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Open AccessCommunication

(−)-Homosalinosporamide A and Its Mode of Proteasome Inhibition: An X-ray Crystallographic Study

Center for Integrated Protein Science Munich at the Department Chemie, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany
Department of Chemistry, Texas A&M University, College Station, TX 77843, USA
Department of Chemistry & Biochemistry, Baylor University, Waco, TX 76798, USA
Authors to whom correspondence should be addressed.
Current address: Chemical and Industrial Services, BHGE, Sugar Land, TX 77478, USA.
Mar. Drugs 2018, 16(7), 240;
Received: 15 June 2018 / Revised: 5 July 2018 / Accepted: 11 July 2018 / Published: 19 July 2018
(This article belongs to the Special Issue Marine Drugs Interact with Functional Proteins)
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. View Full-Text
Keywords: beta-lactone; anticancer natural products; yeast 20S proteasome; aldol-lactonization beta-lactone; anticancer natural products; yeast 20S proteasome; aldol-lactonization
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MDPI and ACS Style

Groll, M.; Nguyen, H.; Vellalath, S.; Romo, D. (−)-Homosalinosporamide A and Its Mode of Proteasome Inhibition: An X-ray Crystallographic Study. Mar. Drugs 2018, 16, 240.

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