15 research outputs found

    Molecular basis of fosmidomycin's action on the human malaria parasite Plasmodium falciparum

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    The human malaria parasite Plasmodium falciparum is responsible for the deaths of more than a million people each year. Fosmidomycin has been proven to be efficient in the treatment of P. falciparum malaria by inhibiting 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR), an enzyme of the non-mevalonate pathway, which is absent in humans. However, the structural details of DXR inhibition by fosmidomycin in P. falciparum are unknown. Here, we report the crystal structures of fosmidomycin-bound complete quaternary complexes of PfDXR. Our study revealed that (i) an intrinsic flexibility of the PfDXR molecule accounts for an induced-fit movement to accommodate the bound inhibitor in the active site and (ii) a cis arrangement of the oxygen atoms of the hydroxamate group of the bound inhibitor is essential for tight binding of the inhibitor to the active site metal. We expect the present structures to be useful guides for the design of more effective antimalarial compounds

    Carbon-rich ruthenium complexes containing Bis(allenylidene) and mixed alkynyl-allenylidene bridges

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    International audienceComplexes cis-[RuCl(dppe)(2)][X] (2a X=PF6, 2b X = CF3SO3) react with a variety of bis(propargylic) alcohols to selectively lead to mono-trans-[Cl(dppe)(2)Ru=C=C=C(R)-T-C(R) (OH)(CdropC-H)][X] (4) [R = H, Ph; T = m,p-(C6H4), 2,5-(thiophene), 5,5'-(2,2'-bithiophene), 5,5”-(2,2':5'2”-terthiophene), -CdropC-] or bis(allenylidene) trans-[Cl(dppe)(2)Ru=C=C=C(R)-T-(R)C= C=C=RuCl(dppe)(2)][X](2) (5) complexes. New dimetallic and trimetallic complexes containing mixed alkynyl-allenylidene bridges, trans-[Cl(dppe)(2)Ru-CdropC-p-(C6H4)-(Ph)C=C=C=RuCl(dppe)(2)][CF3SO3 ](12) and trans-[\Cl(dppe)(2)Ru-CdropC-p(C6H4)\(2)C=C=C=RuCl(dppe)(2)][CF3SO 3] (17), were prepared by modification of the carbon-rich ligand of acetylide precursors. UV/Vis and cyclic voltammetry studies show the influence of the unsaturated conjugated bridge on the electronic interaction between the redox centers, and the fine tuning of this property. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

    Insights into the function and horizontal transfer of isoproturon degradation genes (pdmAB) in a biobed system

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    Biobeds, designed to minimize pesticide point source contamination, rely mainly on biodegradation processes. We studied the interactions of a biobed microbial community with the herbicide isoproturon (IPU) to explore the role of the pdmA gene, encoding the large subunit of an N-demethylase responsible for the initial demethylation of IPU, via quantitative PCR (qPCR) and reverse transcription-PCR (RT-qPCR) and the effect of IPU on the diversity of the total bacterial community and its active fraction through amplicon sequencing of DNA and RNA, respectively. We further investigated the localization and dispersal mechanisms of pdmAB in the biobed packing material by measuring the abundance of the plasmid pSH (harboring pdmAB) of the IPU-degrading Sphingomonas sp. strain SH (previously isolated from the soil used in the biobed) compared with the abundance of the pdmA gene and metagenomic fosmid library screening. pdmA abundance and expression increased concomitantly with IPU mineralization, verifying its major role in IPU transformation in the biobed system. DNA-and RNA-based 16S rRNA gene sequencing analysis showed no effects on bacterial diversity. The pdmAB-harboring plasmid pSH showed a consistently lower abundance than pdmA, suggesting the localization of pdmAB in replicons other than pSH. Metagenomic analysis identified four pdmABcarrying fosmids. In three of these fosmids, the pdmAB genes were organized in a wellconserved operon carried by sphingomonad plasmids with low synteny with pSH, while the fourth fosmid contained an incomplete pdmAB cassette localized in a genomic fragment of a Rhodanobacter strain. Further analysis suggested a potentially crucial role of IS6 and IS256 in the transposition and activation of the pdmAB operon. © 2020 American Society for Microbiology
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