Deciphering the Late Biosynthetic Steps of Antimalarial Compound FR-900098

Tyler W. Johannes; Matthew A. DeSieno; Benjamin M. Griffin; Paul M. Thomas; Neil L. Kelleher; William W. Metcalf; Huimin Zhao

doi:10.1016/j.chembiol.2009.12.009

Deciphering the Late Biosynthetic Steps of Antimalarial Compound FR-900098

Tyler W. Johannes, Matthew A. DeSieno, Benjamin M. Griffin, Paul M. Thomas, Neil L. Kelleher, William W. Metcalf, Huimin Zhao^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

30 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	57-64
Number of pages	8
Journal	Chemistry and Biology
Volume	17
Issue number	1
DOIs	https://doi.org/10.1016/j.chembiol.2009.12.009
State	Published - Jan 29 2010

Keywords

CHEMBIO
MICROBIO

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.chembiol.2009.12.009

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title = "Deciphering the Late Biosynthetic Steps of Antimalarial Compound FR-900098",

abstract = "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.",

keywords = "CHEMBIO, MICROBIO",

author = "Johannes, {Tyler W.} and DeSieno, {Matthew A.} and Griffin, {Benjamin M.} and Thomas, {Paul M.} and Kelleher, {Neil L.} and Metcalf, {William W.} and Huimin Zhao",

note = "Funding Information: We thank Lucas Li at the Metabolomics Center at the University of Illinois for help in LC-MS analysis. This work was supported by grants from the National Institute of General Medical Sciences GM077596 (H.Z., W.W.M., and N.L.K.) and GM59334 (W.W.M.). M.A.D. acknowledges support from the U.S. National Institutes of Health under Ruth L. Kirschstein national research award 5 T32 GM070421 from the National Institute of General Medical Sciences.",

year = "2010",

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doi = "10.1016/j.chembiol.2009.12.009",

language = "English (US)",

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pages = "57--64",

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AU - Johannes, Tyler W.

AU - DeSieno, Matthew A.

AU - Griffin, Benjamin M.

AU - Thomas, Paul M.

AU - Kelleher, Neil L.

AU - Metcalf, William W.

AU - Zhao, Huimin

N1 - Funding Information: We thank Lucas Li at the Metabolomics Center at the University of Illinois for help in LC-MS analysis. This work was supported by grants from the National Institute of General Medical Sciences GM077596 (H.Z., W.W.M., and N.L.K.) and GM59334 (W.W.M.). M.A.D. acknowledges support from the U.S. National Institutes of Health under Ruth L. Kirschstein national research award 5 T32 GM070421 from the National Institute of General Medical Sciences.

PY - 2010/1/29

Y1 - 2010/1/29

N2 - 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.

AB - 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.

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KW - MICROBIO

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Deciphering the Late Biosynthetic Steps of Antimalarial Compound FR-900098

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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