Mycobacterial arabinan biosynthesis: the use of synthetic arabinoside acceptors in the development of an arabinosyl transfer assay

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Abstract
Information on the biosynthesis of the D-arabinans of the cell wall of Mycobacterium tuberculosis is rapidly emerging, with the promise of new targets for drug development against tuberculosis. Accordingly, arabinosyl transferase assays were developed utilizing synthesized [1–14C]-β-D-arabinofuranosyl-1-monophosphoryldecaprenol as donor and a variety of O- and S-alkyl arabinosides as acceptors. These were: α-D-Araf-(1→5)-α-D-Araf-O- and -S-alkyl di-arabinosides and α-D-Araf-(1→5)-α-D-Araf-(1→5)-α-D-Araf-O- and -S-alkyl triarabinosides. Whereas the O- and S-alkyl monosaccharide acceptors were inactive, the O- and S-alkyl disaccharide and the O- and S-alkyl trisaccharide acceptors (O-alkyl disaccharide acceptors with a C8 alkyl chain were more active than those containing the C6 or C10 analogs. Chemical analysis of the enzymatically synthesized products of the reactions demonstrated that β-D-arabinofuranosyl-1-monophosphoryldecaprenol was an effective donor for two of the three potential arabinosyl transferases: β-D-arabinofuranosyl-1-monophosphoryldecaprenol: arabinan α(1→5) arabinosyl transferase and β-D-arabinofuranosyl-1-monophosphoryl-decaprenol: arabinan β(1→2) arabinosyl transferase. The β(1→2) arabinosyl transferase activity was more in evidence in the presence of the O-alkyl disaccharide acceptor, whereas both transferases were about equivalent in the presence of the S-alkyl trisaccharide acceptor. The tuberculosis drug, ethambutol, a known mycobacterial arabinosyl transferase inhibitor, was inactive within these arabinosyl transferase/acceptor based assay systems, supporting other evidence that a third activity, responsible for the formation of α1→3 linkage, is the drug target.

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