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Elucidation of the α‐Keto‐Aldehyde Binding Mechanism: A Lead Structure Motif for Proteasome Inhibition
Author(s) -
Gräwert Melissa Ann,
Gallastegui Nerea,
Stein Martin,
Schmidt Boris,
Kloetzel PeterMichael,
Huber Robert,
Groll Michael
Publication year - 2011
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201005488
Subject(s) - proteasome , chemistry , tripeptide , stereochemistry , proteasome inhibitor , protein subunit , biochemistry , amino acid , gene
Lead role : The role of peptidyl α‐keto aldehydes as proteasome inhibitors is well established, yet their molecular binding mode requires additional investigation (see picture). A cyclization mechanism that proceeds through hemiketal and Schiff base formation with the nucleophilic N‐terminal threonine of β5 is shown to result in the reversible formation of a 5,6‐dihydro‐2 H ‐1,4‐oxazine ring. This agent serves as a new lead for the development of anticancer drugs.