Determination That RmlB And RmlC Genes Are Essential For Growth Of Mycobacteria

Mycobacterium tuberculosis, a species of the genus Mycobacteria is the pathogen of tuberculosis. M. tuberculosis had once been controlled, but now it poses a major public health problem. The emergence of multi-drug resistant strains and co-infection of M. tuberculosis with HIV are the two greatest factors that have contributed to the global resurgence of TB. Thus, more efficient anti-TB drugs are desperately needed.The cell wall is necessary for mycobacterial viability. The mybacterial cell wall core consists of three interconnected 'macromolecules': the outermost, mycolic acids are esterified to the middle component arabinogalacan (AG), and AG is attached to the peptidoglycan via a linker disaccharide, α-L-rhamnosyl-(1→3)-α-D-N acetyl-glucosaminosyl-1-posphate. The structure of the mycobacteria cell wall strongly suggests that the linker disaccharide is an important component. The L-rhamnosyl residue of linker disaccharide is provided with a sugar donor, dTDP-rhamnose. The biosynthetic pathway of dTDP-rhamnose consists of four-step reactions from α-D-glucose-1-phosphate and TTP to dTDP-rhamnose through three intermediates, and four reactions are catalyzed by four enzymes, α-D-glucose-1-phosphate thymidylyltransferase (RmlA), dTDP-D-glucose-4, 6-dehydratase (RmlB), dTDP-4-keto-6-deoxy-glucose-3, 5-epimerase (RmlC), and dTDP-6-deoxy-L-lyxo-4-hexulose reductase (dTDP-4-keto-L-rhamnose reductase) (RmlD), respectively. The rmlA (Rv0334), rmlB (Rv3464), rmlC (Rv3465), and rmlD (Rv3266c) genes for the four enzymes are not located in a locus in the genome of M. tuberculosis H37Rv. The rmlA gene is isolated from any other rhamnosyl formation enzymes, the rmlB and rmlC genes are together in an operon, and rmlD is found in an operon with wbbL (Rv3265c) and manB (Rv3264c). The findings and the facts that there is no salvage pathway for the formation of dTDP-rhamnose and L-rhamnosyl residues are not found in humans support the enzymes involved in dTDP-rhamnose biosynthesis are important targets for...