(−)-Homosalinosporamide A and Its Mode of Proteasome Inhibition: An X-ray Crystallographic Study
| Autor: | Michael Groll, Henry Nguyen, Sreekumar Vellalath, Daniel Romo |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: | |
| Zdroj: | Marine Drugs, Vol 16, Iss 7, p 240 (2018) |
| Druh dokumentu: | article |
| ISSN: | 1660-3397 16070240 |
| DOI: | 10.3390/md16070240 |
| Popis: | Upon acylation of the proteasome by the β-lactone inhibitor salinosporamide A (SalA), tetrahydrofuran formation occurs by intramolecular alkylation of the incipient alkoxide onto the choroethyl sidechain and irreversibly blocks the active site. Our previously described synthetic approach to SalA, utilizing a bioinspired, late-stage, aldol-β-lactonization strategy to construct the bicyclic β-lactone core, enabled synthesis of (–)-homosalinosporamide A (homoSalA). This homolog was targeted to determine whether an intramolecular tetrahydropyran is formed in a similar manner to SalA. Herein, we report the X-ray structure of the yeast 20S proteasome:homoSalA-complex which reveals that tetrahydropyran ring formation does not occur despite comparable potency at the chymotrypsin-like active site in a luminogenic enzyme assay. Thus, the natural product derivative homoSalA blocks the proteasome by a covalent reversible mode of action, opening the door for further fine-tuning of proteasome inhibition. |
| Databáze: | Directory of Open Access Journals |
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