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21 Glycopeptidolipids: a Complex Pathway for Small Pleiotropic Molecules, Page 1 of 2
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This chapter describes the major advances in the understanding of the biology and biosynthesis of glycopeptidolipids (GPLs). Strains from the Mycobacterium fortuitum complex contain surface species-specific lipids, allowing their precise identification. In M. fortuitum bv. Peregrinum, two major GPLs were characterized by a combination of chemical analyses. The M. avium-M. intracellulare-M. scrofulaceum complex (MAC) is among the most common nontuberculous mycobacteria recovered from clinical specimens and is also a prevalent pathogen in AIDS patients. An immunogenic GPL, named GPL X-I, was isolated from M. xenopi, a nontuberculous mycobacterium responsible for pulmonary and disseminated infectious diseases mainly occurring in immunocompromised patients. M. avium subsp. paratuberculosis is closely related to M. avium subsp. avium and is responsible for cattle infections. The isolation of GPL-nonproducing mutants after a transposon mutagenesis of M. smegmatis was greatly facilitated thanks to the characteristic morphotypes of these mutants. The lipopeptide core can be modified by glycosylation, O methylation, and O acetylation, and each of the genes responsible for these modifications has been characterized. Freeze-fracture electron microscopy has been used to study the structure of the envelope of M. avium cells growing inside mouse liver macrophages and has revealed an onion-like structure. A study investigated the consequence of drug treatment with a regimen of clarithromycin and ethambutol on the chemical alterations of GPLs in M. avium. Small metabolites such as sulfolipids, phenolglycolipids, or glycopeptidolipids use the same building blocks that are Pks, FadD, FadE, MmpL, and Gtf and that have evolved substrate specificity.
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General structures of mycobacterial GPLs. (Adapted from Patterson et al., 2000 ; and Villeneuve et al., 2003 .) Ac, acetyl.
(A) Structural aspect of the multilamellar coat (asterisk) that invests intraphagosomal M. avium bacilli in mouse liver cells after 3-month infections as revealed by freeze fracture electron microscopy (magnification, X62,000) ( Rulong et al., 1991 ). (B) Transmission electron micrograph of M. smegmatis strain mc2155 and a non-GPL-producing mutant ( Etienne et al., 2002 ).
Genetic organization of the GPL locus in various mycobacterial species. The ORFs are depicted as arrows and have been drawn proportionally to their size ( Ripoll et al., 2007 ). Color code: light blue, mmpL family; black, unknown; purple, sugar biosynthesis, activation, transfer and modifications; red, lipid biosynthesis, activation, transfer and modifications; green, pseudopeptide biosynthesis; yellow, required for GPL transport to the surface; gray, regulation. (See the color insert for the color version of this figure.)
(A) Transmission electron microscopy analysis of the M. smegmatis wild-type strain mc2155 and the gap mutant strain after ruthenium red staining ( Sonden et al., 2005 ). (B) Topology of Gap protein predicted by Sosui program. (C) Amino acid alignment of various Gap orthologues found in sequenced mycobacterial genomes: M. smegmatis (MSMEG), M. tuberculosis (Rv), M. avium subsp. paratuberculosis (MAP) and M. leprae (ML). Color code: red, high concensus (>90%); blue, low consensus (>50%). The central parts bordered in orange correspond to the predicted cytoplasmic portion and may be the region of selectivity of Gap proteins. (See the color insert for the color version of this figure.)
The mechanism arising in the upstream region of the mps operon in M. smegmatis. In the ATCC607 strain, the mps operon is under the direct or indirect negative control of Lsr2, which leads to a low level of mRNA and a low level of GPLs (Kocincova et al., unpublished data). In the lsr2 mutant, the mps operon is highly expressed because of the absence of the negative regulator Lsr2 that leads to high production of GPLs. In the mc2155 strain, the Lsr2-dependent regulation is lost upon insertion of the mobile element, which leads to a major expression of the mps operon and consequently to a high level of GPL.
Motility on Tween 80-containing plate of M. smegmatis mc2155 (A) and a GPL-nonproducing mutant (B). (Our unpublished data).
Structures of some haptenic oligosaccharide extensions of GPLs from MAC serovars a