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J. Biol. Chem., Vol. 282, Issue 7, 4427-4436, February 16, 2007

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Mitochondrial Fatty Acid Synthesis in Trypanosoma brucei^*

From the Department of Biological Chemistry, Johns Hopkins School of Medicine, Baltimore, Maryland 21205

Whereas other organisms utilize type I or type II synthases to make fatty acids, trypanosomatid parasites such as Trypanosoma brucei are unique in their use of a microsomal elongase pathway (ELO) for de novo fatty acid synthesis (FAS). Because of the unusual lipid metabolism of the trypanosome, it was important to study a second FAS pathway predicted by the genome to be a type II synthase. We localized this pathway to the mitochondrion, and RNA interference (RNAi) or genomic deletion of acyl carrier protein (ACP) and -ketoacyl-ACP synthase indicated that this pathway is likely essential for bloodstream and procyclic life cycle stages of the parasite. In vitro assays show that the largest major fatty acid product of the pathway is C16, whereas the ELO pathway, utilizing ELOs 1, 2, and 3, synthesizes up to C18. To demonstrate mitochondrial FAS in vivo, we radio-labeled fatty acids in cultured procyclic parasites with [¹⁴C]pyruvate or [¹⁴C]threonine, either of which is catabolized to [¹⁴C]acetyl-CoA in the mitochondrion. Although some of the [¹⁴C]acetyl-CoA may be utilized by the ELO pathway, a striking reduction in radiolabeled fatty acids following ACP RNAi confirmed that it is also consumed by mitochondrial FAS. ACP depletion by RNAi or gene knockout also reduces lipoic acid levels and drastically decreases protein lipoylation. Thus, octanoate (C8), the precursor for lipoic acid synthesis, must also be a product of mitochondrial FAS. Trypanosomes employ two FAS systems: the unconventional ELO pathway that synthesizes bulk fatty acids and a mitochondrial pathway that synthesizes specialized fatty acids that are likely utilized intramitochondrially.

Received for publication, September 22, 2006 , and in revised form, December 6, 2006.

^* This work was supported by National Institutes of Health Grant AI21334. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Biological Chemistry, 725 North Wolfe St., Baltimore, MD 21205. Tel.: 410-955-3790; Fax: 410-955-7810; E-mail: penglund{at}jhmi.edu.

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