Dolichol phosphate biosynthesis

Before it participates in the biosynthesis of Dol-P-P-oligosaccharide, dolichol must first be phosphorylated to form dolichol phosphate (Dol-P) in a reaction catalyzed by dolickol kinase and using ATP as the phosphate donor. 

The initial demonstration that isopentenyl diphosphate may be used in the biosynthesis of dolichol phosphate in animals and plants... 

Scheme 1.—Pathway of the Biosynthesis oi Dolichol Phosphate and ot Doliehol-1 inked Saccharides. (Reactions requiring more than one enzyme are indicated by dashed arrows. The Scheme is based on work cited in Refs. 1, 3, 8—25, 35, and 50.)...

Dolichol phosphate is an amphipathic lipid of the endoplasmic reticulum consisting of isoprenoid units and initiating the biosynthesis of the oligosaccharide portion of glycoproteins. 

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]. 

Structures of dolichol phosphate, GlcNAc-P-P-Dol, and Man-P-Dol. GlcNAc-P-P-Dol is the first compound formed in the biosynthesis of the lipid-linked oligosaccharide shown in Figure 16-5. Replacement of GlcNAc by -OH in GIcNAc-P-P-Dol yields dolichol diphosphate (dolichol pyrophosphate). Replacement of Man by Glc in Man-P-Dol yields Glc-P-Dol. 

Figure 16.17 illustrates biosynthesis of the dolichol-phosphate-linked oligosaccharide intermediate. A short summary is as follows ... 

See also Biosynthesis of Amino Sugars, Oligosaccharides and Polysacchardies as Cell Markers (from Chapter 9), Dolichol Phosphate... 

Farnesyl pyrophosphate (Fig. 30.2) is an intermediate in the biosynthesis of cholesterol, ubiquinone, and dolichol phosphates. Based on their site of action, HMGRis will decrease the availability of all four of these compounds and, thus, decrease cell proliferation. Potential applications of this antiproliferative effect include the prevention of restenosis following angioplasty, prevention of glomerular injury in renal disease, treatment of malignant disease, and prevention of organ transplantation rejection (40). 

Daleo, G.R., Hopp, H.E., Romero, P.A. Pont-Lezica, R. (1977) Biosynthesis of Dolichol Phosphate by Subcellular Fractions from Liver , FEBS Letters, 5i, 411-4 Daleo, G.R. Pont-Lezica, R. (1977) Synthesis of Dolichol Phosphate by a Cell-free... 

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

Leloir, L.F. (1951) The Enzymic Transformation of Uridine Diphosphate into a Galactose Derivative , Archives of Biochemistry and Biophysics, 33, 186-90 Leloir, L.F., Staneloni, R.J., Carminatti, H. Behrens, N.H. (1973) Biosynthesis of a N,N-diacetylchitobiose Containing lipid by Liver Microsomes. Probable Dolichol Phosphate Derivative , Biochemical and Biophysical Research Communications, 52, 1285-92... 

Undecaprenol (bactoprenol) from Salmonella contains eleven isoprene units, and two irons and nine cis double bonds In the form of undecaprenyl phosphate, it acts as a carrier of carbohydrate residues in the biosynthesis of bacterial antigenic polysaccharides synthesis of Murein (see) also depends on undecaprenyl phosphate. In eukaryotes the Dolichol phosphates (see) function in the transfer of carbohydrate residues in the synthesis of glycoproteins and glycoli-pids. Probably the long lipid chains of these P serve to anchor them in membranes, while the phosphate group acts as a carrier by protruding into the cytoplasm. It is not known whether all P. function as carbohydrate carriers. The structural relationship between solanesol and plastoquinone-9 and ubiquinone-9, and the joint occurrence of these compounds suggest a precursor role for P. Biosynthesis of P. proceeds from mevalonic acid and the conformation of all double bonds is predetermined in early precursors. 

The participation of polyprenol sugar phosphates as intermediates in the biosynthesis of several types of complex carbohydrate has been clearly established in bacteria (for a review see ref. 11). Tanner in 1969< > presented the first evidence of the possible participation of lipid carriers in yeast. This was confirmed by us and the carrier was found to be a phosphodiester of mannose and an isoprenoid alcohol.Finally, Jung and Tanner purified a lipid which was able to accept mannose from GDP-mannose when added exogenously to a particulate preparation. This lipid was characterized as a dolichol phosphate. 

Y. Maeda, S. Tomita, R. Watanabe, K. Ohishi, and T. Kinoshita, DPM2 regulates biosynthesis of dolichol phosphate-mannose in mammalian cells correct subcellular localization and stabilization of DPMI, and binding of dolichol phosphate, EM BO J. 1998, 17, 4920-4929. 

Long-chain polyisoprenoid. molecules with a terminal alcohol moiety are called, polyprenols. The dolichols, one class of polyprenols (Figure 8.18), consist of 16 to 22 isoprene units and, in the form of dolichyl phosphates, function to carry carbohydrate units in the biosynthesis of glycoproteins in animals. Polyprenyl groups serve to anchor certain proteins to biological membranes (discussed in Chapter 9). 

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.)...

C. Nucleoside Diphosphate Sugars.—A polyprenol phosphate containing eleven isoprene units is involved in the biosynthesis of various bacterial cell-wall components.As mentioned in last year s Report, another isoprenoid phosphate, dolichol monophosphate (40), is an intermediate in sugar... 

Grange and Adair73 isolated 2,3-dehydrodolichyl phosphate from in vitro studies on hen oviduct. It may be derived from 2,3-dehydrodolichyl diphosphate, a likely intermediate in the biosynthesis of dolichyl phosphate. Many questions still remain unanswered, such as is the substrate for the a-isoprene reductase, the diphosphate or the monophosphate of 2,3-dehy-drodolichol Are the unsaturated polyprenols a reserve pool for the synthesis of dolichol in plants What is the function of unsaturated, plant polyprenols How is the synthesis of saturated and unsaturated polyprenols regulated ... 

The concentration of dolichyl phosphate in eukaryotic tissues is very low and is probably rate-limiting for the glycosylation processes. Variation of the concentration in the endoplasmic-reticulum membranes is a possible way of controlling the rate of glycosylation. It is important to point out that the early steps in the dolichol biosynthesis are common to such other prenyl derivatives in plants as steroids, essential oils, hormones, phytol, and carotenes (see Scheme 1), and parameters affecting those reactions that may control the dolichol to dolichyl phosphate step could be another mechanism for regulation of the level of dolichyl phosphate. 

S CTP + dolichol <2-4, 6, 7, 9> (<6> enzyme can function in augmenting the steady-state levels of dolichyl phosphate by phosphorylating preexisting dolichol molecules [4] <2> newly formed dolichyl monophosphate, phosphorylated via CTP is available for biosynthesis of mannosylphos-phoryldolichol and N-acetylglucosaminylpyrophosphoryldolichol [1] <4,7> CTP mediated phosphorylation of dolichol, the terminal step in dolichyl monophospate biosynthesis de novo [12]) (Reversibility <2-4,... 

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