Production of the Bengamide Class of Marine Natural Products in Myxobacteria: Biosynthesis and Structure-Activity Relationships.

2.50
Hdl Handle:
http://hdl.handle.net/10033/614889
Title:
Production of the Bengamide Class of Marine Natural Products in Myxobacteria: Biosynthesis and Structure-Activity Relationships.
Authors:
Wenzel, Silke C; Hoffmann, Holger; Zhang, Jidong; Debussche, Laurent; Haag-Richter, Sabine; Kurz, Michael; Nardi, Frederico; Lukat, Peer; Kochems, Irene; Tietgen, Heiko; Schummer, Dietmar; Nicolas, Jean-Paul; Calvet, Loreley; Czepczor, Valerie; Vrignaud, Patricia; Mühlenweg, Agnes; Pelzer, Stefan; Müller, Rolf ( 0000-0002-1042-5665 ) ; Brönstrup, Mark ( 0000-0002-8971-7045 )
Abstract:
The bengamides, sponge-derived natural products that have been characterized as inhibitors of methionine aminopeptidases (MetAPs), have been intensively investigated as anticancer compounds. We embarked on a multidisciplinary project to supply bengamides by fermentation of the terrestrial myxobacterium M. virescens, decipher their biosynthesis, and optimize their properties as drug leads. The characterization of the biosynthetic pathway revealed that bacterial resistance to bengamides is conferred by Leu 154 of the myxobacterial MetAP protein, and enabled transfer of the entire gene cluster into the more suitable production host M. xanthus DK1622. A combination of semisynthesis of microbially derived bengamides and total synthesis resulted in an optimized derivative that combined high cellular potency in the nanomolar range with high metabolic stability, which translated to an improved half-life in mice and antitumor efficacy in a melanoma mouse model.
Affiliation:
Helmholtz-Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken.
Citation:
Production of the Bengamide Class of Marine Natural Products in Myxobacteria: Biosynthesis and Structure-Activity Relationships. 2015, 54 (51):15560-4 Angew. Chem. Int. Ed. Engl.
Journal:
Angewandte Chemie (International ed. in English)
Issue Date:
14-Dec-2015
URI:
http://hdl.handle.net/10033/614889
DOI:
10.1002/anie.201508277
PubMed ID:
26514647
Type:
Article
Language:
en
ISSN:
1521-3773
Appears in Collections:
publications of the department of microbial natural substances ([HIPS]MINS)

Full metadata record

DC FieldValue Language
dc.contributor.authorWenzel, Silke Cen
dc.contributor.authorHoffmann, Holgeren
dc.contributor.authorZhang, Jidongen
dc.contributor.authorDebussche, Laurenten
dc.contributor.authorHaag-Richter, Sabineen
dc.contributor.authorKurz, Michaelen
dc.contributor.authorNardi, Fredericoen
dc.contributor.authorLukat, Peeren
dc.contributor.authorKochems, Ireneen
dc.contributor.authorTietgen, Heikoen
dc.contributor.authorSchummer, Dietmaren
dc.contributor.authorNicolas, Jean-Paulen
dc.contributor.authorCalvet, Loreleyen
dc.contributor.authorCzepczor, Valerieen
dc.contributor.authorVrignaud, Patriciaen
dc.contributor.authorMühlenweg, Agnesen
dc.contributor.authorPelzer, Stefanen
dc.contributor.authorMüller, Rolfen
dc.contributor.authorBrönstrup, Marken
dc.date.accessioned2016-06-28T11:54:30Z-
dc.date.available2016-06-28T11:54:30Z-
dc.date.issued2015-12-14-
dc.identifier.citationProduction of the Bengamide Class of Marine Natural Products in Myxobacteria: Biosynthesis and Structure-Activity Relationships. 2015, 54 (51):15560-4 Angew. Chem. Int. Ed. Engl.en
dc.identifier.issn1521-3773-
dc.identifier.pmid26514647-
dc.identifier.doi10.1002/anie.201508277-
dc.identifier.urihttp://hdl.handle.net/10033/614889-
dc.description.abstractThe bengamides, sponge-derived natural products that have been characterized as inhibitors of methionine aminopeptidases (MetAPs), have been intensively investigated as anticancer compounds. We embarked on a multidisciplinary project to supply bengamides by fermentation of the terrestrial myxobacterium M. virescens, decipher their biosynthesis, and optimize their properties as drug leads. The characterization of the biosynthetic pathway revealed that bacterial resistance to bengamides is conferred by Leu 154 of the myxobacterial MetAP protein, and enabled transfer of the entire gene cluster into the more suitable production host M. xanthus DK1622. A combination of semisynthesis of microbially derived bengamides and total synthesis resulted in an optimized derivative that combined high cellular potency in the nanomolar range with high metabolic stability, which translated to an improved half-life in mice and antitumor efficacy in a melanoma mouse model.en
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleProduction of the Bengamide Class of Marine Natural Products in Myxobacteria: Biosynthesis and Structure-Activity Relationships.en
dc.typeArticleen
dc.contributor.departmentHelmholtz-Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken.en
dc.identifier.journalAngewandte Chemie (International ed. in English)en

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