Lipid pyrophosphate

Bacitracin is a mixture of polypeptide antibiotics produced by Bacillus subtilis. As with penicillin, it contains a thiazolidine nucleus attached through L-leucine to a peptide composed of both d- and L-amino acids. However, it does not contain a (3-lactam ring. Bacitracin prevents cell wall synthesis by binding to a lipid pyrophosphate carrier that transports cell wall precursors to the growing cell wall. 

In order to find lead inhibitors against PGTs [15], Piet Herdewijn et al. [22] synthesized a series of substrate analogues of lipid I and lipid II with variations in lipid, pyrophosphate, and peptide moieties. Although many efforts were spent in designing and synthesizing lipid I- and lipid II-based inhibitors [23-26], the PGT inhibition assay performed with Escherichia coli PBP1B in vitro and antibacterial activity... 

Bacitracin, a cyclic peptide, has been shown to block mucopeptide synthesis by inhibiting the dephosphorylation of a lipid pyrophosphate intermediate to lipid phosphate. It prevents the lipid carrier from further participating in the reaction cycle of peptidoglycan synthesis causing accumulation of the lipid pyrophosphate23a,b. The antibiotics enduramycin a (g, basic polypeptide), moenomycin b j d prasinomycin (two phosphorus containing antibiotics) are also inhibitors of mucopeptide synthesis. However, the specific reaction inhibited by these three antibiotics is still not well known. 

This type of polysaccharide elongation mechanism is known as an insertion mechanism in which the monomer residue or repeating unit is apparently inserted between the reducing end of the polysaccharide chain and a lipid pyrophosphate coenzyme carrier or an enzyme-protein carrier. Actually, it is not a real insertion, but rather the transfer of the polysaccharide chain from one carrier to the carbohydrate moiety of a monomer or repeating unit attached to another carrier (see Figs. 10.12A section 10.12 on dextran biosynthesis). 

Scheme 1. Posttranslational modification of Ras protein with lipid groups (FPP Farnesyl-pyrophosphate, PalCoA Palmitoyl CoA)...

Bacitracin (Fig. 4) is a cyclic peptide antibiotic. The lipid II molecule involved in the bacterial cell wall biosynthesis has a C55 isoprenyl pyrophosphate moiety that must be dephosphorylated so that it can reparticipate in another round of lipid II transfer. Bacitracin binds to the isoprenyl pyrophosphate and prevents the dephosphorylation which, in turn, blocks cell wall growth by interfering with the release of the muropeptide subunits to the outside of the bacterial cell membrane. Bacitracin inhibits similar reactions in eukaryotic cells. So, it is systemically toxic but is an effective and widely used topical antibiotic. 

The Css polyprenol (154) obtained from leaves of Magnolia campbelUi has been shown to be a mixture of cis- and /ran -isomers. The preparation of dolichyl phosphate (155) by a pea cell-free extract has been described. Evidence has been obtained that a lipid, containing 7V-acetylglucosamine, which was obtained from Phaseolus vulgaris hypocotyls, consists of a mixture of the dolichol (156) derivatives dolichyl pyrophosphate N-acetylglucosamine and dolichyl pyrophosphate di-N-acetylchitobiose. ... 

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... 

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