Lipid synthesis route

Synthesis of most phospholipids starts from glycerol-3-phosphate, which is formed in one step from the central metabolic pathways, and acyl-CoA, which arises in one step from activation of a fatty acid. In two acylation steps the key compound phosphatidic acid is formed. This can be converted to many other lipid compounds as well as CDP-diacylglycerol, which is a key branchpoint intermediate that can be converted to other lipids. Distinct routes to phosphatidylethanolamine and phosphatidylcholine are found in prokaryotes and eukaryotes. The pathway found in eukaryotes starts with transport across the plasma membrane of ethanolamine and/or choline. The modified derivatives of these compounds are directly condensed with diacylglycerol to form the corresponding membrane lipids. Modification of the head-groups or tail-groups on preformed lipids is a common reaction. For example, the ethanolamine of the head-group in phosphatidylethanolamine can be replaced in one step by serine or modified in 3 steps to choline. 

Arabidopsis is a typical 16 3-plant in which both the prokaryotic and eukaryotic pathways [4] contribute to the production of chloroplast lipids. We have investigated the pattern of lipid metabolism in wild type Arabidopsis and calculated the fluxes of carbon involved [5]. An abbreviated version of this analysis is shown in Fig. la. For every 1000 fatty acid molecules synthesized in the chloroplast 390 enter the prokaryotic pathway in the chloroplast envelope while 610 are exported as CoA esters to enter the eukaryotic pathway. Of these 340 are reimported into the chloroplast. Overall, almost equal amounts of chloroplast lipids are produced by each pathway. However, the quantities of individual lipids synthesized by the two routes are very different. All the chloroplast phosphatidylglycerol (PG) and over 70% of the monogalactosyldiacylglycerol (MGD) is derived from the prokaryotic pathway while digalactosyldiacylglycerol is synthesized mainly on the eukaryotic pathway [5]. In this paper we have outlined how four of the Arabidopsis mutants have changed the way we view the operation of the two pathways involved in leaf membrane lipid synthesis. More detailed information on each mutant can be found elsewhere [1-3, 5,6 and in preparation]. 

Jim, S., Ambrose, S. H. and Evershed, R. P. (2003b) Natural abundance stable carbon isotope evidence for the routing and de novo synthesis of bone FA and cholesterol. Lipids 38, 179 186. 

Figure 20-10 Proposed biosynthetic route for synthesis of lipid A and the mature lipopolysaccharide of the E. coli cell wall. After C. R. H. Raetz et al,307...

In summary, we were able to develop a chemically robust synthetic route to lipid I, the penultimate intermediate utilized in bacterial cell wall biosynthesis. The identification of a method for stereoselective introduction of the anomeric phosphate and a protocol to enable diphosphate coupling were pivotal to our success and ultimately provided the precedent for our chemical synthesis of lipid II detailed in the sections that follow. 

Most cationic lipids described in the literature are synthesised by solution synthesis [36-39]. Depending upon the complexity of the structure, the synthetic routes vary from just one or two chemical steps, as in the case of DOTMA (1) and DC-Choi (3), to longer convergent synthesis, as for DOGS (5) (these three compounds being the earliest examples of cationic lipids prepared for transfection purposes [41, 68, 69]) (see Fig. 2). 

For the lipids in Example 6.1, the routes of synthesis (just discussed) are ... 

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