The regioselective functionalization of non-activated carbon atoms such as aliphatic halogenation is a major synthetic challenge. A novel multifunctional enzyme catalyzing the geminal dichlorination of a methyl group was discovered in Aspergillus oryzae (Koji mold), an important fungus that is widely used for Asian food fermentation. A biosynthetic pathway encoded on two different chromosomes yields mono- and dichlorinated polyketides (diaporthin derivatives), including the cytotoxic dichlorodiaporthin as the main product. Bioinformatic analyses and functional genetics revealed an unprecedented hybrid enzyme (AoiQ) with two functional domains, one for halogenation and one for O-methylation. AoiQ was successfully reconstituted in vivo and in vitro, unequivocally showing that this FADH2 -dependent enzyme is uniquely capable of the stepwise gem-dichlorination of a non-activated carbon atom on a freestanding substrate. Genome mining indicated that related hybrid enzymes are encoded in cryptic gene clusters in numerous ecologically relevant fungi.
Cervimycins A-D are novel polyketide glycosides with significant activity against multi-drug-resistant staphylococci and vancomycin-resistant enterococci. They are produced by a strain of Streptomyces tendae, isolated from an ancient cave. The structures of the cervimycins were determined by performing extensive NMR and chemical degradation studies. All cervimycins have a common tetracyclic polyketide core that is substituted with unusual di- and tetrasaccharide chains, composed exclusively of trideoxysugars; however, they differ in the acetyl and carbamoyl ring substituent and in the highly unusual terminal methylmalonyl and dimethylmalonyl residues.
In our ongoing search for new bioactive metabolites from microbial resources, Aspergillus terreus (HKI0499) was examined by chemical metabolite profiling. Together with the known butyrolactone I ( 3), the unusual sulfate derivatives butyrolactone I 3-sulfate ( 1) and butyrolactone I 4''-sulfate ( 2) were discovered. The chemical structures were determined by NMR and MS data analyses. All compounds were tested on CDK1/cyclin B, CDK5/p25, DYRK1A, CK1, and GSK-3alpha/beta kinases; compounds 2 and 3 were also evaluated for their cytotoxic and antiproliferative activities. Butyrolactone I 3-sulfate ( 1) exhibited specific inhibitory activity against CDK1/cyclin B and CDK5/p25, yet 15-30-fold less than butyrolactone I ( 3). Likewise, butyrolactone I 3-sulfate ( 1) exhibited moderate cytotoxicity solely against HeLa cells (CC 50 = 80.7 microM).
Gilvocarcin-type polyketide glycosides represent some of the most powerful antitumor therapeutics. Bioactivity-guided fractionation of a culture extract of Streptomyces polyformus sp. nov. (YIM 33176) yielded the known gilvocarcin V (2) and a novel related compound, polycarcin V (1). Structure elucidation by NMR and chemical derivatization revealed that the congener (1) features a C-glycosidically linked alpha-L-rhamnopyranosyl moiety in lieu of the D-fucofuranose. The concomitant production of two distinct furanosyl and pyranosyl C-glycosides that share the same aglycone is unprecedented in bacteria. A conversion of both isoforms via a quinone methide intermediate can be ruled out, thus pointing to two individual C-glycosylation pathways. Cytotoxicity profiling of polycarcin V in a panel of 37 tumor cell lines indicated significant antitumoral activity with a pronounced selectivity for non-small-cell lung cancer, breast cancer and melanoma cells. As the antiproliferative fingerprint is identical to that of actinomycin D, the known DNA interaction of gilvocarcins was established as a general principle of antitumorigenic activity.
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