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

Bora, Ram Prasad; Özbi̇l, Mehmet; Prabhakar, Rajeev

doi:10.1007/s00775-009-0617-2

Cited by 13 publications

(44 citation statements)

References 53 publications

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“…However, these dipeptides were different from the cleavage sites of HSA. It is substantially lower than the computed barriers for other metal complexes such as metal (Co and Cu)‐cyclen and [Pd (H 2 O) 4 ] 2+ but higher than the barrier for a natural metalloprotease, Insulin degrading enzyme (IDE) . However, from the tetrahedral intermediate ( IN LW ), the barrier for the cleavage of the peptide bond in this step is only 2.3 kcal/mol lower than the barrier in the NW model.…”

Section: Hydrolysis Of Site 4 Through the Ia Mechanismmentioning

confidence: 79%

Hydrolysis of chemically distinct sites of human serum albumin by polyoxometalate: A hybrid QM/MM (ONIOM) study

Jayasinghe‐Arachchige

Sharma

et al. 2018

J Comput Chem

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In this study, mechanisms of hydrolysis of all four chemically diverse cleavage sites of human serum albumin (HSA) by [Zr(OH)(PW11O39)]4− (ZrK) have been investigated using the hybrid two‐layer QM/MM (ONIOM) method. These reactions have been proposed to occur through the following two mechanisms: internal attack (IA) and water assisted (WA). In both mechanisms, the cleavage of the peptide bond in the Cys392‐Glu393 site of HSA is predicted to occur in the rate‐limiting step of the mechanism. With the barrier of 27.5 kcal/mol for the hydrolysis of this site, the IA mechanism is found to be energetically more favorable than the WA mechanism (barrier = 31.6 kcal/mol). The energetics for the IA mechanism are in line with the experimentally measured values for the cleavage of a wide range of dipeptides. These calculations also suggest an energetic preference (Cys392‐Glu393, Ala257‐Asp258, Lys313‐Asp314, and Arg114‐Leu115) for the hydrolysis of all four sites of HSA. © 2018 Wiley Periodicals, Inc.

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Section: Hydrolysis Of Site 4 Through the Ia Mechanismmentioning

confidence: 79%

Hydrolysis of chemically distinct sites of human serum albumin by polyoxometalate: A hybrid QM/MM (ONIOM) study

Jayasinghe‐Arachchige

Sharma

et al. 2018

J Comput Chem

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“…A growing interest has been raised recently on the mechanistic aspects of the IDEs active site, [61,62] as well on its related conformational rearrangements in the presence of Ab peptide. [63] On the other hand, the elucidation of the effects of metal dyshomeostasis on the structure of IDE is still in its infancy.…”

Section: Resultsmentioning

confidence: 99%

Copper(I) and Copper(II) Inhibit Aβ Peptides Proteolysis by Insulin‐Degrading Enzyme Differently: Implications for Metallostasis Alteration in Alzheimer’s Disease

Grasso

Pietropaolo

Spoto

et al. 2011

Chemistry A European J

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Accumulation of neurotoxic amyloid-β peptide (Aβ) and alteration of metal homeostasis (metallostasis) in the brain are two main factors that have been very often associated with neurodegenerative diseases, such as Alzheimer's disease (AD). Aβ is constantly produced from the amyloidprecursor-protein APP precursor and immediately catabolized under normal conditions, whereas dysmetabolism of Aβ and/or metal ions seems to lead to a pathological deposition. Although insulin-degrading enzyme (IDE) is the main metalloprotease involved in Aβ degradation in the brain being up-regulated in some areas of AD brains, the role of IDE for the onset and development of AD is far from being understood. Moreover, the biomolecular mechanisms involved in the recognition and interaction between IDE and its substrates are still obscure. In spite of the important role of metals (such as copper, aluminum, and zinc), which has brought us to propose a "metal hypothesis of AD", a targeted study of the effect of metallostasis on IDE activity has never been carried out. In this work, we have investigated the role that various metal ions (i.e., Cu(2+), Cu(+), Zn(2+), Ag(+), and Al(3+)) play in modulating the interaction between IDE and two Aβ peptide fragments, namely Aβ(1-16) and Aβ(16-28). It was therefore possible to identify the direct effect that such metal ions have on IDE structure and enzymatic activity without interferences caused by metal-induced substrate modifications. Mass spectrometry and kinetic studies revealed that, among all the metal ions tested, only Cu(2+), Cu(+), and Ag(+) have an inhibitory effect on IDE activity. Moreover, the inhibition of copper(II) is reversed by adding zinc(II), whereas the monovalent cations affect the enzyme activity irreversibly. The molecular basis of their action on the enzyme is also discussed on the basis of computational investigations.

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“…However, the exact reaction mechanism and the energetic preference of IDE for the cleavage of these peptide bonds were not known. To address these issues, we investigated hydrolytic cleavage of three chemically distinct peptide bonds: His‐Gln (basic polar‐neutral polar), Phe‐Phe (neutral nonpolar‐neutral nonpolar), and Lys‐Gly (basic polar‐neutral nonpolar) through DFT calculations …”

Section: Peptide and Phosphoester Hydrolysis By Natural Enzymesmentioning

confidence: 99%

“…Based on the available experimental and theoretical information, the most plausible mechanism proposed by these calculations for the hydrolysis of the Lys‐Gly dipeptide is shown in Figure . It included the following three steps: (1) creation of the Zn‐bound nucleophile, (2) formation of the gem‐diol intermediate, and (3) cleavage of the peptide bond of the substrate.…”

Section: Peptide and Phosphoester Hydrolysis By Natural Enzymesmentioning

confidence: 99%

“…There are numerous examples of mono‐ and binuclear metal center containing metallohydrolases; however, the focus of this review is activities of two promiscuous enzymes; i.e., insulin degrading enzyme (IDE) and glycerophosphodiesterase (GpdQ) . IDE is a metallopeptidase that contains a Zn─N 2 O [Zn(His, His, Glu)] catalytic center, where N is the nitrogen atom from His and O is the oxygen atom from Glu (Figure ).…”

Section: Introductionmentioning

confidence: 99%

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Mechanisms of peptide and phosphoester hydrolysis catalyzed by two promiscuous metalloenzymes (insulin degrading enzyme and glycerophosphodiesterase) and their synthetic analogues

Jayasinghe‐Arachchige

Sharma

et al. 2020

WIREs Comput Mol Sci

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The hydrolysis of extremely stable peptide and phosphoester bonds by metalloenzymes is of great interest in biotechnology and industry. However, due to various shortcomings only a handful of these enzymes have been used for industrial applications. Therefore, in the last two decades intensive scientific efforts have been made in rational development of small molecules to imitate the activities of natural enzymes. Despite these efforts, their currently available synthetic analogues are inferior in terms of selectivity, catalytic rate, and turnover and the designing of efficient artificial metalloenzymes remains a distant goal. This is a challenging area of research that necessitates a rigorous integration between experiments and theory. The realization of this goal requires knowledge of the catalytic activities of both enzymes and their existing analogues and an effective fusion of that knowledge. This article reviews several studies in which a plethora of computational techniques have been successfully employed to investigate the functioning of two chemically promiscuous mono‐ and binuclear metalloenzymes (insulin degrading enzyme and glycerophosphodiesterase) and two synthetic analogues. These studies will help us derive fundamental principles of peptide and phosphoester hydrolysis and pave the way to design efficient small molecule catalysts for these reactions. This article is categorized under: Structure and Mechanism > Reaction Mechanisms and Catalysis

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

Cited by 13 publications

References 53 publications

Hydrolysis of chemically distinct sites of human serum albumin by polyoxometalate: A hybrid QM/MM (ONIOM) study

Hydrolysis of chemically distinct sites of human serum albumin by polyoxometalate: A hybrid QM/MM (ONIOM) study

Copper(I) and Copper(II) Inhibit Aβ Peptides Proteolysis by Insulin‐Degrading Enzyme Differently: Implications for Metallostasis Alteration in Alzheimer’s Disease

Mechanisms of peptide and phosphoester hydrolysis catalyzed by two promiscuous metalloenzymes (insulin degrading enzyme and glycerophosphodiesterase) and their synthetic analogues

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