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3bjz

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==Overview==
==Overview==
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The 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.
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The 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.
==About this Structure==
==About this Structure==
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[[Category: Joachimiak, A.]]
[[Category: Joachimiak, A.]]
[[Category: Kudritska, M.]]
[[Category: Kudritska, M.]]
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[[Category: MCSG, Midwest.Center.for.Structural.Genomics.]]
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[[Category: MCSG, Midwest Center for Structural Genomics.]]
[[Category: Osipiuk, J.]]
[[Category: Osipiuk, J.]]
[[Category: Savchenko, A.]]
[[Category: Savchenko, A.]]
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[[Category: Walker, J.R.]]
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[[Category: Walker, J R.]]
[[Category: CL]]
[[Category: CL]]
[[Category: SO4]]
[[Category: SO4]]
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[[Category: sis domain]]
[[Category: sis domain]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Feb 13 08:13:39 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 19:06:17 2008''

Revision as of 17:06, 21 February 2008

Image:3bjz.jpg

3bjz, resolution 2.40Å

Drag the structure with the mouse to rotate

Crystal structure of Pseudomonas aeruginosa phosphoheptose isomerase

Overview

The 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.

About this Structure

3BJZ is a Single protein structure of sequence from Pseudomonas aeruginosa pao1 with and as ligands. Known structural/functional Sites: , , and . Full crystallographic information is available from OCA.

Reference

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

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