Palau’amine and Related Oroidin Alkaloids Dibromophakellin and Dibromophakellstatin Inhibit the Human 20S Proteasome

Theresa A. Lansdell; Nicole M. Hewlett; Amanda P. Skoumbourdis; Matthew D. Fodor; Ian B. Seiple; Shun Su; Phil. S. Baran; Ken S. Feldman; Jetze J. Tepe

doi:10.1021/np300231f

Palau’amine and Related Oroidin Alkaloids Dibromophakellin and Dibromophakellstatin Inhibit the Human 20S Proteasome

Journal of Natural Products ◽

10.1021/np300231f ◽

2012 ◽

Vol 75 (5) ◽

pp. 980-985 ◽

Cited By ~ 31

Author(s):

Theresa A. Lansdell ◽

Nicole M. Hewlett ◽

Amanda P. Skoumbourdis ◽

Matthew D. Fodor ◽

Ian B. Seiple ◽

...

Keyword(s):

20S Proteasome ◽

Oroidin Alkaloids

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Faculty Opinions recommendation of Palau'amine and related oroidin alkaloids dibromophakellin and dibromophakellstatin inhibit the human 20S proteasome.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717748071.793153319 ◽

2012 ◽

Author(s):

Robert Fecik

Keyword(s):

20S Proteasome ◽

Oroidin Alkaloids

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Theoretical Studies of the Acid-Base Equilibria in a Model Active Site of the Human 20S Proteasome

10.26434/chemrxiv.13388753.v1 ◽

2020 ◽

Author(s):

Jon Uranga ◽

Lukas Hasecke ◽

Jonny Proppe ◽

Jan Fingerhut ◽

Ricardo A. Mata

Keyword(s):

Active Site ◽

Boronic Acid ◽

Computational Study ◽

Ubiquitin Proteasome System ◽

Bayesian Optimization ◽

Inhibition Mechanism ◽

20S Proteasome ◽

Acid Base ◽

Ubiquitin Proteasome ◽

Infection Cycles

The 20S Proteasome is a macromolecule responsible for the chemical step in the ubiquitin-proteasome system of degrading unnecessary and unused proteins of the cell. It plays a central role both in the rapid growth of cancer cells as well as in viral infection cycles. Herein, we present a computational study of the acid-base equilibria in an active site of the human proteasome, an aspect which is often neglected despite the crucial role protons play in the catalysis. As example substrates, we take the inhibition by epoxy and boronic acid containing warheads. We have combined cluster quantum mechanical calculations, replica exchange molecular dynamics and Bayesian optimization of non-bonded potential terms in the inhibitors. In relation to the latter, we propose an easily scalable approach to the reevaluation of non-bonded potentials making use of QM/MM dynamics information. Our results show that coupled acid-base equilibria need to be considered when modeling the inhibition mechanism. The coupling between a neighboring lysine and the reacting threonine is not affected by the presence of the inhibitor.

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