Elucidation of insulin degrading enzyme catalyzed site specific hydrolytic cleavage of amyloid beta peptide: a comparative density functional theory study.
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 (Abeta) 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 Abeta substrate.
Bora
Ram Prasad
RP
Department of Chemistry, University of Miami, 1301 Memorial Drive, Coral Gables, FL 33146, USA.
Ozbil
Mehmet
M
Prabhakar
Rajeev
R
D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D055162:Biocatalysis; D020134:Catalytic Domain; D006801:Humans; D006868:Hydrolysis; D007339:Insulysin / Q000737:chemistry* / Q000378:metabolism*; D007700:Kinetics; D008670:Metals / Q000378:metabolism; D008958:Models, Molecular; D011789:Quantum Theory; D013379:Substrate Specificity; D013816:Thermodynamics; D014867:Water / Q000378:metabolism
D016229:Amyloid beta-Peptides; D008670:Metals; D014867:Water; D007339:Insulysin