Undecaprenyl phosphate

FIGURE 8.18 Dolichol phosphate is an initiation point for the synthesis of carbohydrate polymers in animals. The analogous alcohol in bacterial systems, undecaprenol, also known as bactoprenol, consists of 11 isoprene units. Undecaprenyl phosphate delivers sugars from the cytoplasm for the synthesis of cell wall components such as peptidoglycans, lipopolysaccharides, and glycoproteins. Polyprenyl compounds also serve as the side chains of vitamin K, the ubiquinones, plastoquinones, and tocopherols (such as vitamin E). 

Fig. 8.1 Biosynthesis of peptidoglycan. The large circles represent A -acetylglucosamine orN-acetylmuramic acid to the latter is linked initially a pentapeptide chain comprising L-alanine, D-glutamic acid and meso-diaminopiraelic acid (small circles) terminating in two D-alanine residues (small, darker circles). The lipid molecule is undecaprenyl phosphate. In the initial (cytoplasm) stage where inhibition by the antibiotic D-cycloserine is shown, two molecules of Dalanine (small circles) are converted by an isomerase to the D-forms (small, darker circles), alter which a ligase joins the two D-alanines together to produce a D-alanyl-D-alanine dipeptide.

Undecaprenyl-phosphate mannosyltransferase [EC 2.4.1.54] catalyzes the phosphatidylglycerol-dependent reaction of GDP-mannose with undecaprenyl phosphate to produce GDP and D-mannosyl-l-phosphoundeca-prenol. 

One of the most impressive findings has been the discovery of lipid intermediates in the biosynthesis of polysaccharides (see Refs. 2 and 465.) At least two structurally different types of these compounds exist the intermediate may be an isoprenoid alcohol ester of the glycosyl pyrophosphate or the analogous derivative of the glycosyl phosphate. Derivatives of the first type are formed by reaction between the sugar nucleotide and the alcohol phosphate, for example, undecaprenyl phosphate (120), which participates in the biosynthesis of Salmonella lipopolysaccharide.466... 

Scheme 1. — Reactions Involved in the Biosynthesis of D-Mannan from GDP-Mannose. [The acceptor lipid in the reaction, undecaprenyl phosphate, is designated as follows ]...

Pont Lezica355 speculated that the role of dolichyl phosphates, a-satu-rated polyisoprenyl phosphates of chain length between 80 and 105 carbon atoms, in glycosyl transfer during biosynthetic mechanisms is a general feature of eukaryotic cells, whereas, in prokaryotic cells, the lipids fulfilling this function are a-saturated polyisoprenyl phosphates of shorter chain-length, such as undecaprenyl phosphate (which contains 55 carbon atoms). 

A second method that we considered involved condensation of a carbohydrate-derived phosphate salt with an in situ-generated phosphoryl dichloride.21 The requisite phosphoryl dichlorides are prepared via exposure of a lipid phosphate to a Vilsmeier-type reagent. This protocol has been used successfully for the preparation of lipid diphosphate linkages in the dolichol series (i.e., lipids lacking an allylic double bond proximal to the diphosphate linkage). However, we were once again, hesitant to expose our undecaprenyl phosphate precursor to activation conditions that produce HC1 as a by-product. 

Song F., Guan Z., Raetz C.R.H. Biosynthesis of undecaprenyl phosphate-galactosamine and undecaprenyl phosphate-glucose in Francisella novicida. Biochemistry 48 (2009) 1173-1182. 

Touze, T., Tran, A.X., Hankins, J.V., Mengin-Lecreulx, D., Trent, M.S. Periplasmic phosphorylation of lipid A is linked to the synthesis of undecaprenyl phosphate. Mol Microbiol 67 (2008) 264-277. 

Wang, X., Ribeiro, A.A., Guan, Z., Raetz, C.R. Identification of undecaprenyl phosphate-beta-D-galactosamine in Francisella novicida and its function in lipid A modification. Biochemistry 48 (2009) 1162-1172. 

Dolichols are a family of long-chain polyisoprenols that occur only in eukaryotes. They are related in structure and function to undecaprenyl phosphate, a prokaryotic polyisoprenol used in the synthesis of peptido-glycan (see below). Dolichols contain 65-110 carbons arranged as 13-22 isoprene units, two in the trans configuration, the remainder in the cis configuration. The initial isoprene unit is saturated and carries a hydroxyl group, which is esterified with orthophosphoric (monophosphoric) or pyrophosphoric (diphosphoric) acid in dolichol phosphate and pyrophosphate, respectively (Figure 16-6). 

The biogenesis of LPS is a complex process involving various steps that occur at the plasma membrane followed by the translocation of LPS molecules to the bacterial cell surface. LPS biosynthesis employs a large number of enzymes. The core OS is assembled on preformed lipid A by sequential glycosyl transfer of monosaccharides, while the O antigen is independently assembled on undecaprenyl-phosphate (Und-P), a... 

The final cytosolic precursor of PG biosynthesis, UDP-MurNAc-PP, is transferred to an undecaprenyl phosphate, decaprenyl phosphate (DP) in mycobacteria, carrier by MraY forming MurNAc-PP-diphosphor-ylundecaprenol or lipid I. In a subsequent reaction catalyzed by MurG, a GlcNAc residue is transferred to lipid I forming lipid II. Lipid II, which is the final membrane-associated intermediate of PG biosynthesis, is also believed to be the substrate of a putative flippase , that translocates lipid II from the cytosolic face of the membrane, which is the site of synthesis to the outer layer of plasma membrane or the site of utilization although... 

P-ACL), or undecaprenyl phosphate (see p. 396). (The enzymic synthesis of this lipid has been reported. ) The disaccharide-lipid, or L-rhamnosyl-D-galactosyl-PP-ACL, therefore corresponds to undecaprenyl (L-rhamnosyl-D-galactosyl pyrophosphate). 

Cells, when its conversion into undecaprenyl phosphate by a specific phosphatase is inhibited by the antibiotic bacitracin. ... 

Undecaprenyl pyrophosphate is not an acceptor for glycosyl transfers and must be degraded to undecaprenyl phosphate to complete the cycle. This reaction is catalysed by a specific pyrophosphatase and is prevented by the antibiotic bacitracin. This prevention is not a simple inhibition, since bacitracin does not affect the enzyme directly, instead it forms a very strong complex with undecaprenyl pyrophosphate and so renders the substrate unavailable to the enzyme. 

Why do sugar nucleotides accumulate The failure of glycosyl transfer from undecaprenyl pyrophosphoryl disaccharide-peptide to wall glycan will cause the former to accumulate. This may be partially relieved by the formation of the soluble peptidoglycan , but there will be a strong tendency to trap undecaprenyl pyrophosphate as its disaccharide-peptide derivative. This will deplete undecaprenyl phosphate pools and so lead to the accumulation of the A/-acetylmuramyl pentapeptide and its precursors. Consequent upon the depletion, by trapping, of undecaprenyl phosphate, there can be effects of penicillin upon the synthesis of other bacterial glycoconjugates. 

In prokaryotic systems bacitracin has been studied much more extensively and several of its effects have been described (see Chapter 3). Bacitracin inhibits the synthesis of mucopeptide in bacteria by preventing the breakdown of undecaprenyl pyrophosphate. This depletes the pool of undecaprenyl phosphate available to act as an acceptor for the transfer of muramyl penta-peptide and so blocks the undecaprenyl phosphate cycle. A similar inhibition... 

---