Dataset Information

Structure-guided design and biosynthesis of a novel FR-900098 analogue as a potent Plasmodium falciparum 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Dxr) inhibitor.

ABSTRACT: We report here the enzymatic biosynthesis of FR-900098 analogues and establish an in vivo platform for the biosynthesis of an N-propionyl derivative FR-900098P. FR-900098P is found to be a significantly more potent inhibitor of Plasmodium falciparum 1-deoxy-D-xylulose 5-phosphate reductoisomerase (PfDxr) than the parent compound, and thus a more promising antimalarial drug candidate.

SUBMITTER: Cobb RE

PROVIDER: S-EPMC4312176 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Structure-guided design and biosynthesis of a novel FR-900098 analogue as a potent Plasmodium falciparum 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Dxr) inhibitor.

Cobb Ryan E RE Bae Brian B Li Zhi Z DeSieno Matthew A MA Nair Satish K SK Zhao Huimin H

Chemical communications (Cambridge, England) 20150201 13

We report here the enzymatic biosynthesis of FR-900098 analogues and establish an in vivo platform for the biosynthesis of an N-propionyl derivative FR-900098P. FR-900098P is found to be a significantly more potent inhibitor of Plasmodium falciparum 1-deoxy-D-xylulose 5-phosphate reductoisomerase (PfDxr) than the parent compound, and thus a more promising antimalarial drug candidate. ...[more]

PMID: 25567100

Similar Datasets

Project description:The 1-deoxy-d-xylulose-5-phosphate reductoisomerase (DXR; EC1.1.1.267), an NADPH-dependent reductase, plays a pivotal role in the methylerythritol 4-phosphate pathway (MEP), in the conversion of 1-deoxy-d-xylulose-5-phosphate (DXP) into MEP. Photochemical profiles, as well as pharmaceutical activities of Centella asiatica (L.), one of the most valuable medicinal plants, divulge the presence of secondary metabolites called Centellosides. Despite well-studied pharmaceutical activities, not much is known about the genes responsible for the synthesis of these compounds. In the present study, the full-length DXR gene sequence (JQ965955) of Centella submitted in NCBI was characterized using various bioinformatics tools and tissue specific differential expression studies were also carried out. The full-length CDNA of CaDXR contains an open reading frame (ORF) of 1425 bp which encodes a peptide of 474 amino acids. The molecular weight of this protein was found to be 51.5 kDa with isoelectric point of 6.33. The protein contains three conserved domain, namely NADPH (GSTGSIGT and LAAGSNV), substrate binding (LPADSEHSAI and NKGLEVIEAHY) and Cys-Ser-(Ala/Met/Val/Thr) cleavage-site domains. Phylogenetic studies of CaDXR sequence show close homology with DXR sequence of Angelica sinensis and Daucus carota subsp sativus as they all belong to Apiaceae family. In silico analysis predicted that CaDXR protein contains 21 α-helix and 11 β-sheets and further DXR protein model was validated by Ramachandran plot analysis. The results of molecular dynamics (MD) simulations unveil dynamic stability of the proposed model and docking studies suggest that the NDP cofactor tightly binds in the active site of the protein with a strong network of hydrogen and hydrophobic interactions. The expression studies by semi-RT followed by qRT-PCR suggests that CaDXR is differentially expressed in different tissues (with maximal expression in the node and lowest in the roots). Thus, characterization and structure-function analysis of DXR gene in Centella facilitate us to understand not only the functions of DXR gene but also regulatory mechanisms involved in the MEP pathway in C. asiatica plant at the molecular level.Supplementary informationThe online version contains supplementary material available at 10.1007/s13205-021-02723-w.

Dataset Information

Structure-guided design and biosynthesis of a novel FR-900098 analogue as a potent Plasmodium falciparum 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Dxr) inhibitor.

Publications

Structure-guided design and biosynthesis of a novel FR-900098 analogue as a potent Plasmodium falciparum 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Dxr) inhibitor.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets