Lipid pyrophosphate moiety

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. 

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... 

DEAE-cellulose ion-exchange chromatography, which is dependent on the phosphate, pyrophosphate or phosphoethanolamine groups of the lipid A moiety, is widely used for lipid A isolation (El Hamidi et al., 2005 Raetz and Kennedy, 1973). TLC, as a lipids detection method, also can be applied for lipid A isolation (Zhou et al., 1999). In addition, the chromatography techniques based on the molecular... 

Figure 2 Mode of action of the prototypical lantibiotic nisin. (a) The peptidoglycan precursor lipid II is composed of an N-acetylglucosamine-p-1,4-N-acetylmuramic acid disaccharide (GIcNAc-MurNAc) that is attached to a membrane anchor of 11 isoprene units via a pyrophosphate moiety. A pentapeptide is linked to the muramic acid. Transglycosylase and transpeptidase enzymes polymerize multiple lipid II molecules and crosslink their pentapeptide groups, respectively, to generate the peptidoglycan. (b) The NMR solution structure of the 1 1 complex of nisin and a lipid II derivative in DMSO (6). (c) The amino-terminus of nisin binds the pyrophosphate of lipid II, whereas the carboxy-terminus inserts into the bacterial membrane. Four lipid II and eight nisin molecules compose a stable pore, although the arrangement of the molecules within each pore is unknown (5).

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). 

Steroids are members of a large class of lipid compounds called terpenes. Using acetate as a starting material, a variety of organisms produce terpenes by essentially the same biosynthetic scheme (Fig. 8). The self-condensation of two molecules of acetyl coenzyme A (CoA) forms acetoacetyl CoA. Condensation of acetoacetyl CoA with a third molecule of acetyl CoA, then followed by an NADPH-mediated reduction of the thioester moiety produces mevalonic acid [150-97-0] (72). Phosphorylation of (72) followed by concomitant decarboxylation and dehydration processes produce isopentenyl pyrophosphate. Isopentenyl pyrophosphate isomerase establishes an equilibrium between isopentenyl pyrophosphate and 3,3-dimethylallyl pyrophosphate (73). The head-to-tail addition of these isoprene units forms geranyl pyrophosphate. The addition of another isopentenyl pyrophosphate unit results in the sesquiterpene (C15) famesyl pyrophosphate (74). Both of these head-to-tail additions are catalyzed by prenyl transferase. Squalene synthetase catalyzes the head-to-head addition of two achiral molecules of famesyl pyrophosphate, through a chiral cyclopropane intermediate, to form the achiral triterpene, squalene (75). 

Synthesis of the lipid moiety dolichol occurs in the cytoplasm and endoplasmic reticulum, beginning with steps identical to those of cholesterol biosynthesis, up to and including the formation of farnesyl pyrophosphate [7]. At this point, the synthesis pathways of cholesterol and dolichol branch, with dolichol synthesis proceeding with the addition of isoprenyl units to farnesyl pyrophosphate by cis-prenyltransferase, yielding polyprenylpyrophosphate as the product. An important step in the synthesis of dolichol is the reduction of polyprenol, with a double bond in every isoprene unit, to dolichol, in which the a isoprene, the one nearest the hydroxyl unit, is saturated (Figure 1 and [7]). 

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