Roles of conserved proline and glycosyltransferase motifs of EmbC in
SUMMARY D-Arabinans, composed of D-arabinofuranose (D-Araf), dominate the structure of mycobacterial cell walls, in two settings, as part of lipoarabinomannan (LAM) and arabinogalactan (AG), each with markedly different structures and functions. Little is known of the complexity of their biosynthesis. -D-Arabinofuranosyl-1-monophosphoryldecaprenol (C50-P-Araf) is the only known sugar donor, and EmbA, B, and C, products of the paralogous genes embA, B, and C, the sites of resistance to the anti-tuberculosis drug, ethambutol (EMB), are the only known implicated enzymes; EmbA and B apparently contribute to the synthesis of AG whereas EmbC is reserved for the synthesis of LAM. The Emb proteins show no over-all similarity to any known proteins, beyond Mycobacterium and related species. However, functional motifs, equivalent to a proline-rich motif of several bacterial Polysaccharide Co-Polymerases and a superfamily of glycosyltransferases (GT-C), were found. Site-directed mutagenesis in GT-C resulted in complete ablation of LAM synthesis. Point mutations in three amino acids of the proline motif of EmbC resulted in marked reduction of LAM-arabinan synthesis, and accumulation of an unknown intermediate and of the known precursor, lipomannan. Yet the pattern of the differently linked D-Araf units observed in wild type LAM-arabinan was largely retained in the proline motif mutants. The results allow for the presentation of a unique model of arabinan synthesis.
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