Identification of the Herboxidiene Biosynthetic Gene Cluster in Streptomyces chromofuscus ATCC 49982

Abstract

The 53-kb biosynthetic gene cluster for the novel anticholesterol natural product herboxidiene was identified in Streptomyces chromofuscus ATCC 49982 by genome sequencing and gene inactivation. In addition to herboxidiene, a biosynthetic intermediate, 18-deoxy-herboxidiene, was also isolated from the fermentation broth of S. chromofuscus ATCC 49982 as a minor metabolite.

Spliceostatin hemiketal biosynthesis in Burkholderia spp. is catalyzed by an iron/α-ketoglutarate–dependent dioxygenase

“…Likewise, hemiketal 14, isolated from the FMO mutant, has an IC 50 of >100 nM. It is noteworthy that both the herboxidiene and pladienolide gene clusters contain stand-alone FMO genesherE and pldD, respectively-that have been tentatively assigned as encoding epoxidases (17,18).…”

“…Harnessing the biosynthetic potential of the producing organisms for compound production and analog generation is an attractive alternative to chemical synthesis. Pladienolide (17) and herboxidiene (18) are biosynthesized by different Streptomyces species via a canonical type I polyketide synthase (PKS) system, whereas biosynthesis of spliceostatins in two Burkholderia strains (FERM BP-3421 and MSMB 43) is encoded by highly homologous, hybrid trans-acyl transferase (AT) PKS-nonribosomal peptide synthetase (NRPS) gene clusters (19,20).…”

Herboxidiene biosynthesis, production, and structural modifications: prospect for hybrids with related polyketide

“…The biosynthetic pathway of herboxidiene from S. chromofuscus ATCC 49982 was reported by Shao et al 2012. They sequenced the genome of S. chromofuscus to yield 9.6 Mb sequence data (not published) and reported a gene cluster of type I polyketide (PKS) covering a 53 kb region containing seven open reading frames (ORFs) responsible for the biosynthesis of herboxidiene.…”

“…Thus, chemical synthesis of the hybrid of pladienolide and herboxidiene has been attempted to improve the efficacy of the inhibition of premRNA splicing. Looking closely into the gene clusters for biosynthesis of herboxidiene and pladienolides, three ORFs from herboxidiene and four ORFs from pladienolide are involved in polyketide biosynthesis (Shao et al 2012;Machida et al 2008a). Herboxidiene and pladienolide biosynthetic gene clusters share notable similarities with over 60 % identity in each module, with the exception of the last modules of both PKS and PldAIII enclosing modules 8 and 9 in pladienolide PKS (Fig.…”

“…Compounds such as lovastatin, tricholstatin A, and TMC-49A exhibit anti-cholesterol activity by reducing the plasma cholesterol level. Herboxidiene demonstrates better lowdensity lipoprotein (LDL) receptor upregulation activity than these compounds (Koguchi et al 1997;Shao et al 2012). The most promising activity of herboxidiene is as a pre-mRNA splicing inhibitor.…”