Elucidation of insulin degrading enzyme catalyzed site specific hydrolytic cleavage of amyloid β peptide: A comparative density functional theory study

Ram Prasad Bora, Mehmet Ozbil, Rajeev Prabhakar

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

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 polarneutral polar) bonds of the Aβ substrate.

Original languageEnglish (US)
Pages (from-to)485-495
Number of pages11
JournalJournal of Biological Inorganic Chemistry
Volume15
Issue number4
DOIs
StatePublished - May 2010

Keywords

  • Amyloid beta peptide
  • Density functional theory
  • Insulin-degrading enzyme
  • Metallopeptidase
  • Peptide hydrolysis

ASJC Scopus subject areas

  • Biochemistry
  • Inorganic Chemistry

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