Fatty acid biosynthesis in the apicoplast (FAS II system)

The de novo fatty acid biosynthesis takes place in the Apicomplexa via the FAS II pathway. This is similar to the fatty acid biosynthesis mechanism in plants and bacteria. Each reaction of fatty acid chain elongation is catalysed by separate monofunctional enzymes. The growing chain of fatty acid chain is held together by acyl carrier protein (ACP). This pathway takes place in the apicoplast in apicomplexans including Plasmodium species, Toxoplasma gondii and Neospora caninum. This suggests the endosymbiotic origin of this pathway. The experimental evidence showed that inhibition with triclosan or thiolactomycin, preferential inhibitors of FASII over FASI has led to strong growth inhibition in Plasmodium falciparum and T. gondii [1, 2, 3] and the incorporation of 14C-acetate into fatty acids preferentially resulted in the production of C10 to C14 chains and sensitive to triclosan in P. falciparum [4]. These suggests the importance of this pathway in these organisms and the role of apicoplast in de novo synthesis of lipids.

 

In addition to producing fatty acids, this pathway is also important for the synthesis of lipoic acid, an essential co-factor of many enzymes including pyruvate dehydrogenase and keto-acid dehydrogenase complexes. Of these, pyruvate dehydrogenase is localised to apicoplast and de novo synthesis of lipoic acid is essential for its function. The product of FAS II pathway, octanoyl-ACP (8-carbon fatty acyl-ACP) is the substrate for lipoic acid synthesis (refer to lipoic acid metabolism pathway for further details).

 

The bioinformatics predictions suggest that at least one of the isoforms of enzymes glycerol-3-phosphate O-acyltransferase and 1-acyl-glycerol-3-P O-acyltransferase are targeted to the apicoplast in T. gondii. The metabolic labelling studies with 14C-acetate in T. gondii extracellular tachyzoites showed the production of numerous glycerolipids and sphingolipids with 14C labelling. In addition, the inhibition of FAS II pathway with haloxyfop has resulted in reduction in these glycerolipids and sphingolipids. The metabolic labelling of host lipids prior to infection with unlabelled tachyzoites showed that the intracellular parasites were not able to produce at least some of the polar lipids, mainly T. gondii-specific glycerolipids [3]. These evidences demonstrate the role of FAS II pathway in the production of fatty acids for glycerolipid biosynthesis. So, the above mentioned enzymes were added to this pathway. The enzymes involved in the synthesis of glycerolipids from apicoplast synthesised acyl-ACP are also present in the corresponding MPMP metabolic pathway of fatty acid synthesis in the apicoplast.

 

Enzyme EC Number Gene id
3-oxoacyl-[ACP]reductase 1.1.1.100 NCLIV_037010
3-oxoacyl-[ACP]reductase 1.1.1.100 NCLIV_056400
3-oxoacyl-[ACP]reductase 1.1.1.100 NCLIV_062520
Glycerol-3-phosphate dehydrogenase 1.1.1.8 NCLIV_001180
Glycerol-3-phosphate dehydrogenase 1.1.1.8 NCLIV_043550
Acyl-ACP desaturase 1.14.19.2 NCLIV_015790
Enoyl-ACP reductase 1.3.1.9 NCLIV_066970
Cytochrome-b5 reductase 1.6.2.2 NCLIV_025010
Glycerol-3-phosphate O-acyltransferase 2.3.1.15 NCLIV_035870
3-oxoacyl:ACP synthase III 2.3.1.180 NCLIV_031900
[Acyl-carrier-protein] S-malonyltransferase 2.3.1.39 NCLIV_046840
b-ketoacyl-ACP synthase I 2.3.1.41 NCLIV_000530
1-acyl-Glycerol-3-phosphate O-acyltransferase 2.3.1.51 NCLIV_017010
Acyl-ACP thiolesterase 3.1.2.14 Missing in annotation
3-hydroxyacyl-ACP dehydratase 4.2.1.- NCLIV_004340
Carbonic anhydrase 4.2.1.1 NCLIV_006180
Carbonic anhydrase 4.2.1.1 NCLIV_026960
Apicoplast acetyl-CoA carboxylase (ACCase1) 6.3.4.14; 6.4.1.2 NCLIV_004860
Cytochrome b5 none NCLIV_007030
Acyl-carrier protein none NCLIV_023990
Triose phosphate translocator none NCLIV_026210

 

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Sources and fates of metabolites

 

Substrate Source pathways Product Fate pathways
Acetyl-CoA Pyruvate metabolism Fatty acyl-ACP (C8) Lipoic acid metabolism
ACP Pantothenate and CoA biosynthesis Fatty acid (upto C16) Fatty acid elongation in the cytosol, Fatty acid elongation in the ER, Fatty acid recycling and degradation, Phosphatidylethanolamine and phosphatidylserine metabolism
Glycerone-P Glycolysis Diacylglycerol-3P Phosphatidylethanolamine and phosphatidylserine metabolism