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 of 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 both Plasmodium falciparum and Toxoplasma gondii 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].

 

Protein EC Number Gene id Protein localisation Localisation data source
Long chain beta-keto reductase 1.1.1.330 TGME49_271888 Plasma membrane? Previous publication
Fatty acyl-CoA reductase 1.2.1.- TGME49_203580    
Long chain trans-2,3-enoyl-CoA reductase 1.3.1.93 TGME49_285240    
Elongase 2.3.1.199 TGME49_205350 Plasma membrane? Previous publication
Elongase 2.3.1.199 TGME49_242380 Plasma membrane? Previous publication
Elongase 2.3.1.199 TGME49_253880 Plasma membrane? Previous publication
Diacylglycerol O-acyltransferase 2.3.1.20 TGME49_226370    
Diacylglycerol O-acyltransferase 2.3.1.20 TGME49_232730    
Diacylglycerol O-acyltransferase 2.3.1.20 TGME49_275600    
sterol-O-acyltransferase 2.3.1.26 TGME49_263710 Endoplasmic reticulum Apiloc
Fatty-acyl-CoA thioesterase I 3.1.2.2 Missing in annotation    
Long chain 3-hydroxy acyl-CoA dehydratase 4.2.1.134 TGME49_311290    
Carbonic anhydrase 4.2.1.1 TGME49_259950 Nucleus Previous publication
Carbonic anhydrase 4.2.1.1 TGME49_297070 Plasma membrane Previous publication
Long-chain-fatty-acid-CoA-ligase 6.2.1.3 TGME49_243800 Cytosol Previous publication
Long-chain-fatty-acid-CoA-ligase 6.2.1.3 TGME49_247760 Mitochondrion Previous publication
Long-chain-fatty-acid-CoA-ligase 6.2.1.3 TGME49_297220    
Long-chain-fatty-acid-CoA-ligase 6.2.1.3 TGME49_310080 Cytosol Previous publication
Long-chain-fatty-acid-CoA-ligase 6.2.1.3 TGME49_310150 Mitochondrion Previous publication
Cytosolic acetyl-CoA carboxylase (ACCase2) 6.3.4.14; 6.4.1.2 TGME49_218560 Cytosol Apiloc
Acyl-CoA binding protein none TGME49_234510    
Acyl-CoA binding protein none TGME49_251550 Cytosol Previous publication

 

Open in a new window

 

 

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 ?