Cloning, expression, and biochemical characterization of Streptomyces rubellomurinus genes required for biosynthesis of antimalarial compound FR900098.
The antibiotics fosmidomycin and FR900098 are members of a unique class of phosphonic acid natural products that inhibit the nonmevalonate pathway for isoprenoid biosynthesis. Both are potent antibacterial and antimalarial compounds, but despite their efficacy, little is known regarding their biosynthesis. Here we report the identification of the Streptomyces rubellomurinus genes required for the biosynthesis of FR900098. Expression of these genes in Streptomyces lividans results in production of FR900098, demonstrating their role in synthesis of the antibiotic. Analysis of the putative gene products suggests that FR900098 is synthesized by metabolic reactions analogous to portions of the tricarboxylic acid cycle. These data greatly expand our knowledge of phosphonate biosynthesis and enable efforts to overproduce this highly useful therapeutic agent.
Eliot
Andrew C
AC
Department of Microbiology, University of Illinois, 601 South Goodwin Avenue, Urbana, IL 61801, USA.
Griffin
Benjamin M
BM
Thomas
Paul M
PM
Johannes
Tyler W
TW
Kelleher
Neil L
NL
Zhao
Huimin
H
Metcalf
William W
WW
D000818:Animals; D000962:Antimalarials / Q000378:metabolism*; D003001:Cloning, Molecular; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000096:biosynthesis; D015964:Gene Expression Regulation, Bacterial; D051379:Mice; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000235:genetics; D017875:Phosphotransferases (Phosphomutases) / Q000235:genetics / Q000378:metabolism; D013302:Streptomyces / Q000235:genetics* / Q000378:metabolism*; D048170:Streptomyces lividans / Q000235:genetics / Q000378:metabolism
D000962:Antimalarials; D005578:Fosfomycin; C024639:3-(N-acetyl-N-hydroxy)aminopropylphosphonic acid; D017875:Phosphotransferases (Phosphomutases); C057167:phosphoenolpyruvate mutase