Elucidation of insulin degrading enzyme catalyzed site specific hydrolytic cleavage of amyloid β peptide: a comparative density functional theory study
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- Bora, R.P., Ozbil, M. & Prabhakar, R. J Biol Inorg Chem (2010) 15: 485. doi:10.1007/s00775-009-0617-2
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In this B3LYP study, the catalytic mechanisms for the hydrolysis of the three different peptide bonds (Lys28-Gly29, Phe19-Phe20, and His14-Gln15) of Alzheimer amyloid beta (Aβ) peptide by insulin-degrading enzyme (IDE) have been elucidated. For all these peptides, the nature of the substrate was found to influence the structure of the active enzyme–substrate complex. The catalytic mechanism is proposed to proceed through the following three steps: (1) activation of the metal-bound water molecule, (2) formation of the gem-diol intermediate, and (3) cleavage of the peptide bond. With the computed barrier of 14.3, 18.8, and 22.3 kcal/mol for the Lys28-Gly29, Phe19-Phe20, and His14-Gln15 substrates, respectively, the process of water activation was found to be the rate-determining step for all three substrates. The computed energetics show that IDE is the most efficient in hydrolyzing the Lys28-Gly29 (basic polar–neutral nonpolar) peptide bond followed by the Phe19-Phe20 (neutral nonpolar–neutral nonpolar) and His14-Gln15 (basic polar–neutral polar) bonds of the Aβ substrate.