Undecaprenyl pyrophosphate

Apfel, CM., Takacs, B., Fountoulakis, M., Stieger, M., and Keck, W. (1999). Use of genomics to identify bacterial undecaprenyl pyrophosphate synthetase cloning, expression, and characterization of the essential uppS gene. J Bacteriol 181 483 92. 

Polymerization of MurNAc-pentapeptide units to form linear peptidoglycans stage 2 of peptidoglycan biosynthesis. The lipid in these structures is undecaprenol lipid-P-P is undecaprenyl pyrophosphate. The use of tRNA as a carrier and activator of glycine is unusual, since ribo.somes and mRNA are not involved in the reaction. 

Lipid II is translocated to the outer leaflet of the cytoplasmic membrane by a process that is not understood. It has been argued that a protein mi t facilitate this process. However, once it is translocated, it serves as the substrate for transglycosylases, which is a processive event incorporate several NAG-NAM units into the nascent peptioglycan, in the course of which the undecaprenyl pyrophosphate is released and recycled. As the polymerization process catalyzed by the transglycosylases proceed, transpeptidases cross-link the peptide stems from two neighboring peptidoglycan strands to result in the network of the growning cell wall that is critical for the survival of bacteria. 

Another product of this reaction, undecaprenyl pyrophosphate, accumulates both in cell-free incubation mixtures and in intact... 

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... 

The underlying mechanism of this inhibition appears to be the sequestration of undecaprenyl pyrophosphate by bacitracin in the presence of a divalent cation and not the binding of the antibiotic to an enzyme (Stone and Strominger, 1971). Drug resistance in this case is related to elevated levels of undecaprenyl derivatives, rather than to a mutant enzyme in the undecaprenyl phosphate cycle. 

Bacitracin, extracted from B, subtilis, is a decapeptide containing four D-amino acid residues and a thiazoline nucleus. Its point of attack is the formation of a complex with the sugar-transporting undecaprenyl pyrophosphate in the plasma membrane, an early stage in cell-wall synthesis briefly referred to in Section 5.3 (Stone and Strominger, 1971). Too nephrotoxic for internal use, bacitracin is a valuable constituent of antiseptic ointments. It requires a divalent metal for its attack (Section 11.9). 

Chen AP-C, ChenY-H, Liu H-P, LiY-C, Chen C-T, Liang P-H (2002) Synthesis and application of a fluorescent substrate analogue to study ligand interactions for undecaprenyl pyrophosphate synthase. J Am Chem Soc 124 15217-15224... 

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