5ze6

CRYSTAL STRUCTURE OF OCTAPRENYL PYROPHOSPHATE SYNTHASE FROM ESCHERICHIA COLI WITH BPH-981CRYSTAL STRUCTURE OF OCTAPRENYL PYROPHOSPHATE SYNTHASE FROM ESCHERICHIA COLI WITH BPH-981

Structural highlights

5ze6 is a 4 chain structure with sequence from Escherichia coli K-12. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.5Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ISPB_ECOLI Supplies octaprenyl diphosphate, the precursor for the side chain of the isoprenoid quinones ubiquinone and menaquinone.^[1]

Publication Abstract from PubMed

We report that alkyl-substituted bisphosphonates have activity against Bacillus anthracis Sterne (0.40 mug/mL), Mycobacterium smegmatis (1.4 mug/mL), Bacillus subtilis (1.0 mug/mL), and Staphylococcus aureus (13 mug/mL). In many cases, there is no effect of serum binding, as well as low activity against a human embryonic kidney cell line. Targeting of isoprenoid biosynthesis is involved with 74 having IC(50) values of approximately 100 nM against heptaprenyl diphosphate synthase and 200 nM against farnesyl diphosphate synthase. B. subtilis growth inhibition was rescued by addition of farnesyl diphosphate, menaquinone-4 (MK-4), or undecaprenyl phosphate (UP), and the combination of MK-4 and UP resulted in a 25x increase in ED(50), indicating targeting of both quinone and cell wall biosynthesis. Clostridioides difficile was inhibited by 74, and since this organism does not synthesize quinones, cell wall biosynthesis is the likely target. We also solved three X-ray structures of inhibitors bound to octaprenyl diphosphate and/or undecaprenyl diphosphate synthases.

Discovery of Lipophilic Bisphosphonates That Target Bacterial Cell Wall and Quinone Biosynthesis.,Malwal SR, Chen L, Hicks H, Qu F, Liu W, Shillo A, Law WX, Zhang J, Chandnani N, Han X, Zheng Y, Chen CC, Guo RT, AbdelKhalek A, Seleem MN, Oldfield E J Med Chem. 2019 Mar 14;62(5):2564-2581. doi: 10.1021/acs.jmedchem.8b01878. Epub , 2019 Feb 21. PMID:30730737^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Asai K, Fujisaki S, Nishimura Y, Nishino T, Okada K, Nakagawa T, Kawamukai M, Matsuda H. The identification of Escherichia coli ispB (cel) gene encoding the octaprenyl diphosphate synthase. Biochem Biophys Res Commun. 1994 Jul 15;202(1):340-5. PMID:8037730 doi:http://dx.doi.org/S0006-291X(84)71933-4
↑ Malwal SR, Chen L, Hicks H, Qu F, Liu W, Shillo A, Law WX, Zhang J, Chandnani N, Han X, Zheng Y, Chen CC, Guo RT, AbdelKhalek A, Seleem MN, Oldfield E. Discovery of Lipophilic Bisphosphonates That Target Bacterial Cell Wall and Quinone Biosynthesis. J Med Chem. 2019 Mar 14;62(5):2564-2581. PMID:30730737 doi:10.1021/acs.jmedchem.8b01878

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OCA

[1] Asai K, Fujisaki S, Nishimura Y, Nishino T, Okada K, Nakagawa T, Kawamukai M, Matsuda H. The identification of Escherichia coli ispB (cel) gene encoding the octaprenyl diphosphate synthase. Biochem Biophys Res Commun. 1994 Jul 15;202(1):340-5. PMID:8037730 doi:http://dx.doi.org/S0006-291X(84)71933-4

[2] Malwal SR, Chen L, Hicks H, Qu F, Liu W, Shillo A, Law WX, Zhang J, Chandnani N, Han X, Zheng Y, Chen CC, Guo RT, AbdelKhalek A, Seleem MN, Oldfield E. Discovery of Lipophilic Bisphosphonates That Target Bacterial Cell Wall and Quinone Biosynthesis. J Med Chem. 2019 Mar 14;62(5):2564-2581. PMID:30730737 doi:10.1021/acs.jmedchem.8b01878

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