Arabinogalactans biosynthesis

Rose NL, Complete GC, Lin SJ, McNeil M, Palcic MM, Lowary TL. Expression, purification, and characterization of a galactofuranosyltransferase involved in Mycobacterium tuberculosis arabinogalactan biosynthesis. J. Am. Chem. Soc. 2006 128 6721-6729. 

Fincher, G.B., Stone, B.A., and Clarke, A.E. (1983) Arabinogalactan-proteins stracture, biosynthesis, and function. AnnuBev.Plant Physiol. 34 47-70. 

The component(s) of the mycobacterial cell wall responsible for conferring intrinsic resistance to antibiotics are not yet known with any certainty. However, it has been shown [91-93] that inhibitors of arabinogalactan synthesis increase mycobacterial sensitivity to antibiotics. When M. avium is treated with inhibitors of mycolic acid biosynthesis there are significant alterations in outer cell wall layers and the cells show an increased antibiotic susceptibility [93], Thus, arabinogalactan and mycolic acids are components of the wall associated with intrinsic resistance of mycobacteria to chemotherapeutic drugs and alteration of these structural building blocks leads to increased intracellular penetration of antibiotics [88,94,95],... 

Multidrug-resistant M. tuberculosis (MDRTB) strains have become a problem. As pointed out previously, the mycobacterial cell wall presents a major barrier to the entry of chemotherapeutic drugs. Possible solutions are (i) to design drugs of increasing hydrophobicity that will pass through the cell wall, as with isoniazid derivatives [89, 90], (ii) to use a second antibiotic in combination with a known inhibitor of arabinogalactan or mycolic acid biosynthesis [238]. 

Biosynthesis of arabinogalactan. Biosynthetic genes are indicated, where known... 

Disaccharides have also been synthesized as potential cell wall biosynthesis inhibitors, including analogs of the arabinogalactan linkage disaccharide (O Fig. 22e) [286], and small lipid disaccharides containing arabinose and galactose [287]. Some of these have exhibited moderate in vitro activity against TB. 

M. McNeil, S. J. Wallner, and P. J. Brennan, Demonstration that the galactosyl and arabinosyl residues in the cell-wall arabinogalactan of Mycobacterium leprae and Mycobacterium tuberculosis are furanoid, Carbohydr. Res., 166 (1987) 299-308 R. E. Lee, P. J. Brennan, and G. S. Besra, Mycobacterial arabinan biosynthesis the use of synthetic arabinoside acceptors in the development of an arabinosyl transfer assay, Glycobiology, 7 (1997) 1121-1128. 

S. Mahapatra J. Basu P. J. Brennan D. C. Crick, Structure, Biosynthesis and Genetics of the Mycolic Acid-Arabinogalactan-Peptidoglycan Complex. In Tuberculosis and the Tubercle Bacillus] S. T. Cole, K. D. Eisenach, D. N. McMurray, W. R. Jacobs, Eds. ASM Press Washington, DC, 2005 pp 275-285. 

X. Wen, D.C. Crick, P.J. Brennan, P.G. Hultin, Analogues of the mycobacterial arabinogalactan linkage disaccharide as cell wall biosynthesis inhibitors, Bioorg. Med. Chem. 2003, 11, 3579-3587. 

The investigations towards furanosyl transferases was driven by the huge progress made on the comprehension of the biological pathways involved in the biosynthesis of arabinogalactan, the structural polysaccharide expressed at the surface of M. tuberculosis cell wall. Consequently, this part focuses on discoveries made in this field. 

Considering the Gal/" part of the arabinogalactan polysaccharide produced by M tuberculosis (Fig. 3), the biosynthesis begin with connection of a N-acetyl-a-u-glucosamine-l-phosphate (a-o-GlcNAcp-l-P) residue to a decaprenyl phosphate chain, anchored into the biological... 

Fincher G B, Stone B A, Clarke A E 1983 Arabinogalactan-proteins Structure, biosynthesis, and function. Ann Rev Plant Physiol 34 47-70... 

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