ArticleBiochemistry2014
Comparative characterization of the lactimidomycin and iso-migrastatin biosynthetic machineries revealing unusual features for acyltransferase-less type I polyketide synthases and providing an opportunity to engineer new analogues.
Article in Biochemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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13 citing papers in PubMed, 21 citations in OpenAlex.
- Article
- Discrete Acyltransferases and Thioesterases in Iso-Migrastatin and Lactimidomycin Biosynthesis.Biochemistry · 2024Article
- The Genomic-Driven Discovery of Glutarimide-Containing Derivatives fromMolecules (Basel, Switzerland) · 2023Article
- Sequential Allylic Alcohol Formation by a Multifunctional Cytochrome P450 Monooxygenase with Rare Redox Partners.Angewandte Chemie (International ed. in English) · 2022Article
- Insect-Associated Bacteria Assemble the Antifungal Butenolide Gladiofungin by Non-Canonical Polyketide Chain Termination.Angewandte Chemie (International ed. in English) · 2020Article
- Genomics-Driven Discovery of a Novel Glutarimide Antibiotic from Burkholderia gladioli Reveals an Unusual Polyketide Synthase Chain Release Mechanism.Angewandte Chemie (International ed. in English) · 2020Article
- Comparative genome mining and heterologous expression of an orphan NRPS gene cluster direct the production of ashimides.Chemical science · 2019Article
- Cytochromes P450 for natural product biosynthesis in Streptomyces: sequence, structure, and function.Natural product reports · 2017Review
- A Long-Range Acting Dehydratase Domain as the Missing Link for C17-Dehydration in Iso-Migrastatin Biosynthesis.Angewandte Chemie (International ed. in English) · 2017Article
- Overproduction of lactimidomycin by cross-overexpression of genes encoding Streptomyces antibiotic regulatory proteins.Applied microbiology and biotechnology · 2016Article
- Structural and evolutionary relationships of "AT-less" type I polyketide synthase ketosynthases.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- C-S bond cleavage by a polyketide synthase domain.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Deciphering poxvirus gene expression by RNA sequencing and ribosome profiling.Journal of virology · 2015Article
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12 authors at 1 institution in 1 country.
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Abstract
Lactimidomycin (LTM, 1) and iso-migrastatin (iso-MGS, 2) belong to the glutarimide-containing polyketide family of natural products. We previously cloned and characterized the mgs biosynthetic gene cluster from Streptomyces platensis NRRL 18993. The iso-MGS biosynthetic machinery featured an acyltransferase (AT)-less type I polyketide synthase (PKS) and three tailoring enzymes (MgsIJK). We now report cloning and characterization of the ltm biosynthetic gene cluster from Streptomyces amphibiosporus ATCC 53964, which consists of nine genes that encode an AT-less type I PKS (LtmBCDEFGHL) and one tailoring enzyme (LtmK). Inactivation of ltmE or ltmH afforded the mutant strain SB15001 or SB15002, respectively, that abolished the production of 1, as well as the three cometabolites 8,9-dihydro-LTM (14), 8,9-dihydro-8S-hydroxy-LTM (15), and 8,9-dihydro-9R-hydroxy-LTM (13). Inactivation of ltmK yielded the mutant strain SB15003 that abolished the production of 1, 13, and 15 but led to the accumulation of 14. Complementation of the ΔltmK mutation in SB15003 by expressing ltmK in trans restored the production of 1, as well as that of 13 and 15. These results support the model for 1 biosynthesis, featuring an AT-less type I PKS that synthesizes 14 as the nascent polyketide intermediate and a cytochrome P450 desaturase that converts 14 to 1, with 13 and 15 as minor cometabolites. Comparative analysis of the LTM and iso-MGS AT-less type I PKSs revealed several unusual features that deviate from those of the collinear type I PKS model. Exploitation of the tailoring enzymes for 1 and 2 biosynthesis afforded two analogues, 8,9-dihydro-8R-hydroxy-LTM (16) and 8,9-dihydro-8R-methoxy-LTM (17), that provided new insights into the structure-activity relationship of 1 and 2. While 12-membered macrolides, featuring a combination of a hydroxyl group at C-17 and a double bond at C-8 and C-9 as found in 1, exhibit the most potent activity, analogues with a single hydroxyl or methoxy group at C-8 or C-9 retain most of the activity whereas analogues with double substitutions at C-8 and C-9 lose significant activity.
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