Sulfatides of Mycobacterium tuberculosis: the structure of the principal sulfatide (SL-I)

Goren, Mayer B.; Brokl, O. H.; Roller, Peter P.; Fales, Henry M.; Das, Bhupesh C.

doi:10.1021/bi00658a003

Cited by 97 publications

(81 citation statements)

References 18 publications

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“…How this may relate to the establishment of TB is discussed in more detail below. sulfolipids [105], and the cell wall-associated lipid phthiocerol dimycocerosate [106,107].…”

Section: Does Structure Matter?mentioning

confidence: 99%

Towards understanding the functional diversity of cell wall mycolic acids of Mycobacterium tuberculosis

Verschoor

Baird

Grooten

2012

Progress in Lipid Research

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Mycolic acids constitute the waxy layer of the outer cell wall of Mycobacterium spp and a few other genera. They are diverse in structure, providing a unique chromatographic foot-print for almost each of the more than seventy Mycobacterium species. Although mainly esterified to cell wall arabinogalactan, trehalose or glucose, some free mycolic acid is secreted during in vitro growth of M. tuberculosis. In M. tuberculosis, alpha-, keto-and methoxy-mycolic acids are the main classes, each differing in their ability to attract neutrophils, induce foamy macrophages or adopt an antigenic structure for antibody recognition. Of interest is their particular relationship to cholesterol, discovered by their ability to attract cholesterol, to bind Amphotericin B or to be recognised by monoclonal antibodies that cross-react with cholesterol. The structural elements that determine this diverse functionality include the carboxylic acid in the mycolic motif, as well as the nature and stereochemistry of the two functional groups in the merochain. The functional diversity of mycolic acid classes implies that much information may be contained in the selective expression and secretion of mycolic acids to establish tuberculosis after infection of the host. Their cholesteroid nature may relate to how they utilize host cholesterol for their persistent survival.

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“…How this may relate to the establishment of TB is discussed in more detail below. sulfolipids [105], and the cell wall-associated lipid phthiocerol dimycocerosate [106,107].…”

Section: Does Structure Matter?mentioning

confidence: 99%

Towards understanding the functional diversity of cell wall mycolic acids of Mycobacterium tuberculosis

Verschoor

Baird

Grooten

2012

Progress in Lipid Research

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“…These findings support the idea that fine structural differences in TDM do influence clinical outcome, at least in the mouse model. (20), and the cell wall-associated complex free lipid phthiocerol dimycocerosate (21)(22)(23).…”

Section: Mycolic Acids and Their Effect On Host Immune Responsementioning

confidence: 99%

Of mice, men, and elephants: Mycobacterium tuberculosis cell envelope lipids and pathogenesis

Riley¹

2006

Journal of Clinical Investigation

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“…The most abundant sulfatide, termed Sulfolipid-1 (SL-1), consists of a trehalose core, four fatty acyl groups, and a sulfate ester (Fig. 1A) (10)(11)(12)(13). Despite the discovery of SL-1 nearly 50 years ago, the biological function of the molecule is not known.…”

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confidence: 99%

PapA1 and PapA2 are acyltransferases essential for the biosynthesis of theMycobacterium tuberculosisvirulence factor Sulfolipid-1

Kumar

Schelle²,

Jain³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

111

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pathogenesis ͉ biochemistry ͉ glycolipid ͉ sulfation T he thick Mycobacterium tuberculosis (M. tb) cell wall consists of numerous glycolipids that are distinctive to the mycobacterial genus, including phosphatidylinositol mannosides, trehalose mycolates, and lipoarabinomannans (1). These molecules are essential for many of the characteristics that distinguish mycobacterial pathogenesis, such as the inhibition of phagosomal maturation, drug resistance, and alteration of the host immune response (2-6). A family of cell surface sulfated lipids (dubbed sulfatides) were identified in M. tb extracts and correlated to strain virulence (7-9). The most abundant sulfatide, termed Sulfolipid-1 (SL-1), consists of a trehalose core, four fatty acyl groups, and a sulfate ester (Fig. 1A) (10-13). Despite the discovery of SL-1 nearly 50 years ago, the biological function of the molecule is not known. Conflicting reports suggest a role for SL-1 in superoxide (O 2 Ϫ ) release from human neutrophils or monocytes, alteration of trehalose dimycolate toxicity, and inhibition of trehalose dimycolate-induced macrophage recruitment (14-19). The relevance of these studies to the physiological role of SL-1 in M. tb infection is debatable.Although the role of SL-1 remains elusive, advances in genetics and metabolite analysis have sped the discovery of genes, proteins, and intermediates associated with SL-1 biosynthesis (20). Currently, three proteins are known to be involved in SL-1 assembly: Stf0, Pks2, and MmpL8. The sulfotransferase Stf0 sulfates trehalose at the 2-position, forming trehalose-2-sulfate (T2S), thereby initiating SL-1 biosynthesis (21). Meanwhile, the polyketide synthase Pks2 synthesizes the phthioceranoyl and hydroxyphthioceranoyl lipids that occupy the 6-, 6Ј-, and 3Ј-positions of SL-1 (Fig. 1 A) (22). The proteins responsible for transfer of the Pks2 products and the palmitoyl group to the T2S core, and the order in which these lipids are added, have not yet been defined.Insight into the order of lipid addition came from characterization of the putative lipid transporter MmpL8 (23,24). A mutant strain, ⌬mmpL8, lacks SL-1 but accumulates the diacylated intermediate SL 1278 (named for its observed mass) inside the cell (Fig. 1B). This intermediate possesses two of the four SL-1-associated lipids: a hydroxyphthioceranoyl group at the 3Ј-position and a palmitoyl group at the 2Ј-position (24). SL 1278 was recently found to be an immunostimulant in human tuberculosis patients (25). The glycolipid is presented on the surface of M. tb-infected antigen-presenting cells by CD1b, a member of the MHC class I-like CD1 family. Intriguingly, the ⌬mmpL8 mutant, which lacks SL-1 but accumulates SL 1278 , shows attenuated virulence in mice (23,24). By contrast, a ⌬pks2 mutant, which lacks both SL-1 and SL 1278 , is indistinguishable from WT M. tb in mice and guinea pigs (23,26). These observations suggest that SL 1278 , and possibly other SL-1 intermediates, modulate M. tb pathogenesis.In our effort to define the functions of M. tb sulf...

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Sulfatides of Mycobacterium tuberculosis: the structure of the principal sulfatide (SL-I)

Cited by 97 publications

References 18 publications

Towards understanding the functional diversity of cell wall mycolic acids of Mycobacterium tuberculosis

Towards understanding the functional diversity of cell wall mycolic acids of Mycobacterium tuberculosis

Of mice, men, and elephants: Mycobacterium tuberculosis cell envelope lipids and pathogenesis

PapA1 and PapA2 are acyltransferases essential for the biosynthesis of theMycobacterium tuberculosisvirulence factor Sulfolipid-1

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