Enzymatic Macrolactonization in the Presence of DNA Leading to Triostin A Analogs
| Autor: | Hideaki Oikawa, Kenji Watanabe, Hiroki Oguri, Kento Koketsu |
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| Rok vydání: | 2008 |
| Předmět: |
Time Factors
Stereochemistry Cysteamine Clinical Biochemistry Echinomycin Biochemistry Catalysis chemistry.chemical_compound Hydrolysis Quinoxaline Protein structure Thioesterase Quinoxalines Drug Discovery Cloning Molecular Molecular Biology chemistry.chemical_classification Pharmacology Chemistry DNA General Medicine Intercalating Agents Protein Structure Tertiary CHEMBIO Enzyme Gene Expression Regulation Cyclization Product inhibition Molecular Medicine Thiolester Hydrolases Dimerization |
| Zdroj: | Chemistry & Biology. 15(8):818-828 |
| ISSN: | 1074-5521 |
| DOI: | 10.1016/j.chembiol.2008.05.022 |
| Popis: | SummaryExcised thioesterase domains are versatile catalysts for macrocyclization. However, thioesterase-catalyzed cyclization is often precluded due to the occurrence of hydrolysis and product inhibition. To circumvent these obstacles, we devised an unprecedented strategy: coincubation with DNA to capture the cyclic products possessing DNA-binding properties. In experiments involving echinomycin thioesterase-catalyzed macrolactonization leading to the cyclic triostin A analog TANDEM, we found that the addition of DNA drastically improved the yield of TANDEM (19% → 67%), with a complete reversal of the cyclization:hydrolysis ratio (1:2 → 18:1). Furthermore, the applicability of this protocol was demonstrated for a variety of substrates. The results described herein provide insight into the mechanism of echinomycin thioesterase-catalyzed conversions and also pave the way for chemoenzymatic synthesis of the quinoxaline antibiotics and their analogs. |
| Databáze: | OpenAIRE |
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