Dorrigocins: Novel antifungal antibiotics that change the morphology of ras-transformed NIH/3T3 cells to that of normal cells. I. Taxonomy of the producing organism, fermentation and biological activity.

Karwowski, James P.; Jackson, Marianna; Sunga, Gabriela N.; Sheldon, Paul J.; Poddig, Jennifer B.; Kohl, William L.; Kadam, Sunil

doi:10.7164/antibiotics.47.862

Cited by 25 publications

(13 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It was striking that only isomigrastatin, LTM, and closely related analogs inhibited cell proliferation, while all migrastatin and dorrigocin analogs had no effect, in agreement with previous reports that neither compound had cytotoxic effects on mammalian cells8,9,12,13. Among all analogs tested, LTM stood out as the most potent inhibitor of cell proliferation (Supplementary Fig.…”

Section: Resultssupporting

confidence: 90%

“…Migrastatin was found to inhibit tumor cell migration and has served as an anti-metastatic drug lead6,7. The dorrigocins ( 5 , 6 ) appear to inhibit a carboxyl methyltransferase involved in the processing of Ras-related proteins8,9. We have recently established that isomigrastatin is the nascent natural product and migrastatin and dorrigocins are shunt metabolites of isomigrastatin10.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of eukaryotic translation elongation by cycloheximide and lactimidomycin

et al. 2010

View full text Add to dashboard Cite

Although the protein synthesis inhibitor cycloheximide (CHX) has been known for decades, its precise mechanism of action remains incompletely understood. The glutarimide portion of CHX is seen in a family of structurally related natural products including migrastatin, isomigrastatin and lactimidomycin (LTM). LTM, isomigrastatin and analogs were found to have a potent antiproliferative effect on tumor cell lines and selectively inhibit protein translation. A systematic comparative study of the effects of CHX and LTM on protein translation revealed both similarities and differences between the two inhibitors. Both LTM and CHX were found to block the translocation step in elongation. Footprinting experiments revealed protection of a single cytidine nucleotide (C3993) in the E-site of the 60S ribosomal subunit, defining a common binding pocket for both inhibitors in the ribosome. These results shed new light on the molecular mechanism of inhibition of translation elongation by both CHX and LTM.

show abstract

Section: Resultssupporting

confidence: 90%

mentioning

confidence: 99%

Inhibition of eukaryotic translation elongation by cycloheximide and lactimidomycin

et al. 2010

View full text Add to dashboard Cite

show abstract

“…1) are potent inhibitors of human tumor cell migration and thus represent novel leads for anticancer drug discovery (2)(3)(4)(5). Synthetic analogs of these natural products have also been investigated and found to retain potent activity despite significant structural truncation (6 -8).…”

mentioning

confidence: 99%

iso-Migrastatin, Migrastatin, and Dorrigocin Production in Streptomyces platensis NRRL 18993 Is Governed by a Single Biosynthetic Machinery Featuring an Acyltransferase-less Type I Polyketide Synthase

Lim

Zazopoulos³

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

iso-Migrastatin and related glutarimide-containing polyketides are potent inhibitors of tumor cell migration and their implied potential as antimetastatic agents for human cancers has garnered significant attention. Genome scanning of Streptomyces platensis NRRL 18993 unveiled two candidate gene clusters (088D and mgs); each encodes acyltransferase-less type I polyketide synthases commensurate with iso-migrastatin biosynthesis. Both clusters were inactivated by -RED-mediated PCR-targeting mutagenesis in S. platensis; iso-migrastatin production was completely abolished in the ⌬mgsF mutant SB11012 strain, whereas inactivation of 088D-orf7 yielded the SB11006 strain that exhibited no discernible change in iso-migrastatin biosynthesis. These data indicate that iso-migrastatin production is governed by the mgs cluster. Systematic gene inactivation allowed determination of the precise boundaries of the mgs cluster and the essentiality of the genes within the mgs cluster in iso-migrastatin production. The mgs cluster consists of 11 open reading frames that encode three acyltransferase-less type I polyketide synthases (MgsEFG), one discrete acyltransferase (MgsH), a type II thioesterase (MgsB), three post-PKS tailoring enzymes (MgsIJK), two glutarimide biosynthesis enzymes (MgsCD), and one regulatory protein (MgsA). A model for isomigrastatin biosynthesis is proposed based on functional assignments derived from bioinformatics and is further supported by the results of in vivo gene inactivation experiments.Cell migration is essential for invasion of the extracellular matrix and for cell dissemination during tumor metastasis (1). The glutarimide-containing polyketides iso-migrastatin (iso-MGS), 2 migrastatin (MGS), the dorrigocins (DGNs), and lactimidomycin (LTM) (Fig. 1) are potent inhibitors of human tumor cell migration and thus represent novel leads for anticancer drug discovery (2-5). Synthetic analogs of these natural products have also been investigated and found to retain potent activity despite significant structural truncation (6 -8). Retention of activity by such analogs supports the effectiveness of the privileged scaffolds highlighted by iso-MGS, MGS, LTM, and related natural products. Complementary to organic synthesis, combinatorial biosynthesis offers an alternative means of accessing natural product structural diversity. We have previously studied the biosynthetic pathway of these polyketides and shown that MGS and the DGNs are shunt metabolites of iso-MGS (9). As has been demonstrated in Streptomyces platensis NRRL 18993, one of the known iso-MGS producers, iso-MGS, MGS, and the DGNs are produced by a single biosynthetic machinery and iso-MGS undergoes H 2 O-mediated, non-enzymatic ring-expansion, and ring-opening rearrangements to afford MGS and the DGNs as shunt metabolites. We have also isolated iso-MGS congeners as minor fermentation products, produced a small library of glutarimide-containing polyketides featuring the iso-MGS, LTM, MGS, and DGN scaffolds, and found selected analogs with biological a...

show abstract

“…Dorrigocins A and B isolated from Streptomyces platensis subsp. rosaceus strain have moderate antifungal activity against some Aspergillus and Fusarium spp., but not against yeasts (Karwowski et al 1994). Recently, four compounds (SCH 378161, SCH 217048, SCH 378199, SCH 378167) isolated from a taxonomically unidentified fungus were found to selectively inhibit the human NK 2 receptor, tachykinin (Hegde et al 2001).…”

Section: Inhibitors Of Electron Transportmentioning

confidence: 98%

Antifungal antibiotics

Gupte

2002

Applied Microbiology and Biotechnology

View full text Add to dashboard Cite

show abstract

Dorrigocins: Novel antifungal antibiotics that change the morphology of ras-transformed NIH/3T3 cells to that of normal cells. I. Taxonomy of the producing organism, fermentation and biological activity.

Cited by 25 publications

References 0 publications

Inhibition of eukaryotic translation elongation by cycloheximide and lactimidomycin

Inhibition of eukaryotic translation elongation by cycloheximide and lactimidomycin

iso-Migrastatin, Migrastatin, and Dorrigocin Production in Streptomyces platensis NRRL 18993 Is Governed by a Single Biosynthetic Machinery Featuring an Acyltransferase-less Type I Polyketide Synthase

Antifungal antibiotics

Contact Info

Product

Resources

About