2i22 | pdb_00002i22
Crystal structure of Escherichia coli phosphoheptose isomerase in complex with reaction substrate sedoheptulose 7-phosphate
Structural highlights
FunctionGMHA_ECOLI Catalyzes the isomerization of sedoheptulose 7-phosphate in D-glycero-D-manno-heptose 7-phosphate.[1] [2] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe barrier imposed by lipopolysaccharide (LPS) in the outer membrane of Gram-negative bacteria presents a significant challenge in treatment of these organisms with otherwise effective hydrophobic antibiotics. The absence of L-glycero-D-manno-heptose in the LPS molecule is associated with a dramatically increased bacterial susceptibility to hydrophobic antibiotics and thus enzymes in the ADP-heptose biosynthesis pathway are of significant interest. GmhA catalyzes the isomerization of D-sedoheptulose 7-phosphate into D-glycero-D-manno-heptose 7-phosphate, the first committed step in the formation of ADP-heptose. Here we report structures of GmhA from Escherichia coli and Pseudomonas aeruginosa in apo, substrate, and product-bound forms, which together suggest that GmhA adopts two distinct conformations during isomerization through reorganization of quaternary structure. Biochemical characterization of GmhA mutants, combined with in vivo analysis of LPS biosynthesis and novobiocin susceptibility, identifies key catalytic residues. We postulate GmhA acts through an enediol-intermediate isomerase mechanism. Structure and function of sedoheptulose-7-phosphate isomerase, a critical enzyme for lipopolysaccharide biosynthesis and a target for antibiotic adjuvants.,Taylor PL, Blakely KM, de Leon GP, Walker JR, McArthur F, Evdokimova E, Zhang K, Valvano MA, Wright GD, Junop MS J Biol Chem. 2008 Feb 1;283(5):2835-45. Epub 2007 Dec 3. PMID:18056714[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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