An Esterase-like Lyase Catalyzes Acetate Elimination in Spirotetronate/Spirotetramate Biosynthesis
| Autor: | James E. M. Stach, Nicholas R. Lees, Jonathan A. Davies, Matthew J. Byrne, Marc W. van der Kamp, Alice E. Parnell, Christine L. Willis, Paul R. Race, Pollyanna E. J. Moreland, Li-Chen Han |
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| Rok vydání: | 2018 |
| Předmět: |
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Molecular biocatalysis Stereochemistry enzymology Lyases BrisSynBio Acetates 010402 general chemistry Crystallography X-Ray 01 natural sciences Esterase Catalysis antibiotics Polyketide chemistry.chemical_compound BCS and TECS CDTs Biosynthesis Hydrolase Spiro Compounds Synthetic biology chemistry.chemical_classification Molecular Structure 010405 organic chemistry Bristol BioDesign Institute General Chemistry Lyase Enzyme structure 0104 chemical sciences enzyme structure Enzyme chemistry Biocatalysis polyketides |
| Zdroj: | Lees, N R, Han, L-C, Byrne, M, Davies, J, Parnell, A, Moreland, P, Stach, J E M, Van der Kamp, M, Willis, C & Race, P 2019, ' An Esterase-like Lyase Catalyzes Acetate Elimination in Spirotetronate/Spirotetramate Biosynthesis ', Angewandte Chemie-International Edition, vol. 58, no. 8, pp. 2305-2309 . https://doi.org/10.1002/anie.201812105 |
| ISSN: | 1521-3773 |
| Popis: | Spirotetronate and spirotetramate natural products include a multitude of compounds with potent antimicrobial and antitumor activities. Their biosynthesis incorporates many unusual biocatalytic steps, including regio- and stereo-specific modifications, cyclizations promoted by Diels–Alderases, and acetylation-elimination reactions. Here we focus on the acetate elimination catalyzed by AbyA5, implicated in the formation of the key Diels–Alder substrate to give the spirocyclic system of the antibiotic abyssomicin C. Using synthetic substrate analogues, it is shown that AbyA5 catalyzes stereospecific acetate elimination, establishing the (R)-tetronate acetate as a biosynthetic intermediate. The X-ray crystal structure of AbyA5, the first of an acetate-eliminating enzyme, reveals a deviant acetyl esterase fold. Molecular dynamics simulations and enzyme assays show the use of a His-Ser dyad to catalyze either elimination or hydrolysis, via disparate mechanisms, under substrate control. |
| Databáze: | OpenAIRE |
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