Journal
FEBS JOURNAL
Volume 279, Issue 6, Pages 1093-1105Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1742-4658.2012.08506.x
Keywords
adenosine binding; biotin synthesis pathway; crystal structure; dethiobiotin synthesis; nucleotide recognition
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Funding
- NIH PSI [GM074942]
- US Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357]
- MRC [MC_UP_A025_1012] Funding Source: UKRI
- Medical Research Council [MC_UP_A025_1012] Funding Source: researchfish
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Dethiobiotin synthetase (DTBS) is involved in the biosynthesis of biotin in bacteria, fungi, and plants. As humans lack this pathway, DTBS is a promising antimicrobial drug target. We determined structures of DTBS from Helicobacter pylori (hpDTBS) bound with cofactors and a substrate analog, and described its unique characteristics relative to other DTBS proteins. Comparison with bacterial DTBS orthologs revealed considerable structural differences in nucleotide recognition. The C-terminal region of DTBS proteins, which contains two nucleotide-recognition motifs, differs greatly among DTBS proteins from different species. The structure of hpDTBS revealed that this protein is unique and does not contain a C-terminal region containing one of the motifs. The single nucleotide-binding motif in hpDTBS is similar to its counterpart in GTPases; however, isothermal titration calorimetry binding studies showed that hpDTBS has a strong preference for ATP. The structural determinants of ATP specificity were assessed with X-ray crystallographic studies of hpDTBS center dot ATP and hpDTBS center dot GTP complexes. The unique mode of nucleotide recognition in hpDTBS makes this protein a good target for H. pylori-specific inhibitors of the biotin synthesis pathway.
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