J Biol Chem. 2011 Dec 16. [Epub ahead of print]
The apicoplast and endoplasmic reticulum cooperate in fatty acid biosynthesis in the apicomplexan parasite Toxoplasma gondii.
Ramakrishnan S, Docampo MD, Macrae JI, Pujol FM, Brooks CF, van Dooren GG, Hiltunen JK, Kastaniotis AJ, McConville MJ, Striepen B.
University of Georgia, United States;
Apicomplexan parasites are responsible for high impact human diseases such as malaria, toxoplasmosis and cryptosporidiosis. These obligate intracellular pathogens are dependent on both de novo lipid biosynthesis as well as the uptake of host lipids for biogenesis of parasite membranes. Genome annotations and biochemical studies indicate that apicomplexan parasites can synthesize fatty acids via a number of different biosynthetic pathways that are differentially compartmentalized. However, the relative contribution of each of these biosynthetic pathways to total fatty acid composition of intracellular parasite stages remains poorly defined. Here we use a combination of genetic, biochemical and metabolomic approaches to delineate the contribution of fatty acid biosynthetic pathways in Toxoplasma gondii. Metabolic labeling studies with (13)Parasite fatty acid synthesis is an attractive drug target but complex and poorly understood.C-glucose showed that intracellular tachyzoites synthesized a range of long and very long chain fatty acids (C14:0-26:1). Genetic disruption of the apicoplast localized type II fatty acid synthase (FASII) resulted in greatly reduced synthesis of saturated fatty acids up to eighteen carbons long. Ablation of FASII activity resulted in reduced intracellular growth that was partially restored by addition of long chain fatty acids. In contrast, synthesis of very long chain fatty acids was primarily dependent on a fatty acid elongation system comprising three elongases, two reductases and a dehydratase that were localized to the endoplasmic reticulum. The function of these enzymes was confirmed by heterologous expression in yeast. This elongase pathway appears to have a unique role in generating very long unsaturated fatty acids (C26:1) that cannot be salvaged from the host.
PMID: 22179608 [PubMed - as supplied by publisher]