3twd

glmuC1 in complex with an antibacterial inhibitor

spinqualitylabelsall models 3twd, resolution 1.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3twd is a 2 chain structure with sequence from Ecoli. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: GOB, SO4 Gene: glmU, yieA, b3730, JW3708 (ECOLI) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [GLMU_ECOLI] Catalyzes the last two sequential reactions in the de novo biosynthetic pathway for UDP-N-acetylglucosamine (UDP-GlcNAc). The C-terminal domain catalyzes the transfer of acetyl group from acetyl coenzyme A to glucosamine-1-phosphate (GlcN-1-P) to produce N-acetylglucosamine-1-phosphate (GlcNAc-1-P), which is converted into UDP-GlcNAc by the transfer of uridine 5-monophosphate (from uridine 5-triphosphate), a reaction catalyzed by the N-terminal domain. Publication Abstract from PubMed GlmU is a bifunctional enzyme that is essential for bacterial growth, converting D-glucosamine-1-phosphate into UDP-GlcNAc via acetylation and subsequent uridyl transfer. A biochemical screen of AstraZeneca's compound library using GlmU of Escherichia coli identified novel sulfonamide inhibitors of the acetyl transferase reaction. Steady state kinetics, ligand-observe NMR, isothermal titration calorimetry and X-ray crystallography showed that the inhibitors were competitive with acetyl-CoA substrate. Iterative chemistry efforts improved biochemical potency against Gram-negative isozymes 300-fold and afforded antimicrobial activity against a strain of Haemophilus influenzae lacking its major efflux pump. Inhibition of precursor incorporation into bacterial macromolecules was consistent with the antimicrobial activity being caused by disruption of peptidoglycan and fatty acid biosyntheses. Isolation and characterization of two different resistant mutant strains identified the GlmU acetyl transferase domain as the molecular target. These data, along with X-ray co-crystal structures, confirmed the binding mode of the inhibitors and explained their relative lack of potency against Gram-positive GlmU isozymes. This is the first example of antimicrobial compounds mediating their growth inhibitory effects specifically via GlmU. In Vitro validation of the acetyl transferase activity of GlmU as an antibacterial target in Haemophilus influenzae.,Buurman ET, Andrews B, Gao N, Hu J, Keating TA, Lahiri S, Otterbein LR, Patten AD, Stokes SS, Shapiro AB J Biol Chem. 2011 Oct 7. PMID:21984832 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also N-acetylglucosamine-1-phosphate uridyltransferase

Proteopedia Page Contributors and Editors (what is this?)

OCA