Details
| Original language | English |
|---|---|
| Pages (from-to) | 540-547 |
| Number of pages | 8 |
| Journal | ChemBioChem |
| Volume | 12 |
| Issue number | 4 |
| Publication status | Published - 27 Jan 2011 |
Abstract
New ansamitocin derivatives were prepared by feeding aminobenzoic acid derivatives to cultures of Actinosynnema pretiosum HGF073, a mutant strain blocked in the biosynthesis of the required 3-amino-5-hydroxybenzoic acid (AHBA) starter unit. Use of several aminobenzoic acids as precursors led to a spectrum of products, reflecting the sequence of post-PKS tailoring steps involved in the generation of ansamitocins and adding novel aspects to the published suggestion model of post-PKS tailoring logic and flexibility. The studies provide insights into the substrate flexibility of the enzymes required for ansamitocin biosynthesis in A. pretiosum, whereas preliminary biological testing of the derivatives isolated and fully characterized by NMR spectroscopy allowed structure-activity relationship assignments to be made for a variety of intermediates occurring during the post-PKS tailoring sequence in ansamitocin biosynthesis. Mutasynthesis: Feeding aminobenzoic acid derivatives to a Actinosynnema pretiosum mutant that could not biosynthesize the essential starter unit 3-amino-5-hydroxybenzoic acid led to novel ansamitocin derivatives, which were isolated, characterized and subjected to in vitro biological testing. Our studies provided insights into the flexibility of ansamitocin biosynthesis in A. pretiosum and gave a deeper understanding of structure-activity relationships.
Keywords
- Ansamitocin, Antitumor agents, Mutasynthesis, Polyketide biosynthesis, Structure-activity relationships
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Biochemistry
- Biochemistry, Genetics and Molecular Biology(all)
- Molecular Medicine
- Biochemistry, Genetics and Molecular Biology(all)
- Molecular Biology
- Chemistry(all)
- Organic Chemistry
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In: ChemBioChem, Vol. 12, No. 4, 27.01.2011, p. 540-547.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Mutational Biosynthesis of Ansamitocin Antibiotics
T2 - A Diversity-Oriented Approach to Exploit Biosynthetic Flexibility
AU - Knobloch, Tobias
AU - Harmrolfs, Kirsten
AU - Taft, Florian
AU - Thomaszewski, Binia
AU - Sasse, Florenz
AU - Kirschning, Andreas
PY - 2011/1/27
Y1 - 2011/1/27
N2 - New ansamitocin derivatives were prepared by feeding aminobenzoic acid derivatives to cultures of Actinosynnema pretiosum HGF073, a mutant strain blocked in the biosynthesis of the required 3-amino-5-hydroxybenzoic acid (AHBA) starter unit. Use of several aminobenzoic acids as precursors led to a spectrum of products, reflecting the sequence of post-PKS tailoring steps involved in the generation of ansamitocins and adding novel aspects to the published suggestion model of post-PKS tailoring logic and flexibility. The studies provide insights into the substrate flexibility of the enzymes required for ansamitocin biosynthesis in A. pretiosum, whereas preliminary biological testing of the derivatives isolated and fully characterized by NMR spectroscopy allowed structure-activity relationship assignments to be made for a variety of intermediates occurring during the post-PKS tailoring sequence in ansamitocin biosynthesis. Mutasynthesis: Feeding aminobenzoic acid derivatives to a Actinosynnema pretiosum mutant that could not biosynthesize the essential starter unit 3-amino-5-hydroxybenzoic acid led to novel ansamitocin derivatives, which were isolated, characterized and subjected to in vitro biological testing. Our studies provided insights into the flexibility of ansamitocin biosynthesis in A. pretiosum and gave a deeper understanding of structure-activity relationships.
AB - New ansamitocin derivatives were prepared by feeding aminobenzoic acid derivatives to cultures of Actinosynnema pretiosum HGF073, a mutant strain blocked in the biosynthesis of the required 3-amino-5-hydroxybenzoic acid (AHBA) starter unit. Use of several aminobenzoic acids as precursors led to a spectrum of products, reflecting the sequence of post-PKS tailoring steps involved in the generation of ansamitocins and adding novel aspects to the published suggestion model of post-PKS tailoring logic and flexibility. The studies provide insights into the substrate flexibility of the enzymes required for ansamitocin biosynthesis in A. pretiosum, whereas preliminary biological testing of the derivatives isolated and fully characterized by NMR spectroscopy allowed structure-activity relationship assignments to be made for a variety of intermediates occurring during the post-PKS tailoring sequence in ansamitocin biosynthesis. Mutasynthesis: Feeding aminobenzoic acid derivatives to a Actinosynnema pretiosum mutant that could not biosynthesize the essential starter unit 3-amino-5-hydroxybenzoic acid led to novel ansamitocin derivatives, which were isolated, characterized and subjected to in vitro biological testing. Our studies provided insights into the flexibility of ansamitocin biosynthesis in A. pretiosum and gave a deeper understanding of structure-activity relationships.
KW - Ansamitocin
KW - Antitumor agents
KW - Mutasynthesis
KW - Polyketide biosynthesis
KW - Structure-activity relationships
UR - http://www.scopus.com/inward/record.url?scp=79952015068&partnerID=8YFLogxK
U2 - 10.1002/cbic.201000608
DO - 10.1002/cbic.201000608
M3 - Article
C2 - 22238146
AN - SCOPUS:79952015068
VL - 12
SP - 540
EP - 547
JO - ChemBioChem
JF - ChemBioChem
SN - 1439-4227
IS - 4
ER -