Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 365, Issue 1, Pages 146-159Publisher
ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2006.09.063
Keywords
site-directed mutagenesis; X-ray crystallography; drug design; epimerization; enzyme
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Funding
- Austrian Science Fund FWF [P 18013] Funding Source: Medline
- Biotechnology and Biological Sciences Research Council [BBS/E/J/000C0618] Funding Source: Medline
- NIAID NIH HHS [P01 AI057836] Funding Source: Medline
- Wellcome Trust [067305, 081862] Funding Source: Medline
- Biotechnology and Biological Sciences Research Council [BBS/E/J/000C0618] Funding Source: researchfish
- BBSRC [BBS/E/J/000C0618] Funding Source: UKRI
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The striking feature of carbohydrates is their constitutional, conformational and configurational diversity. Biology has harnessed this diversity and manipulates carbohydrate residues in a variety of ways, one of which is epimerization. Rm1C catalyzes the epimerization of the C3' and C5' positions of dTDP-6-deoxy-D-xylo-4-hexulose, forming dTDP-6-deoxy-L-lyxo-4-hexulose. Rm1C is the third enzyme of the rhamnose pathway, and represents a validated anti-bacterial drug target. Although several structures of the enzyme have been reported, the mechanism and the nature of the intermediates have remained obscure. Despite its relatively small size (22 kDa), Rm1C catalyzes four stereospecific proton transfers and the substrate undergoes a major conformational change during the course of the transformation. Here we report the structure of Rm1C from several organisms in complex with product and product mimics. We have probed site-directed mutants by assay and by deuterium exchange. The combination of structural and biochemical data has allowed us to assign key residues and identify the conformation of the carbohydrate during turnover. Clear knowledge of the chemical structure of Rm1C reaction intermediates may offer new opportunities for rational drug design.
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