title: Biosynthesis of D-arabinose in mycobacteria - a novel bacterial pathway with implications for antimycobacterial therapy.
abstract: Decaprenyl-phospho-arabinose (beta-D-arabinofuranosyl-1-O-monophosphodecaprenol), the only known donor of d-arabinose in bacteria, and its precursor, decaprenyl-phospho-ribose (beta-D-ribofuranosyl-1-O-monophosphodecaprenol), were first described in 1992. En route to D-arabinofuranose, the decaprenyl-phospho-ribose 2'-epimerase converts decaprenyl-phospho-ribose to decaprenyl-phospho-arabinose, which is a substrate for arabinosyltransferases in the synthesis of the cell-wall arabinogalactan and lipoarabinomannan polysaccharides of mycobacteria. The first step of the proposed decaprenyl-phospho-arabinose biosynthesis pathway in Mycobacterium tuberculosis and related actinobacteria is the formation of D-ribose 5-phosphate from sedoheptulose 7-phosphate, catalysed by the Rv1449 transketolase, and/or the isomerization of d-ribulose 5-phosphate, catalysed by the Rv2465 d-ribose 5-phosphate isomerase. d-Ribose 5-phosphate is a substrate for the Rv1017 phosphoribosyl pyrophosphate synthetase which forms 5-phosphoribosyl 1-pyrophosphate (PRPP). The activated 5-phosphoribofuranosyl residue of PRPP is transferred by the Rv3806 5-phosphoribosyltransferase to decaprenyl phosphate, thus forming 5'-phosphoribosyl-monophospho-decaprenol. The dephosphorylation of 5'-phosphoribosyl-monophospho-decaprenol to decaprenyl-phospho-ribose by the putative Rv3807 phospholipid phosphatase is the committed step of the pathway. A subsequent 2'-epimerization of decaprenyl-phospho-ribose by the heteromeric Rv3790/Rv3791 2'-epimerase leads to the formation of the decaprenyl-phospho-arabinose precursor for the synthesis of the cell-wall arabinans in Actinomycetales. The mycobacterial 2'-epimerase Rv3790 subunit is similar to the fungal D-arabinono-1,4-lactone oxidase, the last enzyme in the biosynthesis of D-erythroascorbic acid, thus pointing to an evolutionary link between the D-arabinofuranose- and L-ascorbic acid-related pathways. Decaprenyl-phospho-arabinose has been a lead compound for the chemical synthesis of substrates for mycobacterial arabinosyltransferases and of new inhibitors and potential antituberculosis drugs. The peculiar (omega,mono-E,octa-Z) configuration of decaprenol has yielded insights into lipid biosynthesis, and has led to the identification of the novel Z-polyprenyl diphosphate synthases of mycobacteria. Mass spectrometric methods were developed for the analysis of anomeric linkages and of dolichol phosphate-related lipids. In the field of immunology, the renaissance in mycobacterial polyisoprenoid research has led to the identification of mimetic mannosyl-beta-1-phosphomycoketides of pathogenic mycobacteria as potent lipid antigens presented by CD1c proteins to human T cells.
authors.affiliation: Laboratory of Mycobacterial Biochemistry, Institute of Public Health, Brussels, Belgium. bwolucka@pasteur.be
authors.forename: Beata A
authors.initials: BA
authors.lastname: Wolucka
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000890:Anti-Infective Agents / Q000494:pharmacology*; D001089:Arabinose / Q000737:chemistry*; D002473:Cell Wall / Q000378:metabolism; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D004977:Ethambutol / Q000737:chemistry; D006801:Humans; D007107:Immune System; D008055:Lipids / Q000737:chemistry; D008956:Models, Chemical; D009161:Mycobacterium / Q000378:metabolism*; D010754:Phosphoribosyl Pyrophosphate / Q000737:chemistry; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D008055:Lipids; D010754:Phosphoribosyl Pyrophosphate; D004977:Ethambutol; D001089:Arabinose