The dolichol cycle and protein N-glycosylation.

<p>The dolichol cycle consists of a series of reactions (heavy dashed blue lines) involved in the construction of the oligosaccharide precursor (Glc₃Man₉GlcNAc₂) on a dolichol carrier. The cycle is completed by reactions (heavy dashed pink lines) involved in the recycling of dolichol-phosphate (dol-P). Mature lipid linked oligosaccharide (DLO) is generated by the transfer of two residues of N-acetylglucosamine (blue squares), 9 residues of mannose (green circles) and 3 residues of glucose (blue circles) onto the lipid carrier dolichol-P (zig zag line). The monosaccharides are added sequentially, in the order indicated by their numbers, by glycosyltransferases whose gene names are shown in yellow ovals and whose order of action is also indicated. The first seven sugars are added by cytoplasmically orientated UDP-GlcNAc- and GDP-Man-requiring glycosyltransferases. The growing DLO is then flipped into the lumen of the ER by a process thought to involve the RFT1 gene product. Subsequently dolichol-P-Man (DPM)- and dolichol-P-Glc (DPG)-requiring glycosyltransferases complete DLO biosynthesis. The addition of the last glucose residue to the growing DLO allows efficient oligosaccharyltransferase (OST)-mediated transfer of the oligosaccharide from lipid onto nascent polypeptides (-N-X-T/S-) in the ER. As indicated by the heavy dashed pink lines, a series of reactions carried out by gene products indicated in the yellow ovals, ensure that the lumenally orientated dol-P and dol-PP molecules that are generated during the construction of mature DLO are reorientated towards the cytosolic face of the ER. The different type I congenital disorders of glycosylation subtypes (CDG Ia-p, indicated by letters in red circles on the gene name) are caused by mutations in genes encoding enzymes involved in either the construction of mature DLO or dolichol recycling.