Fatty acids remodelling

Biosynthesis of GPI anchors starts with the core structure assembly by sequential addition of UDP-GlcNAc (followed by iV-deacetylation), dolichol-phosphate-mannose, and phospho-ethanolamine to phosphatidylinositol and culminates in the en bloc transfer to protein shortly after the protein is synthesized. However, the biosynthetic pathways can differ strikingly between different organisms with respect to specific modifications and fatty acid remodeling occurring after completion of the core glycan. This also applies for the point when certain modifications are introduced, e. g. before or after the transfer of the GPI-moiety to the protein. GPI anchors can be cleaved at defined positions by an array of enzymatic and chemical methods, respectively (O Fig. 5). Thus, it becomes possible to identify GPI-anchored proteins and, moreover, analyze the structure and biosynthesis of GPI anchors [103]. 

Y. S. Morita and P. T. Englund, Fatty acid remodeling of glycosyl phosphatidylinositol anchors in Trypanosoma brucei incorporation of fatty acids other than myristate, Mol. Biochem. Parasitol., 115 (2001) 157-164. 

Yamashita A, Sugiura T, Waku K. Acyl transferases and transacylases involved in fatty acid remodeling of phosphohpids and metabolism of bioaclive hpids in mammalian cells. J Biochem (Tokyo) 1997 122 1-16. 

Prior to protein attachment, the fatty acids of the GPI anchor may be replaced in a conversion process termed fatty acid remodeling [91]. Although myristate is the sole fatty acid component in mature trypanosome GPI anchors, earlier GPI intermediates contain more hydrophobic stearate fatty acids. These longer fatty acid chains are replaced by an alternating sequence of removal and replacement of a fatty acid from each position on the glycerol [91]. Lipid remodeling may not be unique to trypanosome GPI anchor biosynthesis since mature yeast GPI anchors contain ceramide, whereas an early yeast GPI intermediate has a diacylglycerol species [33]. 

Figure 2. Biosynthetic pathways for GPI precursors in T. brucei, human, and yeast. Note that some intermediates in each species have an acylated inositol. In T. brucei, early mannosylated intermediates as well as glycolipid A are in equilibrium with inositol-acylated forms (not shown) [53]. The insect form of T. brucei undergoes neither inositol deacylation nor the last three reactions of the fatty acid remodeling, resulting in a lyso GPI precursor containing an acylated inositol. This lyso GPI is also found in PARP (Figure 1C).

There are other examples of remodeling acyl residues on glycerol. In the insect form of T. brucei, a partial remodeling occurs, whereby the sn-2 fatty acid is removed to form a lyso GPI that is then attached to proteins [59]. In L. mexicana free GPIs, fatty acid remodeling involves myristate replacing a longer sn-2 fatty acid... 

W. J. Masterson, J. Raper, T. L. Doering, G. W. Hart P. T. Englund. Fatty acid remodeling a novel reaction sequence in the biosynthesis of trypanosome glycosyl phosphatidylinosi-tol membrane anchors. Cell, 1990, 62, 73-80. 

J. E. Ralton M. J. McConville. Delineation of three pathways of glycosylphosphatidylinositol biosynthesis in Leishmania mexicana. Precursors from different pathways are assembled on distinct pools of phosphatidylinositol and undergo fatty acid remodeling. J Biol Chem, 1998, 273, 4245-4257. 

The pathway for the synthesis of dipalmitoyl-phos-phatidylcholine is illustrated in figure 19.5. The starting species of phosphatidylcholine is made by the CDP-choline pathway (see fig. 19.4). The fatty acid at the sn-2 position, which is usually unsaturated, is hydrolyzed by phospholi-pase A2, and the lysophosphatidylcholine is reacylated with palmitoyl-CoA. This modification permits alteration of the properties of the phospholipid without resynthesis of the entire molecule, a strategy called remodeling. Deacylation-reacylation of phosphatidylcholine occurs in other tissues and provides an important route for alteration of the fatty acid substituents at both the sn-1 and sn-2 positions. For example, fatty acids at the sn-2 position can be replaced by arachidonic acid, which is stored there until needed for eicosanoid biosynthesis, as we discuss later in this chapter. 

In some cases the functions of phospholipases in cells are purely degradative and result in the release of the phospholipid components (fatty acids, glycerol, phosphate, and head-groups). But in many cases phospholipases have important roles in synthesis and regulation. For example, we have seen how phospholipase A2 catalyzes the first step in the remodeling of phosphatidylcholine to the surfactant... 

Rapoport S. I. (1999). In vivo fatty acid incorporation into brain phospholipids in relation to signal transduction and membrane remodeling. Neurochem. Res. 24 1403-1415. 

Fatty acids are incorporated into complex lipids through de novo synthetic and remodeling pathways. As detailed below and shown in Fig. 2a, intracellular pools of acyl-CoA are involved in processes outside of lipid metabolism and, in many instances, function as important regulatory molecules. Figure 2b illustrates an overview of glycerol phospholipid synthesis and how fatty acids in the form of acyl-CoA enter these metabolic pathways. Readers are referred to the article entitled Lipid Synthesis in this series for specific details regarding these pathways. 

Dramatic changes in the fatty acids of the frontal cortex were detected within 1 wk after the fish-oil diet was given as demonstrated in the individual data in the frontal lobe biopsy specimens from five juvenile monkeys. All four major phospholipid classes of the brain underwent extensive remodeling of their constituent fatty acids. The data in Fig. 3 is for the fatty acids of phosphatidylethanolamine from each of the five experimental monkeys. By 12-28 wk, the total n-3 fatty acids increased from 4% to 36%of total fatty acids (Connor et al., 1990b). The major increase was in DHA, from 4% to 29%, whereas EPA and 22 5n-3, another n-3 fatty acid found in fish oil, each increased from 0% to almost 3%. To be emphasized, as will be discussed later, is the apparent conversion of EPA to DHA in the brain. The total n-6 fatty acids reciprocally decreased from 44% to 16% of the total fatty acids, with the major reduction occurring in 22 5n-6, from 18% to 2%, and 22 4n-6, from 12% to 4%. There was also a moderate decrease of arachidonic acid from 12.8% to 8.9% of total fatty acids. Again, a major remodeling of the phospholipid fatty acids from n-6 to n-3 fatty acids was evident. 

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