Dolichol-phosphatate-mannose

R Mazhari-Tabrizi, V Eckert, M Blank, R Muller, D Mumberg, M Funk, RT Schwarz. Cloning and functional expression of glycosyltransferases from parasitic protozoans by heterologous complementation in yeast the dolichol phosphate mannose synthase from Trypanosoma brucei. Biochem J 316 853-858, 1996. 

UDP-D-xylose, GDP-D-mannose, GDP-L-Fucose, or CMP-D-A-acetylneuraminic acid. Mammalian GTs also use dolichol-diphosphate-GlcNAc2Man9GlC3, dolichol-phosphate-mannose and dolichol-phosphate-glucose (Fig. 2). 

Biosynthesis of GPI anchors starts with the core structure assembly by sequential addition of UDP-GlcNAc (followed by iV-deacetylation), dolichol-phosphate-mannose, and phospho-ethanolamine to phosphatidylinositol and culminates in the en bloc transfer to protein shortly after the protein is synthesized. However, the biosynthetic pathways can differ strikingly between different organisms with respect to specific modifications and fatty acid remodeling occurring after completion of the core glycan. This also applies for the point when certain modifications are introduced, e. g. before or after the transfer of the GPI-moiety to the protein. GPI anchors can be cleaved at defined positions by an array of enzymatic and chemical methods, respectively (O Fig. 5). Thus, it becomes possible to identify GPI-anchored proteins and, moreover, analyze the structure and biosynthesis of GPI anchors [103]. 

Orlean, P., Albright, C., and Robbins, P. W. (1988). Cloning and sequencing of the yeast gene for dolichol phosphate mannose synthase, an essential protein./. Biol. Chem. 263,17499-17507. 

Kean, E.L. (1982) Activation by Dolichol phosphate-mannose of the Biosynthesis of... 

The scheme shown in Fig. 1 does not show all the reactions in which dolichol phosphate has been found to be involved. Thus yeast enzymes have been found to transfer mannose from dolichol-phosphate-mannose to serine or threonine residues (Babczinki ... 

Fig. 20.1. Abbreviated scheme of the synthesis of a diantennary N-glycan. Fucose modification has been omitted. 20.1, Phosphomannomutase 2 (PMM2) 20.2, phosphoman-nose isomerase (PMI) 20.3, glucosyltransferase I (GT I) 20.4, mannosyltransferase VI (MT VI) 20.5, dolichol phosphate-mannose synthase-1 (DPM synthase-1) 20.5, N-acet-ylglucosaminyltransferase II (GnT II) 20.7, glucosidase I (G I) GDP, guanosine diphosphate Marly mannose GlcNACy N-acetylglucosamine Do/, dolichol P, phosphate G/c, glucose Gal galactose SiUy sialic acid. Dotted arrow indicates multiple steps...

Table 20 5 Dolichol phosphate-mannose synthase-1 deficiency (CDG-Ie)...

Kim S, Westphal V, Srikrishna G, et al. Dolichol phosphate mannose synthase (DPMI) mutations define congenital disorder of glycosylation le (CDG-Ie). / Clin Invest 2000 105 191-198. 

Imbach T, Schenk B, Schollen E, et al. Deficiency of dolichol-phosphate-mannose synthase-1 causes congenital disorder of glycosylation type le. / Clin Invest 2000 105 233-239. 

P.A. Colussi, C.H. Taron, J.C. Mack, and P. Orlean, Human and Saccharomyces cerevisiae dolichol phosphate mannose synthases represent two classes of the enzyme, but both function in Schizosaccharomyces pomhe, Proc. Natl Acad. Sci. USA 1997, 94, 7873-7878. 

S. Tomita, N. Inoue, Y. Maeda, K. Ohishi, J. Takeda, and T. Kinoshita, A homologue of Saccharomyces cerevisiae Dpmlp is not sufficient for synthesis of dolichol-phosphate-mannose in mammalian cells, J. Biol Chem. 1998, 272, 9249-9254. 

Figure 47-7. Pathway of biosynthesis of dolichol-P-P-oligosaccharide. The specific linkages formed are indicated in Figure 47-8. Note that the first five internal mannose residues are donated by GDP-mannose, whereas the more external mannose residues and the glucose residues are donated by dolichol-P-mannose and dolichol-P-glucose. (UDP, uridine diphosphate Dol, dolichol P, phosphate UMP, uridine monophosphate GDP, guanosine diphosphate M, mannose G, glucose.)...

R7. Richards, J. B., Evans, P. J., and Hemming, F. W., Dolichol phosphates as acceptors of mannose from guanosine diphosphate mannose in liver systems. Biochem. J. 124, 957-959 (1971). 

In the synthesis of most glycoproteins containing mannose, the intermediate carrier of the mannosyl moiety is the polyene dolichol phosphate. However, in some systems, retinyl phosphate can act as the intermediate carrier between UDP-mannose and the acceptor glycoprotein. Retinyl phosphate maimose seems to be involved especially in the synthesis of hydrophobic regions of glycoproteins (DeLuca, 1977 Frot-Coutaz et al., 1985). 

---