Elucidation of the alpha-keto-aldehyde binding mechanism: a lead structure motif for proteasome inhibition

Lead role: The role of peptidyl alpha-keto aldehydes as proteasome inhibitors is well established, yet their molecular binding mode requires additional investigation. 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-2H-1,4-oxazine ring. This agent serves as a new lead for the development of anticancer drug