Artificial Metalloprotease Based on Co(III)oxacyclen-Aldehyde Conjugate

Kim, Min Gyum; Kim, Hye Mi; Suh, Junghun

doi:10.5012/bkcs.2011.32.8.3113

Cited by 4 publications

(7 citation statements)

References 16 publications

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“…This trend is clearly observed when the experimental rate constants of the cobalt(III) and copper(II) cyclen complexes are compared, ,, for which the estimated energy difference is ∼2 kcal mol –1 (Table S2). For oxacyclen complexes, the energy difference is smaller (Table S2), ,,, but a comparison between them is more difficult because Co and Cu complexes could be active in different structural isomers. In fact, we characterized another structural isomer, 1 Cu′ (depicted in Figure S3), which lies 1.5 kcal mol –1 below 1 Cu .…”

Section: Resultsmentioning

confidence: 89%

“…Importantly, this value is significantly closer to the experimental rate constants, from which we can estimate free-energy barriers of ca. 25–26 kcal mol –1 (Table S2), , than that from the previously proposed mechanism (∼40 kcal mol –1 ) . To check our methodology, we have reevaluated the initial steps of the mechanism using a larger basis set and introduced dispersion corrections to the density functional theory (DFT) method (the B3LYP-D3/TZVP level, where B3LYP = Becke, three-parameter, Lee–Yang–Parr; see Computational Details).…”

Section: Resultsmentioning

confidence: 99%

“…In general, cobalt complexes with oxacyclen [N 3 O 1 ] ligands ( 1 in Figure ) perform better than Co-cyclen [N 4 ] ones ( 1b in Figure ), attaining hydrolysis of the substrate up to ten times faster . In addition, Suh and co-workers showed that Cu(II)-oxacyclen complexes can exhibit greater hydrolytic activity than their Co(III)-based analogues, ,,, although they are less popular for in vivo applications because Cu(II) ions can be more easily released from the catalyst structure to the medium in a living body . The proposed metal-hydroxo base-assisted mechanism provides a new platform to evaluate the influence of the ligand and the metal nature on the peptide hydrolysis activity by comparing different catalytic structures.…”

Section: Resultsmentioning

confidence: 99%

“…Specifically, Co(III)- and Cu(II)-based complexes with tetradentate 1,4,7,10-tetraazacyclododecane (cyclen) or 1-oxa-4,7,10-triazacyclododecane (oxacyclen) ligands have shown the ability to hydrolyze selectively a wide range of biological molecules such as lysozyme, myoglobin, albumin, globulin, amyloid-β (Aβ) peptide, or human islet amyloid peptide (h-IAPP). − Importantly, the cyclen family of ligands can incorporate an organic alkyl or aryl pendant that induces an enzyme-like recognition of the catalyst by the biological system, in such a way that the hydrolysis process becomes highly selective. This approach has been successfully applied to hydrolyze Aβ oligopeptides selectively at peptide bonds of Phe20–Ala21 and Ala21–Glu22, , making metal cyclen complexes highly attractive as a novel family of drugs for Alzheimer’s disease, which is presumably caused by the formation of misfolded aggregates of Aβ oligomers .…”

Section: Introductionmentioning

confidence: 99%

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Peptide Hydrolysis by Metal (Oxa)cyclen Complexes: Revisiting the Mechanism and Assessing Ligand Effects

et al. 2021

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The mechanism responsible for peptide bond hydrolysis by Co(III) and Cu(II) complexes with (oxa)cyclen ligands has been revisited by means of computational tools. We propose that the mechanism starts by substrate coordination and an outer-sphere attack on the amide C atom of a solvent water molecule assisted by the metal hydroxo moiety as a general base, which occurs through six-membered ring transition states. This new mechanism represents a more likely scenario than the previously proposed mechanisms that involved an inner-sphere nucleophilic attack through more strained four-membered rings transition states. The corresponding computed overall free-energy barrier of 25.2 kcal mol–1 for hydrolysis of the peptide bond in PheAla by a cobalt(III) oxacyclen catalyst (1) is consistent with the experimental values obtained from rate constants. Also, we assessed the influence of the nature of the ligand throughout a systematic replacement of N by O atoms in the (oxa)cyclen ligand. Increasing the number of coordinating O atoms accelerates the reaction by increasing the Lewis acidity of the metal ion. On the other hand, the higher reactivity observed for the copper(II) oxacyclen catalyst with respect to the analogous Co(III) complex can be attributed to the larger Brönsted basicity of the copper(II) hydroxo ligand. Ultimately, the detailed understanding of the ligand and metal nature effects allowed us to identify the double role of the metal hydroxo complexes as Lewis acids and Brönsted bases and to rationalize the observed reactivity trends.

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Section: Resultsmentioning

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Peptide Hydrolysis by Metal (Oxa)cyclen Complexes: Revisiting the Mechanism and Assessing Ligand Effects

et al. 2021

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“…For the Co(III)-containing complexes, the measured rate constant (k cat ) of 0.40 (h −1 ) for the cleavage of myoglobin by 2-Co corresponds to a barrier of 24.7 kcal/mol at pH = 8.0 and 50 °C (Table 1). 94 The measured k cat values were converted into barriers using the Arrhenius equation (k = A e −E a /RT , where A is the pre-exponential factor, E a is the activation energy, R is the gas constant, and T is the temperature). In the absence of a pendant, 1′-Co and 2′-Co complexes cleave this substrate with barriers of 25.9 and 24.9 kcal/mol, respectively (Table 1) at pH 9.0 and 50 °C (Table 1).…”

Section: Introductionmentioning

confidence: 99%

Peptide Hydrolysis by Metal-Cyclen Complexes and Their Analogues: Insights from Theoretical Studies

2014

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In the present DFT study, mechanisms of peptide hydrolysis by Co(III)- and Cu(II)-containing complexes of 1,4,7,10-tetraazacyclododecane (cyclen), 1-Co and 1-Cu, respectively, and 1-oxa-4,7,10-triazacyclododecane (oxacyclen), 2-Co and 2-Cu, respectively, and their analogues have been investigated. In addition, the effects of the ligand environment, pendant (an organic group containing a recognition site) and metal ion (Co(III), Cu(II), Ni(II), Zn(II), Cd(II), and Pd(II)), on the energetics of this reaction have been elucidated. The reactant of the 1-Co complex exists in the syn–anti conformation, while that of 1-Cu in the syn–syn form. For both these complexes, stepwise and concerted mechanisms were found to occur with similar barriers. The substitution of one of the nitrogen atoms in the cyclen macrocycle to create oxacyclen should occur at position 10 in the Co(III) case and at position 4 in the Cu(II) case. A comparison between the barriers using the common conformation (syn–anti) of 1-Co and 2-Co showed that both complexes hydrolyze the peptide bond with similar barriers, i.e., 39.8 kcal/mol for the former and 40.1 kcal/mol for the latter. This result is in line with the measured data that suggest that the oxacyclen complex exhibits just four times greater activity than the cyclen complex. The removal of the pendant (−C2H5) group in the Co(III)- and Cu(II)-cyclen complexes (1′-Co and 1′-Cu, respectively) reduced the barriers by 9.3 and 3.0 kcal/mol, respectively. For 1′-Co, the barrier of 30.5 kcal/mol is in agreement with the experimental value of 25.9 kcal/mol for the cleavage of myoglobin at pH 9.0 and 50 °C. The reactants of 1′-Cu, 1′-Zn, 1′-Pd, and 1′-Cd adopt the syn–syn conformation, whereas 1′-Ni and 1′-Co exist in the syn–anti geometry. The barriers for 1′-Ni (triplet spin state), 1′-Cu (doublet spin state), 1′-Cd (singlet spin state), 1′-Co (singlet spin state), and 1′-Zn (singlet spin state) are similar, i.e., 27.2, 29.7, 30.5, 30.5, and 31.9 kcal/mol, respectively, and the highest barrier (41.5 kcal/mol) is computed for 1′-Pd (singlet spin state).

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Metal-based methods for protein inactivation

Prakash

Kodanko

2013

Current Opinion in Chemical Biology

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Artificial Metalloprotease Based on Co(III)oxacyclen-Aldehyde Conjugate

Cited by 4 publications

References 16 publications

Peptide Hydrolysis by Metal (Oxa)cyclen Complexes: Revisiting the Mechanism and Assessing Ligand Effects

Peptide Hydrolysis by Metal (Oxa)cyclen Complexes: Revisiting the Mechanism and Assessing Ligand Effects

Peptide Hydrolysis by Metal-Cyclen Complexes and Their Analogues: Insights from Theoretical Studies

Metal-based methods for protein inactivation

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