Biosynthesis of the galactan component of the mycobacterial cell wall

The structural core of the cell walls of Mycobacterium spp. consists of pep tidoglycan bound by a Linker unit (-alpha -L-Rhap-(1-->3)-D-GlcNAc-P-) to a galactofuran, which in turn is attached to arabinofuran and mycolic acids. The sequence of reactions leading to the biogenesis of this complex starts with the formation of the Linker unit on a polyprenyl-P to produce polypre nyl-P-P-GlcNAc-Rha (Mikusova, K., Mikus, M., Besra, G. S., Hancock, I., and Brennan, P. J. (1996) J. Biol. Chem. 271, 7820-7828), me now establish tha t formation of the galactofuran takes place on this intermediate with UDP-G alf as the Galf donor presented in the form of UDP-Galp and UDP-Galp mutase (the glf gene product) and is catalyzed by galactofuranosyl transferases, one of which, the Mycobacterium tuberculosis H37Rv3808c gene product, has b een identified. Evidence is also presented for the growth of the arabinofur an on this polyprenyl-P-P-linker unit-galactan intermediate catalyzed by un identified arabinosyl transferases, with decaprenyl-P-Araf or B-P-ribosyl-P P as the Araf donor, The product of these steps, the lipid-linked-LU-galaet an-arabinan has been partially characterized in terms of its heterogeneity, size, and composition. Biosynthesis of the major components of mycobacteri al cell walls is proving to be extremely complex. However, partial definiti on of arabinogalactan synthesis, the site of action of several major anti-t uberculosis drugs, facilitates the present day thrust for new drugs to coun teract multiple drug-resistant tuberculosis.