Mode of action of lipoprotein modification enzymes—Novel antibacterial targets

Abstract

Volkmar Braun first discovered bacterial lipoproteins in 1973 through the identification of a fatty-acid modification of Lpp, or Braun's lipoprotein, in E. coli (Hantke and Braun, 1973). Through early biochemical and genetics studies and more recent structural analysis, the lipoprotein modification pathway is increasingly well understood. A general consensus exists regarding the well-studied tripartite stages of the lipoprotein modification pathway. Upon insertion into the cytoplasmic membrane, a diacylglyceryl group is added to the lipoprotein, the membrane-spanning signal peptide is cleaved and the protein stays membrane anchored by its diacylglyceryl moiety. Finally, N-acylation results in the formation of mature triacylated lipoprotein (Figure 1). In diderm bacteria, including proteobacteria and some high GC content Gram-positive bacteria, including Streptomyces, Corynebacteria, and Mycobacteria, lipoproteins are triacylated following this classical pathway, although in some instances Lnt and/or Lsp are not essential components for cell viability (discussed below). In monoderm bacteria it was long thought that only diacylated lipoproteins existed; however, recent studies illustrate that alternative lipid modifications occur in firmicutes and mollicutes, but not all enzymes catalyzing these reactions have been

Structural basis of lipoprotein recognition by the bacterial Lol trafficking chaperone LolA

“…Lipoproteins, anchored by an N-terminal triacyl group, are essential components of this barrier underlying its structural integrity and forming vital components of machineries essential for lipopolysaccharide (LPS) insertion, outer membrane protein assembly, and maintenance of its asymmetry ( 2 – 4 ). They also underpin a myriad of other vital functions, including nutrient acquisition, stress sensing, and bacterial virulence ( 5 , 6 ), rendering the systems involved in their synthesis and transport key targets for antimicrobial therapy ( 7 , 8 ). Lipoproteins are initially produced in the cytosol and targeted by an N-terminal signal peptide to the inner membrane where they are transported by the Sec or Tat pathways ( 9 , 10 ).…”

In Vitro, In Vivo, and In Silico Activities of Ginkgolic Acid C15:1 against Streptococcus agalactiae Clinical Isolates

“…Particularly noteworthy is lipoprotein signaling peptidase II (lspA), which plays a key enzyme involved in the post-translational processing of lipoproteins . Bacterial lipoprotein is a class of membrane proteins with diverse functions that are essential for normal bacterial growth, differentiation, and development. − Many reports have claimed that lipoprotein is a potential target for the design of novel antimicrobials. , LspA is an aspartyl protease that cleaves the transmembrane helix signal peptide of lipoproteins as an essential member of the lipoprotein-biosynthetic pathway. Several LspA inhibitors have been developed, demonstrating its utility as a potential target. − …”

“…21−23 Many reports have claimed that lipoprotein is a potential target for the design of novel antimicrobials. 24,25 LspA is an aspartyl protease that cleaves the transmembrane helix signal peptide of lipoproteins as an essential member of the lipoprotein-biosynthetic pathway. Several LspA inhibitors have been developed, demonstrating its utility as a potential target.…”

A Defect in Lipoprotein Modification by Lgt Leads to Abnormal Morphology and Cell Death in Escherichia coli That Is Independent of Major Lipoprotein Lpp

“…Lipoproteins play an important role in physiology and viability of bacteria and are involved in essential processes for the cell envelope, such as cell wall biogenesis, transport and insertion of membrane proteins and lipopolysaccharides, nutrient uptake, and efflux of toxic molecules ( 1 – 3 ). They are anchored in membranes through their fatty acid-linked amino termini, which also play an important role in virulence by signaling the innate immune response via interaction with Toll-like receptors ( 4 ).…”