Lipid diphosphate

Colvin155 was the first to postulate a lipid-bound D-glucose as an intermediate in the biosynthesis of bacterial cellulose. Lipid-sugar derivatives, tentatively identified as lipid-diphosphate-D-glucose, lipid-diphosphate-cellobiose, and, perhaps, higher polymers, were detected in this system.128 These lipid-sugar compounds, which were acid- and alkali-labile, seemed to be formed prior to cellulose, and their formation was inhibited by adding... 

At this point, we had achieved access to an orthogonally protected phosphomuramyl pentapeptide derivative poised to enable completion of our lipid I total synthesis. The technical hurdles that remained to be addressed were 1) identification of a mild method for installation of the lipid diphosphate linkage, 2) global deprotection, and 3) final purification of our synthetic lipid I. Our solutions to these problems are addressed in the following section. 

A second method that we considered involved condensation of a carbohydrate-derived phosphate salt with an in situ-generated phosphoryl dichloride.21 The requisite phosphoryl dichlorides are prepared via exposure of a lipid phosphate to a Vilsmeier-type reagent. This protocol has been used successfully for the preparation of lipid diphosphate linkages in the dolichol series (i.e., lipids lacking an allylic double bond proximal to the diphosphate linkage). However, we were once again, hesitant to expose our undecaprenyl phosphate precursor to activation conditions that produce HC1 as a by-product. 

Ultimately, we settled on a protocol that relied on in situ generation of a carbohydrate-derived phosphorimidazolidate for coupling with a lipid monophosphate [Scheme 9]., 24 The procedure involved activation of an anomeric phosphate by exposure to carbonyldiimidazole (CDI) followed by quenching of the CDI with methanol. The activated intermediate is then exposed to a lipid phosphate salt and was reported to provide the lipid diphosphate in quantitative yield for the coupling step. Coward has successfully applied this protocol toward the construction of dolichyl-linked lipid diphosphates (see below),23 but the basic reaction conditions... 

Following the lipid I analogy, we would introduce the lipid diphosphate at a late stage in the synthesis that would leave only a global deprotection as a final step.26 Disconnecting the diphosphate linkage provided the first retrosynthetic intermediates, disaccharyl pentapeptide... 

In the Chapter 6 Focus On, "Terpenes Naturally Occurring Alkenes," we looked briefly at terpenoids, a vast and diverse group of lipids found in all living organisms. Despite their apparent structural differences, all terpenoids are related. All contain a multiple of five carbons and are derived biosynthetically from the five-carbon precursor isopentenyl diphosphate (Figure 27.6). Note that formally, a... 

Eicosanoids and terpenoids are still other classes of lipids. Eicosanoids, of which prostaglandins are the most abundant kind, are derived biosynthetically from arachidonic acid, are found in all body tissues, and have a wide range of physiological activity. Terpenoids are often isolated from the essential oils of plants, have an immense diversity of structure, and are produced biosynthetically from the five-carbon precursor isopentenyl diphosphate (IPP). lsopentenyl diphosphate is itself biosynthesized from 3 equivalents of acetate in the mevalonate pathway. 

S-prenylation is the most recent of the four major types of lipid modifications to be described. As with -acylation, S-prenylation is posttranslational. The lipid substrates for these modifications are farnesyl diphosphate and geranylgeranyl diphosphate. The mechanism... 

In the first Section, the dolichol pathway of protein glycosylation is introduced, and the reader is made familiar with the various reactions in the formation of the lipid and carbohydrate moieties of lipid-linked saccharides. Three different classes of compound are known so far (a) isoprenoid alcohol esters of monosaccharide monophosphates, such as D-mannosyl and D-glucosyl (dolichol phosphate), (b) such isoprenoid alcohol esters of saccharide diphosphates as dolichol diphosphate linked to 2-acetamido-2-deoxy-D-glucose and to oligosaccharides, and (c) retinol (D-mannosyl phosphate). The dolichol-linked sugars occur in all eukaryotes. 

How, exactly, retinol affects protein glycosylation is not yet known, but the formation of retinol phosphate, the D-mannosylation of retinol phosphate by GDP-Man, and the transfer of Man from D-mannosyl (retinol phosphate) to pronase-sensitive glycoconjugates are well established.5857,59 On the other hand, the formation and role of other gly-cosyl esters of retinol phosphate are still controversial.2,80 It is very probable that the D-mannosylation of retinol phosphate, and also the transfer of Man from this lipid derivative to protein, are catalyzed by enzymes different from those involved in the dolichol pathway,81-83 and this finding points to the different physiological roles of Man-P-Dol and D-mannosyl (retinol phosphate). Thus, whereas Man-P-Dol can serve to D-mannosylate dolichol diphosphate-linked oligosaccharides (see Section III), such a role has not been found for D-mannosyl (retinol phosphate).81,83... 

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