Discovery and Assembly Line Biosynthesis of the Lymphostin Pyrroloquinoline Alkaloid Family of mTOR Inhibitors in Salinispora Bacteria
| Autor: | Xidong Feng, Akimasa Miyanaga, Hongbo Liu, Margaret M. Leighton, Leonard A. McDonald, Jeffrey E. Janso, Bradley S. Moore, Laurel R. Barbieri, Guy T. Carter, Alessandra S. Eustáquio, Paul R. Jensen, Min He, Elisha N. Fielding, Frank E. Koehn |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
chemistry.chemical_classification
Natural product ATP synthase biology TOR Serine-Threonine Kinases General Chemistry Gene mutation Biochemistry Catalysis Article chemistry.chemical_compound Colloid and Surface Chemistry Alkaloids chemistry Biosynthesis Nonribosomal peptide Actinomycetales biology.protein Quinolines Pyrroles Enzyme Inhibitors Gene PI3K/AKT/mTOR pathway |
| Popis: | The pyrroloquinoline alkaloid family of natural products, which includes the immunosuppressant lymphostin, has long been postulated to arise from tryptophan. We now report the molecular basis of lymphostin biosynthesis in three marine Salinispora species that maintain conserved biosynthetic gene clusters harboring a hybrid nonribosomal peptide synthetase-polyketide synthase that is central to lymphostin assembly. Through a series of experiments involving gene mutations, stable isotope profiling, and natural product discovery, we report the assembly-line biosynthesis of lymphostin and nine new analogues that exhibit potent mTOR inhibitory activity. |
| Databáze: | OpenAIRE |
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