Details
| Original language | English |
|---|---|
| Article number | 105152 |
| Journal | Journal of Biological Chemistry |
| Volume | 299 |
| Issue number | 9 |
| Early online date | 9 Aug 2023 |
| Publication status | Published - Sept 2023 |
Abstract
The ESKAPE bacteria are the six highly virulent and antibiotic-resistant pathogens that require the most urgent attention for the development of novel antibiotics. Detailed knowledge of target proteins specific to bacteria is essential to develop novel treatment options. The methylerythritol-phosphate (MEP) pathway, which is absent in humans, represents a potentially valuable target for the development of novel antibiotics. Within the MEP pathway, the enzyme 1-deoxy-D-xylulose-5-phosphate synthase (DXPS) catalyzes a crucial, rate-limiting first step and a branch point in the biosynthesis of the vitamins B1 and B6. We report the high-resolution crystal structures of DXPS from the important ESKAPE pathogens Pseudomonas aeruginosa and Klebsiella pneumoniae in both the co-factor-bound and the apo forms. We demonstrate that the absence of the cofactor thiamine diphosphate results in conformational changes that lead to disordered loops close to the active site that might be important for the design of potent DXPS inhibitors. Collectively, our results provide important structural details that aid in the assessment of DXPS as a potential target in the ongoing efforts to combat antibiotic resistance.
Keywords
- 1-deoxy-D-xylulose 5-phosphate synthase, conformational changes, DXPS, Klebsiella pneumonia, Pseudomonas aeruginosa, X-ray crystallography
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Biochemistry
- Biochemistry, Genetics and Molecular Biology(all)
- Molecular Biology
- Biochemistry, Genetics and Molecular Biology(all)
- Cell Biology
Cite this
- Standard
- Harvard
- Apa
- Vancouver
- BibTeX
- RIS
In: Journal of Biological Chemistry, Vol. 299, No. 9, 105152, 09.2023.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - 1-deoxy-D-xylulose-5-phosphate synthase from Pseudomonas aeruginosa and Klebsiella pneumoniae reveals conformational changes upon cofactor binding
AU - Hamid, Rawia
AU - Adam, Sebastian
AU - Lacour, Antoine
AU - Monjas, Leticia
AU - Köhnke, Jesko
AU - Hirsch, Anna K.H.
N1 - Funding Information: The authors would like to thank Dr Nicolas Frank and Dr Timo Risch for native MS and intact MS measurements. We acknowledge the Paul Scherrer Institute, Villigen, Switzerland for the provision of synchrotron radiation beamtime at beamline X06DA-PXIII and X06SA-PXI of the SLS and the European Synchrotron Radiation Facility (ESRF), Grenoble, France for provision of beamline ID23 to 1. A. K. H. H. R. H. and S. A. conceptualization; R. H. and S. A. writing–original draft; A. L. and L. M. synthesis. A. K. H. H. R. H. S. A. A. L. L. M. and J. K. writing–review and editing; A. K. H. H. supervision. The Helmholtz Association's Initiative and Networking Fund (to A. K. H. H.) and the Schlumberger Foundation faculty for the future (FFTF) (to R. H.) funded this work.
PY - 2023/9
Y1 - 2023/9
N2 - The ESKAPE bacteria are the six highly virulent and antibiotic-resistant pathogens that require the most urgent attention for the development of novel antibiotics. Detailed knowledge of target proteins specific to bacteria is essential to develop novel treatment options. The methylerythritol-phosphate (MEP) pathway, which is absent in humans, represents a potentially valuable target for the development of novel antibiotics. Within the MEP pathway, the enzyme 1-deoxy-D-xylulose-5-phosphate synthase (DXPS) catalyzes a crucial, rate-limiting first step and a branch point in the biosynthesis of the vitamins B1 and B6. We report the high-resolution crystal structures of DXPS from the important ESKAPE pathogens Pseudomonas aeruginosa and Klebsiella pneumoniae in both the co-factor-bound and the apo forms. We demonstrate that the absence of the cofactor thiamine diphosphate results in conformational changes that lead to disordered loops close to the active site that might be important for the design of potent DXPS inhibitors. Collectively, our results provide important structural details that aid in the assessment of DXPS as a potential target in the ongoing efforts to combat antibiotic resistance.
AB - The ESKAPE bacteria are the six highly virulent and antibiotic-resistant pathogens that require the most urgent attention for the development of novel antibiotics. Detailed knowledge of target proteins specific to bacteria is essential to develop novel treatment options. The methylerythritol-phosphate (MEP) pathway, which is absent in humans, represents a potentially valuable target for the development of novel antibiotics. Within the MEP pathway, the enzyme 1-deoxy-D-xylulose-5-phosphate synthase (DXPS) catalyzes a crucial, rate-limiting first step and a branch point in the biosynthesis of the vitamins B1 and B6. We report the high-resolution crystal structures of DXPS from the important ESKAPE pathogens Pseudomonas aeruginosa and Klebsiella pneumoniae in both the co-factor-bound and the apo forms. We demonstrate that the absence of the cofactor thiamine diphosphate results in conformational changes that lead to disordered loops close to the active site that might be important for the design of potent DXPS inhibitors. Collectively, our results provide important structural details that aid in the assessment of DXPS as a potential target in the ongoing efforts to combat antibiotic resistance.
KW - 1-deoxy-D-xylulose 5-phosphate synthase
KW - conformational changes
KW - DXPS
KW - Klebsiella pneumonia
KW - Pseudomonas aeruginosa
KW - X-ray crystallography
UR - http://www.scopus.com/inward/record.url?scp=85169906147&partnerID=8YFLogxK
U2 - 10.1016/j.jbc.2023.105152
DO - 10.1016/j.jbc.2023.105152
M3 - Article
C2 - 37567475
AN - SCOPUS:85169906147
VL - 299
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 9
M1 - 105152
ER -