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Jacobs J Biotechnol Bioeng. 2015 Apr;2(1). pii: 009. Epub 2014 Dec 18.

Engineered Production of Tryprostatins in E. coli through Reconstitution of a Partial ftm Biosynthetic Gene Cluster from Aspergillus sp.

Author information

1
Department of Biological Sciences, University of Wisconsin-Milwaukee, PO Box 413, Milwaukee, Wisconsin 53201, USA.
2
Department of Biological Sciences, University of Wisconsin-Milwaukee, PO Box 413, Milwaukee, Wisconsin 53201, USA ; UNT System College of Pharmacy, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, Texas 76107, USA.

Abstract

Tryprostatin A and B are indole alkaloid-based fungal products that inhibit mammalian cell cycle at the G2/M phase. They are biosynthetic intermediates of fumitremorgins produced by a complex pathway involving a nonribosomal peptide synthetase (FtmA), a prenyltransferase (FtmB), a cytochrome P450 hydroxylase (FtmC), an O-methyltransferase (FtmD), and several additional enzymes. A partial fumitremorgin biosynthetic gene cluster (ftmABCD) from Aspergillus sp. was reconstituted in Escherichia coli BL21(DE3) cells, with or without the co-expression of an Sfp-type phosphopantetheinyltransferase gene (Cv_sfp) from Chromobacterium violaceum No. 968. Several recombinant E. coli strains produced tryprostatin B up to 106 mg/l or tryprostatin A up to 76 mg/l in the fermentation broth under aerobic condition, providing an effective way to prepare those pharmaceutically important natural products biologically.

KEYWORDS:

ftm biosynthetic gene cluster; heterologous production; tryprostatins

PMID:
26640821
PMCID:
PMC4670043

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