Abstract
Lipoarabinomannan (LAM) is a high molecular weight, heterogenous lipoglycan present in abundant quantities in Mycobacterium tuberculosis and many other actinomycetes. In M. tuberculosis, the non-reducing arabinan termini of the LAM are capped with alpha1-->2 mannose residues; in some other species, the arabinan of LAM is not capped or is capped with inositol phosphate. The nature and extent of this capping plays an important role in disease pathogenesis. MT1671 in M. tuberculosis CDC1551 was identified as a glycosyltransferase that could be involved in LAM capping. To determine the function of this protein a mutant strain of M. tuberculosis CDC1551 was studied, in which MT1671 was disrupted by transposition. SDS-PAGE analysis showed that the LAM of the mutant strain migrated more rapidly than that of the wild type and did not react with concanavalin A as did wild-type LAM. Structural analysis using NMR, gas chromatography/mass spectrometry, endoarabinanase digestion, Dionex high pH anion exchange chromatography, and matrix-assisted laser desorption ionization-time-of-flight mass spectrometry demonstrated that the LAM of the mutant strain was devoid of mannose capping. Since an ortholog of MT1671 is not present in Mycobacterium smegmatis mc(2)155, a recombinant strain was constructed that expressed this protein. Analysis revealed that the LAM of the recombinant strain was larger than that of the wild type, had gained concanavalin A reactivity, and that the arabinan termini were capped with a single mannose residue. Thus, MT1671 is the mannosyltransferase involved in deposition of the first of the mannose residues on the non-reducing arabinan termini and the basis of much of the interaction between the tubercle bacillus and the host cell.
Highlights
JULY 21, 2006 VOLUME 281 NUMBER 29 wide spectrum of immunomodulatory effects
The PI anchor is composed of a myo-inositol phosphoryl diacylglycerol substituted at the 2 position with a single mannopyranose (Manp) and at the 6 position with the mannan; this structure is identical to those found in the mycobacterial phosphatidylinositolmannosides and lipomannan [1, 2], which are thought to be biosynthetic precursors of LAM [3]
It has been suggested that the type of LAM capping is a major structural feature in determining how the immune system is modulated [14], and a recent publication suggests that dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) may act as a pattern recognition receptor and discriminate between Mycobacterium species through selective recognition of the Manp caps on LAM molecules [16]
Summary
JULY 21, 2006 VOLUME 281 NUMBER 29 wide spectrum of immunomodulatory effects. Its structure is complex and heterogeneous with three distinct structural domains, including a phosphatidylinositol anchor (PI anchor), a branched mannan, and a branched arabinan (Fig. 1). Identification of MT1671 as a GT Potentially Involved in LAM Capping—MT1671 from M. tuberculosis CDC1551 met all of the criteria proposed for a GT involved in Manp capping of LAM; it is classified as a putative GT-C GT [22], species of mycobacteria known to have ManLAM have orthologs of this protein, and M. smegmatis, which has PILAM, does not (Fig. 2A).
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