8jnw
PfDXR - Mn2+ - NADPH - MAMK89 quaternary complex
Structural highlights
FunctionDXR_PLAFX Catalyzes the NADP-dependent rearrangement and reduction of 1-deoxy-D-xylulose-5-phosphate (DXP) to 2-C-methyl-D-erythritol 4-phosphate (MEP).[1] Publication Abstract from PubMedReverse analogs of the phosphonohydroxamic acid antibiotic fosmidomycin are potent inhibitors of the nonmevalonate isoprenoid biosynthesis enzyme 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR, IspC) of Plasmodium falciparum. Some novel analogs with large phenylalkyl substituents at the hydroxamic acid nitrogen exhibit nanomolar PfDXR inhibition and potent in vitro growth inhibition of P. falciparum parasites coupled with good parasite selectivity. X-ray crystallographic studies demonstrated that the N-phenylpropyl substituent of the newly developed lead compound 13e is accommodated in a subpocket within the DXR catalytic domain but does not reach the NADPH binding pocket of the N-terminal domain. As shown for reverse carba and thia analogs, PfDXR selectively binds the S-enantiomer of the new lead compound. In addition, some representatives of the novel inhibitor subclass are nanomolar Escherichia coli DXR inhibitors, whereas the inhibition of Mycobacterium tuberculosis DXR is considerably weaker. Reverse N-Substituted Hydroxamic Acid Derivatives of Fosmidomycin Target a Previously Unknown Subpocket of 1-Deoxy-d-xylulose 5-Phosphate Reductoisomerase (DXR).,Abdullaziz MA, Takada S, Illarionov B, Pessanha de Carvalho L, Sakamoto Y, Hofmann S, Knak T, Kiffe-Delf AL, Mazzone F, Pfeffer K, Kalscheuer R, Bacher A, Held J, Fischer M, Tanaka N, Kurz T ACS Infect Dis. 2024 May 10;10(5):1739-1752. doi: 10.1021/acsinfecdis.4c00100. , Epub 2024 Apr 22. PMID:38647213[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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