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. 2014 May 23;77(5):1224-30.
doi: 10.1021/np500155d. Epub 2014 May 1.

Griseorhodins D-F, Neuroactive Intermediates and End Products of post-PKS Tailoring Modification in Griseorhodin Biosynthesis

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Griseorhodins D-F, Neuroactive Intermediates and End Products of post-PKS Tailoring Modification in Griseorhodin Biosynthesis

Zhenjian Lin et al. J Nat Prod. .
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Abstract

The griseorhodins belong to a family of extensively modified aromatic polyketides that exhibit activities such as inhibition of HIV reverse transcriptase and human telomerase. The vast structural diversity of this group of polyketides is largely introduced by enzymatic oxidations, which can significantly influence the bioactivity profile. Four new compounds, griseorhodins D-F, were isolated from a griseorhodin producer, Streptomyces sp. CN48+, based upon their enhancement of calcium uptake in a mouse dorsal root ganglion primary cell culture assay. Two of these compounds, griseorhodins D1 and D2, were shown to be identical to the major, previously uncharacterized products of a grhM mutant in an earlier griseorhodin biosynthesis study. Their structures enabled the establishment of a more complete hypothesis for the biosynthesis of griseorhodins and related compounds. The other two compounds, griseorhodins E and F, represent new products of post-polyketide synthase tailoring in griseorhodin biosynthesis and showed significant binding activity in a human dopamine active transporter assay.

Figures

Figure 1
Figure 1
Structural diversity in the griseorhodin and its close biosynthetic relatives. (A) Postulated early steps in griseorhodin and fredericamycin biosynthesis. The structures of the intermediates in brackets are supported by 1H NMR spectra and MS data. Here, we show that for the griseorhodin case the spectra represent those of a dimer. (B) Benastatin biosynthesis. A methyltransferase knockout led to accumulation of an unstable dimer, while methylation affords the natural product. The dimer in the griseorhodin pathway is similar to that of benastatin.
Chart 1
Chart 1
Figure 2
Figure 2
Key NOESY, HMBC, and COSY correlations for compounds 1a, 1b, 3, and 4.
Figure 3
Figure 3
ESIMS fragmentation of compounds 1a/b and 2.
Scheme 1
Scheme 1. Proposed Pathway for the Biosynthesis of 3 and 4

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