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3 Biosynthesis of the Arabinogalactan-Peptidoglycan Complex of Mycobacterium tuberculosis, Page 1 of 2
< Previous page | Next page > /docserver/preview/fulltext/10.1128/9781555815783/9781555814687_Chap03-1.gif /docserver/preview/fulltext/10.1128/9781555815783/9781555814687_Chap03-2.gifAbstract:
Recent developments in genomics, bioinformatics, proteomics, and analytical techniques have resulted in a more detailed and thorough understanding of the structure of the mycobacterial cell wall core and its biosynthesis. Indeed, much of the current interest in its biosynthesis is driven by the need for novel, alternative drugs to counteract drug-resistant tuberculosis. The tetrapeptide side chains of peptidoglycan (PG) consist of L-alanyl-D-isoglutaminylmeso-diaminopimelyl-D-alanine (L-Ala-D-Glu-A2pm- D-Ala), with the Glu and A2pm being further amidated. Recent mass spectrometric analysis suggests that the arabinan chains released from the cell wall by an endogenous arabinase are also approximately 30 residues long and indicates that galactosamine (GalNH2) residues in Arabinogalactan (AG) isolated from the Mycobacterium tuberculosis CSU20 strain are found on the C2 position of some of the internal 3,5-branched Araf residues. Many of the insights to understanding the biosynthesis of the cell wall core are derived from earlier structural analysis. In general, polyprenyl diphosphate (Pol-P-P) molecules are synthesized through sequential condensation of isopentenyl diphosphate (IPP, derived from methylerythritol phosphate in mycobacteria) with allylic diphosphates, reactions that are catalyzed by prenyl diphosphate synthases. Synthesis of AG begins with the formation of the linker unit, and then there appears to be a concomitant extension of the galactan and arabinan moieties. The structural complexity of mycobacterial arabinofuran present in AG is likely to be reflected in a complex biosynthetic pathway, and arabinosyl transferases are now being rapidly identified in Mycobacterium spp.
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Schematic diagram of the mycolyl-arabinogalactan-peptidoglycan complex of M. tuberculosis. The positions of the succinyl and d-galactosamine residues are indicated ( Crick et al., 2008 ).
Schematic diagram showing key intermediates in mycolyl-arabinogalactan-peptidoglycan complex synthesis and the central role played by decaprenyl phosphate.
Pathways involved in the biosynthesis of decaprenyl phosphate and peptidoglycan with respect to the topology of the plasma membrane. A simple hypothetical scheme for decaprenyl phosphate recycling has been included; more complex possibilities exist, as is discussed in the text. Gene (Rv) numbers have been provided for enzymes from M. tuberculosis which have been biochemically demonstrated to catalyze the indicated reaction. Symbols used:
, phosphate;
, N-acylmuramic acid;
, N-acetylglucosamine.
Pathways involved in arabinogalactan synthesis showing the intersection of galactan synthesis and decaprenylphosphorylarabinose (DPA) synthesis. Gene (Rv) numbers have been provided for enzymes from M. tuberculosis, which have been biochemically demonstrated to catalyze the indicated reaction ( Crick et al., 2008 ).