Fatty acid elongation via elongase pathway of ER

There are two different types of fatty acid elongation takes place in different organisms. These elongation pathways use Coenzyme-A as acyl carrier rather than acyl carrier protein (ACP) of fatty acid synthesis systems FAS I and FAS II. The first type, mitochondrial fatty acid elongation is the reversal of fatty acid oxidation. This utilises acetyl-CoA as a substrate and extends the chain length of fatty acids with two carbons. This process acts mainly on acyl-CoA shorter than C16. The second process is the elongation pathway of endoplasmic reticulum, which is present in plants, mammals, yeast and other lower eukaryotes. This is a four-step reaction each catalysed by individual enzymes. These enzymes are beta-ketoacyl-CoA synthase, beta-ketoacyl-CoA reductase, beta-hydroxyacyl-CoA dehydratase and trans-2-enoyl-CoA reductase. This pathway mainly acts with acyl-CoA of chain length C16 or larger and important in the generation very long chain fatty acids. This process utilises malonyl-CoA rather than acetyl-CoA for chain elongation. The first enzyme which leads to condensation of malonyl-CoA with acyl-CoA (beta-ketoacyl-CoA synthase) is also called as elongase. There are three different genes which code for elongases in yeast and they have different substrate specificities. The substrate specificities of these enzymes ELO1, ELO2 and ELO3 are shorter saturated fatty acids (C14-C16), longer saturated & monounsaturated fatty acids and monounsaturated & polyunsaturated fatty acids respectively [1]. In contrast, Trypanosoma brucei have two elongase genes which has specificity to shorter fatty acids (ELO1 – C4 to C10 elongation and ELO2 – C10 to C14 elongation) [2].The orthologs of the three yeast elongase genes were identified in Plasmodium falciparum, Toxoplasma gondii and Neospora caninum and they might have similar substrate specificity to that of yeast. Although these genes are present in P. falciparum genome, fatty acid elongation pathway was not reconstructed in MPMP.

 

In addition to fatty acid elongation, fatty acid salvage has also been included to this pathway. The fatty acids salvaged from host with the action of acyl-CoA binding proteins (ACBP) can be converted to triacylglycerides and cholesterol ester with the action of ER-localised enzymes diacylglycerol O-acyltransferase (DGAT) and sterol O-acyltransferase respectively and can be stored in lipid bodies. There is strong biochemical evidence in P. falciparum and T. gondii to support the acquisition of fatty acids from host [3, 4].

 

Enzyme EC Number Gene id
Long chain beta-keto reductase 1.1.1.330 NCLIV_035250
Fatty acyl-CoA reductase 1.2.1.- NCLIV_021430
Long chain trans-2,3-enoyl-CoA reductase 1.3.1.93 NCLIV_014950
Elongase 2.3.1.199 NCLIV_008210
Elongase 2.3.1.199 NCLIV_017540
Elongase 2.3.1.199 NCLIV_020350
Diacylglycerol O-acyltransferase 2.3.1.20 NCLIV_007300
Diacylglycerol O-acyltransferase 2.3.1.20 NCLIV_032680
Diacylglycerol O-acyltransferase 2.3.1.20 NCLIV_046590
sterol-O-acyltransferase 2.3.1.26 NCLIV_024240
Fatty-acyl-CoA thioesterase I 3.1.2.2 Missing in annotation
Long chain 3-hydroxy acyl-CoA dehydratase 4.2.1.134 NCLIV_055210
Carbonic anhydrase 4.2.1.1 NCLIV_006180
Carbonic anhydrase 4.2.1.1 NCLIV_026960
Long-chain-fatty-acid-CoA-ligase 6.2.1.3 NCLIV_006300
Long-chain-fatty-acid-CoA-ligase 6.2.1.3 NCLIV_018500
Long-chain-fatty-acid-CoA-ligase 6.2.1.3 NCLIV_054200
Long-chain-fatty-acid-CoA-ligase 6.2.1.3 NCLIV_054250
Long-chain-fatty-acid-CoA-ligase 6.2.1.3 NCLIV_063970
Cytosolic acetyl-CoA carboxylase (ACCase2) 6.3.4.14; 6.4.1.2 NCLIV_061720
Acyl-CoA binding protein none NCLIV_066640

 

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Sources and fates of metabolites

 

Substrate Source pathways Product Fate pathways
Fatty acid (upto C16) Fatty acid biosynthesis in the apicoplast, Host Long-chain Fatty acid Phosphatidylethanolamine and phosphatidylserine metabolism, Fatty acid recycling and degradation
Acetyl-CoA Tricarboxylic acid (TCA) cycle, Fatty acid recycling and degradation, Leucine, isoleucine and valine metabolism, Pyruvate metabolism Acyl-CoA GPI anchor biosynthesis, Sphingomyelin and ceramide metabolism
Diacylglycerol Phosphatidylethanolamine and phosphatidylserine metabolism, Inositol phosphate metabolism Triacylglycerol Recycling of phospholipids, Storage in lipid bodies
Cholesterol Host Cholesterol ester Storage in lipid biodies
CoA Pantothenate and CoA biosynthesis Alcohol ?