Lipid pathway, of protein glycosylation, and

THE LIPID PATHWAY OF PROTEIN GLYCOSYLATION AND ITS INHIBITORS THE BIOLOGICAL SIGNIFICANCE OF PROTEIN-BOUND CARBOHYDRATES... 

Schwarz RT, Datema R. The lipid pathway of protein glycosylation and its inhibitors the biological significance of protein-bound carbohydrates. Adv Carbohydr Chem Biochem 1982 40 287-379. 

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. 

Although sterols like cholesterol are not synthesized de novo by parasitic flatworms, they do possess an active mevalonate pathway (Fig. 20.3) (reviewed in Coppens and Courtoy, 1996). This pathway has been studied in 5. mansoni, and all available evidence indicates that it is similar to the lipid metabolism seen in F. hepatica. The mevalonate pathway was shown to be used by 5. mansoni for the synthesis of dolichols for protein glycosylation, of quinones as electron transporters in the respiratory chain and of farnesyl and geranylgeranyl pyrophosphates as substrates for the isopreny-lation of proteins (Chen and Bennett, 1993 Foster et a/., 1993). A key enzyme in the mevalonate pathway is 3-hydroxymethylglutaryl-CoA reductase (HMG-CoA reductase) and it was shown that the schistosomal enzyme differs from the mammalian type, both structurally and in its regulatory properties (Rajkovic et ai, 1989 Chen et at., 1991). Farnesyl pyrophosphate plays a key role in the mevalonate pathway as it is the last common substrate for the synthesis of all end products (Fig. 20.3). As mentioned already, the branch leading from farnesyl pyrophosphate via squalene to cholesterol is not operative in parasitic flatworms, whereas the other branches are active, at least in S. mansoni and probably also in F. hepatica and FI. diminuta. 

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... 

Abstract Glycosylation of proteins, lipids and mucins has gained increasing complexity in the course of evolution. Metazoans and mammals exhibit extensively exploited pathways of /V-glycan biosynthesis, with unique features that are not found in plants or protozoans. 

Endoplasmic reticulum A highly folded membranous compartment within the cytoplasm that is responsible for a great variety of cellular tasks, including the glycosylation and trafficking of proteins destined for secretion or for the cell membrane or some organelles. It also functions in lipid synthesis, and the enzymes of many pathways of intermediate metabolism are located on its surface. 

---