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Novel oxidative strategies en route to rebeccamycin & staurosporine
Author(s) -
HowardJones Annaleise R.,
Walsh Christopher T.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a274-b
Subject(s) - chemistry , staurosporine , aglycone , oxidative phosphorylation , stereochemistry , oxidative decarboxylation , enzyme , tryptophan , biochemistry , amino acid , protein kinase c , glycoside
The indolocarbazoles rebeccamycin and staurosporine, originally isolated from the actinomycetes, Lechevalieria aerocolonigenes and Streptomyces longisporoflavus , have received much attention due to their strong anticancer activities. These natural products are biosynthesized by parallel pathways, involving complex oxidative transformations and couplings to fashion the fused six‐ring aglycones from a starting pair of L‐tryptophan molecules. This overall 10–14 electron oxidation of two L‐tryptophans (or 7‐chloro‐L‐tryptophans) is catalyzed by only four enzymes: RebO, RebD, RebP and RebC (or their Sta homologues). RebP and StaP, in particular, are of interest due to their ability to catalyze both aryl‐aryl coupling and oxidative decarboxylation, effecting a net 4–8 electron oxidation to three distinct aglycone products. Their flavin partner enzymes, RebC and StaC, direct the oxidative flux of the reaction to yield only one of these aglycone forms. We have reconstituted the complete biosynthetic pathway to the rebeccamycin and staurosporine aglycones. This work reveals some of Nature's unique mechanistic strategies in constructing natural products by oxidative pathways.