构
[1] Univ Georgia, Paul D Coverdell Ctr, Dept Cellular Biol, Athens, GA 30602 USA
[2] Univ Georgia, Paul D Coverdell Ctr, Ctr Trop & Emerging Global Dis, Athens, GA 30602 USA
[3] Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA
基金
英国惠康基金;
关键词
apicomplexa; fatty acid biosynthesis; lipoic acid; plasmodium; plastid;
D O I
10.1073/pnas.0603391103
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:13192 / 13197
页数:6
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