PMID- 16920791
OWN - NLM
STAT- MEDLINE
DCOM- 20060929
LR  - 20181113
IS  - 0027-8424 (Print)
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 103
IP  - 35
DP  - 2006 Aug 29
TI  - Apicoplast fatty acid synthesis is essential for organelle biogenesis and 
      parasite survival in Toxoplasma gondii.
PG  - 13192-7
AB  - 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.
FAU - Mazumdar, Jolly
AU  - Mazumdar J
AD  - 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.
FAU - H Wilson, Emma
AU  - H Wilson E
FAU - Masek, Kate
AU  - Masek K
FAU - A Hunter, Christopher
AU  - A Hunter C
FAU - Striepen, Boris
AU  - Striepen B
LA  - eng
GR  - R01 AI042334/AI/NIAID NIH HHS/United States
GR  - AI42334/AI/NIAID NIH HHS/United States
GR  - AI64671/AI/NIAID NIH HHS/United States
GR  - AI045806-01A1/AI/NIAID NIH HHS/United States
GR  - R21 AI045806/AI/NIAID NIH HHS/United States
GR  - R01 AI045806/AI/NIAID NIH HHS/United States
GR  - Wellcome Trust/United Kingdom
GR  - R01 AI064671/AI/NIAID NIH HHS/United States
GR  - AI05093/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20060818
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Acetates)
RN  - 0 (Acyl Carrier Protein)
RN  - 0 (Carbon Radioisotopes)
RN  - 0 (Fatty Acids)
RN  - 0 (Multienzyme Complexes)
RN  - 0 (Mutant Proteins)
RN  - 0 (Pyruvate Dehydrogenase Complex)
RN  - EC 2.3.1.- (Acetyltransferases)
RN  - EC 6.- (Fatty Acid Synthase, Type II)
RN  - F8VB5M810T (Tetracycline)
SB  - IM
MH  - Acetates/metabolism
MH  - Acetyltransferases/metabolism
MH  - Acyl Carrier Protein/genetics/metabolism
MH  - Animals
MH  - Carbon Radioisotopes
MH  - Chloroplasts/*metabolism
MH  - Fatty Acid Synthase, Type II
MH  - Fatty Acids/*biosynthesis
MH  - Gene Expression Regulation/drug effects
MH  - Gene Targeting
MH  - Humans
MH  - Mice
MH  - Multienzyme Complexes/metabolism
MH  - Mutant Proteins/isolation & purification
MH  - Parasites/*cytology/growth & development/*metabolism/pathogenicity
MH  - Pyruvate Dehydrogenase Complex/metabolism
MH  - Tetracycline/pharmacology
MH  - Toxoplasma/*cytology/growth & development/*metabolism/pathogenicity
MH  - Virulence
PMC - PMC1559775
COIS- Conflict of interest statement: No conflicts declared.
EDAT- 2006/08/22 09:00
MHDA- 2006/09/30 09:00
PMCR- 2007/02/28
CRDT- 2006/08/22 09:00
PHST- 2006/08/22 09:00 [pubmed]
PHST- 2006/09/30 09:00 [medline]
PHST- 2006/08/22 09:00 [entrez]
PHST- 2007/02/28 00:00 [pmc-release]
AID - 0603391103 [pii]
AID - 3211 [pii]
AID - 10.1073/pnas.0603391103 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2006 Aug 29;103(35):13192-7. doi: 
      10.1073/pnas.0603391103. Epub 2006 Aug 18.