Chemoenzymatic synthesis of 7-chloro-4-Dimethylallyl-L-Tryptophan, a fragment of krisynomycin

The krisynomycins are macrocyclic depsipeptide natural products from Streptomyces that act as imipenem potentiators against methicillin-resistant Staphylococcus aureus (MRSA). The flagship molecule of this family, krisynomycin, features a unique 7-chloro-4-dimethylallyl-l-tryptophan (7-Cl-4-Pren-Trp...

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Bibliographic Details
Published in:Tetrahedron 2024-08, Vol.162, p.134127, Article 134127
Main Authors: Mowzoon-Mogharrabi, Riaz, Stout, Carter N., Renata, Hans
Format: Article
Language:English
Subjects:
bacterial enzymes
bioactive properties
biosynthesis
computer simulation
dimethylallyltranstransferase
family
imipenem
methicillin-resistant Staphylococcus aureus
multigene family
Streptomyces
tryptophan
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Summary:The krisynomycins are macrocyclic depsipeptide natural products from Streptomyces that act as imipenem potentiators against methicillin-resistant Staphylococcus aureus (MRSA). The flagship molecule of this family, krisynomycin, features a unique 7-chloro-4-dimethylallyl-l-tryptophan (7-Cl-4-Pren-Trp) fragment that is both essential for biological activity and unprecedented among bacterial natural products. In silico analysis of the putative biosynthetic gene cluster revealed an aromatic prenyltransferase and a tryptophan halogenase, though the precise reaction order en route to 7-Cl-4-Pren-Trp remained ambiguous. We report herein a brief chemoenzymatic synthesis of 7-Cl-4-Pren-Trp through a prenylation-chlorination sequence, which contains the first ever C4 prenylation of tryptophan by a bacterial enzyme. Furthermore, our efforts provide tentative evidence that the same reaction sequence is operative in the biosynthesis of krisynomycin. [Display omitted]
ISSN:0040-4020
1464-5416
DOI:10.1016/j.tet.2024.134127