Synthesis of novel acceptor substrates for the dolichyl phosphate mannose synthase from yeast

Dolichols are polyisoprenoid lipid components of mammalian membranes consisting of an average of 20 head-to-tail linked isoprene units of which the first isoprene is fully saturated. The unusual size of these lipids is intriguing and poses questions about the role of dolichol structure in biological processes. In order to probe structure and function we have synthesised potential dolichyl analogues that retain only the first two isoprene units and carry a second functional group within the terminal lipid chain. Such analogues were evaluated as substrates for a key enzyme in the dolichyl-dependent pathway of glycan biosynthesis, dolichyl phosphate mannose (Dol-P-Man) synthase. It was shown that some functional groups, including labels such as biotin, could be tolerated. When the synthetic analogues were attached to a solid support they were still substrates for the Dol-P-Man system and thus allowed the enzymatic solid-phase synthesis of glycolipids.