Biosynthesis of the Antibiotic Echinosporin by a Novel Branch of the Shikimate Pathway

Abstract

Echinosporin (1), a known antibiotic with a unique tricyclic acetal-lactone structure, is produced by Streptomyces erythraeus (strain Tü 4015), together with the novel 7-deoxyechinosporin (2) as minor compound, which was fully characterized. The biosynthesis of 1 was established by feeding experiments with 13 C-labelled precursors. The results revealed that 1 was formed by the shikimate pathway, with chorismate as a biosynthetic intermediate. The proposed mechanism for

Diversity‐Oriented Production of Metabolites Derived from Chorismate and Their Use in Organic Synthesis

“…The application of 13 C‐ or 15 N‐labeled substrates results in the formation of specifically labeled metabolites (results not shown), which are valuable in elucidating as yet unexplored branches derived from the shikimate/chorismate pathway 38. The microbial production of uncommon structures derived from chorismate (such as echinosporin) 39 becomes feasible as demonstrated by the thiamine diphosphate (ThDP)‐dependent MenD‐catalyzed CC bond formation resulting in the production of 6 . Given the multipurpose activity and broad substrate range of ThDP‐dependent enzymes,40 it is justified to suppose that MenD variants or other ThDP‐dependent enzymes will accept chorismate, isochorismate, and derivatives as a substrate.…”

Amycolasporins and Dibenzoyls from Lichen-Associated Amycolatopsis hippodromi and Their Antibacterial and Anti-inflammatory Activities

“…Compound 6 was identified as echinosporin by the 1 H NMR, 13 C NMR, and MS spectroscopic data analysis and comparison with the literature . Echinosporin was initially reported from a streptomycete in 1982, and its antitumor activity, total synthesis, and biosynthesis pathway were consecutively reported. − In the current study, new compounds 1 – 4 possessed a cyclopenta­[ c ]­pyridine skeleton, while 5 possessed a cyclopenta­[ c ]­pyran skeleton. Although several cyclopenta­[ c ]­pyran compounds (e.g., cerbinal, cerberic acid, fulvoipolamiide, torricellate, viburtinal) were isolated as a subclass of the iridoids from a plant source, we propose the biosynthetic pathway of 5 is different from those reported known compounds because of differences in the positions of the substituents.…”

Antitumor Compounds from Marine Actinomycetes

“…Echinosporin and 7-deoxyechinosporin ( Figure 16 ), tricyclic acetal-lactones, are produced by S. albogriseolus A2002 isolated from a sea sediment sample collected in Jiaozhou Bay, China [ 180 ] and have been previously described as produced by S. echinosporus MK-213 [ 181 ] and by Sac. erythraea Tü 4015 (formerly S. erythraeus ) where it was shown by feeding experiments that echinosporin is synthesized by the shikimate pathway with chorismate as a biosynthetic intermediate [ 182 ]. Echinosporin was shown to inhibit the proliferation of human myelogenous leukemia K562, colon carcinoma HCT-15 and mouse mammary carcinoma tsFT210 cell lines in vitro [ 180 ], human breast adenocarcinoma MCF7, hepatocellular carcinoma Huh7 and HepG2 cell lines in vitro [ 182 ] and on rodent tumor models such as leukemia P388, P388/VCR, and fibrosarcoma Meth 1 in vivo [ 183 ].…”

“…erythraea Tü 4015 (formerly S. erythraeus ) where it was shown by feeding experiments that echinosporin is synthesized by the shikimate pathway with chorismate as a biosynthetic intermediate [ 182 ]. Echinosporin was shown to inhibit the proliferation of human myelogenous leukemia K562, colon carcinoma HCT-15 and mouse mammary carcinoma tsFT210 cell lines in vitro [ 180 ], human breast adenocarcinoma MCF7, hepatocellular carcinoma Huh7 and HepG2 cell lines in vitro [ 182 ] and on rodent tumor models such as leukemia P388, P388/VCR, and fibrosarcoma Meth 1 in vivo [ 183 ]. 7-deoxyechinosporin showed a weaker effect than echinosporin on K562, HCT-15 and tsFT210 cell lines [ 180 ].…”