Deciphering the late biosynthetic steps of antimalarial compound FR-900098.
FR-900098 is a potent chemotherapeutic agent for the treatment of malaria. Here we report the heterologous production of this compound in Escherichia coli by reconstructing the entire biosynthetic pathway using a three-plasmid system. Based on this system, whole-cell feeding assays in combination with in vitro enzymatic activity assays reveal an unusual functional role of nucleotide conjugation and lead to the complete elucidation of the previously unassigned late biosynthetic steps. These studies also suggest a biosynthetic route to a second phosphonate antibiotic, FR-33289. A thorough understanding of the FR-900098 biosynthetic pathway now opens possibilities for metabolic engineering in E. coli to increase production of the antimalarial antibiotic and combinatorial biosynthesis to generate novel derivatives of FR-900098.
Johannes
Tyler W
TW
Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
DeSieno
Matthew A
MA
Griffin
Benjamin M
BM
Thomas
Paul M
PM
Kelleher
Neil L
NL
Metcalf
William W
WW
Zhao
Huimin
H
D000962:Antimalarials / Q000378:metabolism*; D053898:Biosynthetic Pathways; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism*; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000378:metabolism; D005798:Genes, Bacterial; D006801:Humans; D008288:Malaria / Q000188:drug therapy*
D000962:Antimalarials; D029968:Escherichia coli Proteins; D005578:Fosfomycin; C024639:3-(N-acetyl-N-hydroxy)aminopropylphosphonic acid