Molecular Dynamics Simulations Reveal a Novel Mechanism for ATP Inhibition of Insulin Degrading Enzyme

Cruz, Carlos; Seabra, Gustavo

doi:10.1021/ci400695m

Cited by 15 publications

(20 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…27 Briefly, the initial IDE structure was obtained from the Protein Data Bank (PDB) (PDB ID: 2WK3). The protonation states of ionizable residues were determined by MolProbity.…”

Section: ■ Methodologymentioning

confidence: 99%

“…In this case, the population of hydrogen bonds TYR831− phe19 is reduced, while a hydrogen bond is formed TYR831− ala21. 27 From each of the trajectories generated (with and without ATP), one structure was chosen with the requirements that (a) those interactions are reproduced and (b) the reaction coordinates had values close to the starting point in the umbrella sampling path (see below).…”

Section: ■ Methodologymentioning

confidence: 99%

“…Recently, on the basis of the results of extensive molecular dynamics (MD) calculations of IDE bound to Aβ42 in the absence or presence of ATP, we have proposed a molecular model for this inhibition. 27 Our model ATP, which is bound to IDE-C, interacts with Aβ42 bound to the opposite half (IDE-N), creating a link that connects the two halves of IDE trapping the enzyme in the closed (inactive) conformation and ultimately inhibiting its catalytic function. We also observed that ATP induces geometric changes in the active site, which can be related to the destabilization of the reaction intermediates, negatively impacting the reaction kinetics.…”

Section: ■ Introductionmentioning

confidence: 99%

See 2 more Smart Citations

QM/MM Simulations of Amyloid-β 42 Degradation by IDE in the Presence and Absence of ATP

Cruz

Seabra

2015

J. Chem. Inf. Model.

Self Cite

View full text Add to dashboard Cite

The ability of the insulin-degrading enzyme (IDE) to degrade amyloid-β 42 (Aβ42), a process regulated by ATP, has been studied as an alternative path in the development of drugs against Alzheimer's disease. In this study, we calculated the potential of mean force for the degradation of Aβ42 by IDE in the presence and absence of ATP by umbrella sampling with hybrid quantum mechanics and molecular mechanics (QM/MM) calculations, using the SCC-DFTB QM Hamiltonian and Amber ff99SB force field. Results indicate that the reaction occurs in two steps: The first step is characterized by the formation of the intermediate. The second step is characterized by breaking the peptide bond of the substrate, the latter being the rate-determining step. In our simulations, the activation energy barrier in the absence of ATP is 15 ± 2 kcal mol(-1), which is 7 kcal mol(-1) lower than in the presence of ATP, indicating that the presence of the nucleotide decreases the reaction rate by about 10(5) times.

show abstract

“…27 Briefly, the initial IDE structure was obtained from the Protein Data Bank (PDB) (PDB ID: 2WK3). The protonation states of ionizable residues were determined by MolProbity.…”

Section: ■ Methodologymentioning

confidence: 99%

Section: ■ Methodologymentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

See 1 more Smart Citation

QM/MM Simulations of Amyloid-β 42 Degradation by IDE in the Presence and Absence of ATP

Cruz

Seabra

2015

J. Chem. Inf. Model.

Self Cite

View full text Add to dashboard Cite

show abstract

“…There are many reports on degradation of β-amyloid by IDE protease (insulin-degrading enzyme) [ 91 , 92 ]. ATP was reported to affect the β-amyloid degradation in a presence of IDE [ 93 , 94 ]. It was shown that ATP activates the IDE degradation of small peptides, but it decreases the rate degradation of large peptides like Aβ42.…”

Section: Role Of Adenine Nucleotides and P2 Receptors In The Alzheimementioning

confidence: 99%

Role of purinergic receptors in the Alzheimer’s disease

Cieślak¹,

Wojtczak

2018

Purinergic Signalling

View full text Add to dashboard Cite

Etiology of the Alzheimer’s disease (AD) is not fully understood. Different pathological processes are considered, such as amyloid deposition, tau protein phosphorylation, oxidative stress (OS), metal ion disregulation, or chronic neuroinflammation. Purinergic signaling is involved in all these processes, suggesting the importance of nucleotide receptors (P2X and P2Y) and adenosine receptors (A1, A2A, A2B, A3) present on the CNS cells. Ecto-purines, ecto-pyrimidines, and enzymes participating in their metabolism are present in the inter-cellular spaces. Accumulation of amyloid-β (Aβ) in brain induces the ATP release into the extra-cellular space, which in turn stimulates the P2X7 receptors. Activation of P2X7 results in the increased synthesis and release of many pro-inflammatory mediators such as cytokines and chemokines. Furthermore, activation of P2X7 leads to the decreased activity of α-secretase, while activation of P2Y2 receptor has an opposite effect. Simultaneous inhibition of P2X7 and stimulation of P2Y2 would therefore be the efficient way of the α-secretase activation. Activation of P2Y2 receptors present in neurons, glia cells, and endothelial cells may have a positive neuroprotective effect in AD. The OS may also be counteracted via the purinergic signaling. ADP and its non-hydrolysable analogs activate P2Y13 receptors, leading to the increased activity of heme oxygenase, which has a cytoprotective activity. Adenosine, via A1 and A2A receptors, affects the dopaminergic and glutaminergic signaling, the brain-derived neurotrophic factor (BNDF), and also changes the synaptic plasticity (e.g., causing a prolonged excitation or inhibition) in brain regions responsible for learning and memory. Such activity may be advantageous in the Alzheimer’s disease.

show abstract

“…In the present study, we used circular dichroism (CD) to monitor the IDE-dependent degradation of unlabeled insulin. By using the observed ellipticity at 222 nm as a measure of the extent of degradation, we were able to obtain Michaelis–Menten kinetic constants in the absence and presence of adenosine triphosphate (ATP), which has been hypothesized to regulate IDE in vivo [ 10 , 16 , 17 , 26 , 27 ]. Our results show that ATP regulates IDE-dependent degradation of insulin, but the addition of Mg 2+ abolishes the regulation.…”

Section: Introductionmentioning

confidence: 99%

Enzyme kinetics from circular dichroism of insulin reveals mechanistic insights into the regulation of insulin-degrading enzyme

et al. 2018

View full text Add to dashboard Cite

Insulin-degrading enzyme (IDE) is a zinc metalloprotease that selectively degrades biologically important substrates associated with type 2 diabetes and Alzheimer’s disease (AD). As such, IDE is an attractive target for therapeutic innovations. A major requirement is an understanding of how other molecules present in cells regulate the activity of the enzyme toward insulin, IDE’s most important physiologically relevant substrate. Previous kinetic studies of the IDE-dependent degradation of insulin in the presence of potential regulators have used iodinated insulin, a chemical modification that has been shown to alter the biological and biochemical properties of insulin. Here, we present a novel kinetic assay that takes advantage of the loss of helical circular dichroic signals of insulin with IDE-dependent degradation. As proof of concept, the resulting Michaelis–Menten kinetic constants accurately predict the known regulation of IDE by adenosine triphosphate (ATP). Intriguingly, we found that when Mg2+ is present with ATP, the regulation is abolished. The implication of this result for the development of preventative and therapeutic strategies for AD is discussed. We anticipate that the new assay presented here will lead to the identification of other small molecules that regulate the activity of IDE toward insulin.

show abstract

Molecular Dynamics Simulations Reveal a Novel Mechanism for ATP Inhibition of Insulin Degrading Enzyme

Cited by 15 publications

References 53 publications

QM/MM Simulations of Amyloid-β 42 Degradation by IDE in the Presence and Absence of ATP

QM/MM Simulations of Amyloid-β 42 Degradation by IDE in the Presence and Absence of ATP

Role of purinergic receptors in the Alzheimer’s disease

Enzyme kinetics from circular dichroism of insulin reveals mechanistic insights into the regulation of insulin-degrading enzyme

Contact Info

Product

Resources

About