The structure of sedoheptulose-7-phosphate isomerase from Burkholderia pseudomallei reveals a zinc binding site at the heart of the active site.
Heptoses are found in the surface polysaccharides of most bacteria, contributing to structures that are essential for virulence and antibiotic resistance. Consequently, the biosynthetic enzymes for these sugars are attractive targets for novel antibiotics. The best characterized biosynthetic enzyme is GmhA, which catalyzes the conversion of sedoheptulose-7-phosphate into D-glycero-D-manno-heptopyranose-7-phosphate, the first step in the biosynthesis of heptose. Here, the structure of GmhA from Burkholderia pseudomallei is reported. This enzyme contains a zinc ion at the heart of its active site: this ion stabilizes the active, closed form of the enzyme and presents coordinating side chains as a potential acid and base to drive catalysis. A complex with the product demonstrates that the enzyme retains activity in the crystal and thus suggests that the closed conformation is catalytically relevant and is an excellent target for the development of therapeutics. A revised mechanism for the action of GmhA is postulated on the basis of this structure and the activity of B. pseudomallei GmhA mutants.
Harmer
Nicholas J
NJ
School of Biosciences, University of Exeter, Geoffrey Pope Building, Stocker Road, Exeter EX4 4QD, UK. N.J.Harmer@exeter.ac.uk
D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry*; D001665:Binding Sites; D016957:Burkholderia pseudomallei / Q000201:enzymology*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D053858:Metabolic Networks and Pathways; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D019998:Racemases and Epimerases / Q000737:chemistry*; D016415:Sequence Alignment; D013403:Sugar Phosphates / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism*
D001426:Bacterial Proteins; D013403:Sugar Phosphates; C020495:sedoheptulose 7-phosphate; D019998:Racemases and Epimerases; D015032:Zinc