Synthetic arabinofuranosyl oligosaccharides as Mycobacterial arabinosyltransferase substrates

Ayers, Joseph D.; Lowary, Todd L.; Morehouse, Caroline B.; Besra, Gurdyal S.

doi:10.1016/s0960-894x(98)00049-3

Cited by 61 publications

(45 citation statements)

References 18 publications

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“…To initiate a study on ag85C-mediated acyl-transfer we are required to synthesize an acyl donor 1, and three acceptors 2-3 [20,22,23] and 9 [24]. Acyl donor 1 for enzymatic reaction was synthesized by literature procedure [21].…”

Section: Resultsmentioning

confidence: 99%

Antigen 85C-mediated acyl-transfer between synthetic acyl donors and fragments of the arabinan

et al. 2008

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Antigen 85 (ag85) is a complex of acyltransferases (ag85A-C) known to play a role in the mycolation of the D-arabino-D-galactan (AG) component of the mycobacterial cell wall. In order to better understand the chemistry and substrate specificity of ag85, a trehalose monomycolate mimic p-nitrophenyl 6-O-octanoyl-beta-D-glucopyranoside (1) containing an octanoyl moiety in lieu of a mycolyl moiety was synthesized as an acyl donor. Arabinofuranoside acceptors, methyl alpha-D-arabinofuranoside (2), methyl beta-D-arabinofuranoside (3), and methyl 2-O-beta-D-arabinofuranosyl-alpha-D-arabinofuranoside (9) were synthesized to mimic the terminal saccharides found on the AG. The acyl transfer reaction between acyl donor 1 and acceptors 2, 3, and 9 in the presence of ag85C from Mycobacterium tuberculosis (M. tuberculosis) resulted in the formation of esters, methyl 2, 5-di-O-octanoyl-alpha-D-arabinofuranoside (10), methyl 5-O-octanoyl-beta-D-arabinofuranoside (11), and methyl 2-O-(5-O-octanoyl-beta-D-arabinofuranosyl)-5-O-octanoyl-alpha-D-arabinofuranoside (12) in 2 h, 2 h and 8 h, respectively. The initial velocities of the reactions were determined with a newly developed assay for acyltransferases. As expected, the regioselectivity corresponds to mycolylation patterns found at the terminus of the AG in M. tuberculosis. The study shows that D-arabinose-based derivatives are capable of acting as substrates for ag85C-mediated acyl-transfer and the acyl glycoside 1 can be used in lieu of TMM extracted from bacteria to study ag85-mediated acyl-transfer and inhibition leading to the better understanding of the ag85 protein class.

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Section: Resultsmentioning

confidence: 99%

Antigen 85C-mediated acyl-transfer between synthetic acyl donors and fragments of the arabinan

et al. 2008

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“…As explained in Section IV, although the normal acceptor substrates for mycobacterial arabinosyltransferases are high molecular weight glycolipids, some (and probably most, if not all) of these enzymes will recognize small oligosaccharide fragments of these large glycans. [49,55] In this regard, these enzymes appear to be similar to mammalian glycosyltransferases. [65] Therefore, these small oligosaccharides are invaluable tools not only for mapping out substrate specificities of these enzymes but also as templates for the design of potentially inhibitory analogs.…”

Section: Synthesis Of D-arabinofuranosidesmentioning

confidence: 93%

“…A few of the oligoarabinosides that have been shown to be substrates for these enzymes are illustrated in Figure 6. [49,55] Arabinofuranose disaccharides appear to be the minimum epitopes. Furthermore, investigation of the AraT recognition of the disaccharide a-D-Araf-(1 !…”

Section: Arabinan Biosynthesismentioning

confidence: 99%

“…[49,50] The assay measures the incorporation of radiolabeled arabinose from 10 into arabinan, and it has been used to screen both potential substrates and inhibitors. [46,47,55,56] Although the natural acceptor substrates for these enzymes are lipid-bound intermediates, these AraT's also recognize small arabinofuranosyl oligosaccharides. A few of the oligoarabinosides that have been shown to be substrates for these enzymes are illustrated in Figure 6.…”

Section: Arabinan Biosynthesismentioning

confidence: 99%

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d-ARABINOFURANOSIDES FROM MYCOBACTERIA: SYNTHESIS AND CONFORMATION

Lowary

2002

Journal of Carbohydrate Chemistry

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“…[5] Renewed interest in oligoarabinofuranoside construction [10Ϫ17] has arisen from the isolation of a mycobacterial arabinose donor [18] and the development of an arabinosyl transferase assay that allows in vitro testing of inhibitors with synthetic oligoarabinofuranosidic acceptors. [4,11,19] Although the glycosylation reaction, involving coupling of a glycosyl donor with an acceptor to give a disaccharide (Figure 2), is simple in principle, the synthesis of complex oligosaccharides is still a long and complicated task, owing to the variety of the linkages between sugar units involved. Control over the stereochemical outcome of the glycosylation can be obtained by an appropriate choice of substituent on the hydroxy group in position 2 in the donor: ester or similar groups give α-glycosides, while β-glycosides are obtained by use of the internal aglycon delivery (IAD) approach [20Ϫ26] (see Figure 2).…”

Section: Introductionmentioning

confidence: 99%