Mycobacterium glutamine synthetase

X-ray crystal structures of glutamine synthetase from both Salmonella typhimuriuni and Mycobacterium tuberculosis are very similar. Structures of wild type enzymes and of active site mutants have been determined. All structures have been solved with Mn in the active site. There are twelve identical subunits arranged in two face-to-face symmetrical hexamers. The active sites are in funnel-shaped open-ended cavities located between adjacent subunits of the hexamer. These cavities are 45 A long, 30 A wide at the outer end, and 10 A wide at the inner end and the active site with the two Mn " ions is approximately halfway down the cavity. The metal-metal distance is 5.8 A. The more tightly bound Mn is coordinated to the side chains of Glu-131, Glu-212, Glu-220, and two water molecules, one of which is shared by both metal ions. Glu-129, Glu-357, His-269, and two additional water molecules are bound to the Mn + at the lower affinity site. A schematic view of the active site metal coordination is shown in Figure 36. 

G Harth, MA Horwitz (1999) An inhibitor of exported Mycobacterium tuberculosis glutamine synthetase selectively blocks the growth of pathogenic mycobacteria in axenic culture and in human monocytes extracellular proteins as potential novel drug targets, J Exp Med 189(9) 1425-1436... 

G Harth, MA Horwitz (2003) Inhibition of Mycobacterium tuberculosis glutamine synthetase as a novel antibiotic strategy against tuberculosis demonstration of efficacy in vivo, Infect Immun 71(l) 456-464... 

The compounds prepared were tested for their inhibitory activity against Mycobacterium tuberculosis glutamine synthetase (MtGS), an enzyme that plays a key role in mycobacterial cell-wall biosynthesis and nitrogen metabolism. Compound... 

---