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Ceruloplasmin Deamidation in Neurodegeneration: From Loss to Gain of Function

by Alan Zanardi and Massimo Alessio

Int. J. Mol. Sci. 2021, 22(2), 663; https://doi.org/10.3390/ijms22020663 - 11 Jan 2021

Cited by 18 | Viewed by 4445

Neurodegenerative disorders can induce modifications of several proteins; one of which is ceruloplasmin (Cp), a ferroxidase enzyme found modified in the cerebrospinal fluid (CSF) of neurodegenerative diseases patients. Cp modifications are caused by the oxidation induced by the pathological environment and are usually associated with activity loss. Together with oxidation, deamidation of Cp was found in the CSF from Alzheimer’s and Parkinson’s disease patients. Protein deamidation is a process characterized by asparagine residues conversion in either aspartate or isoaspartate, depending on protein sequence/structure and cellular environment. Cp deamidation occurs at two Asparagine-Glycine-Arginine (NGR)-motifs which, once deamidated to isoAspartate-Glycine-Arginine (isoDGR), bind integrins, a family of receptors mediating cell adhesion. Therefore, on the one hand, Cp modifications lead to loss of enzymatic activity, while on the other hand, these alterations confer gain of function to Cp. In fact, deamidated Cp binds to integrins and triggers intracellular signaling on choroid plexus epithelial cells, changing cell functioning. Working in concert with the oxidative environment, Cp deamidation could reach different target cells in the brain, altering their physiology and causing detrimental effects, which might contribute to the pathological mechanism. Full article

(This article belongs to the Special Issue Ferroportin and Ceruloplasmin: Structure and Function in Health and Disease)

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17 pages, 5097 KiB

Open AccessArticle

Phosphate-Catalyzed Succinimide Formation from an NGR-Containing Cyclic Peptide: A Novel Mechanism for Deammoniation of the Tetrahedral Intermediate

by Ryota Kirikoshi, Noriyoshi Manabe and Ohgi Takahashi

Molecules 2018, 23(9), 2217; https://doi.org/10.3390/molecules23092217 - 31 Aug 2018

Cited by 5 | Viewed by 4281

Abstract

Spontaneous deamidation in the Asn-Gly-Arg (NGR) motif that yields an isoAsp-Gly-Arg (isoDGR) sequence has recently attracted considerable attention because of the possibility of application to dual tumor targeting. It is well known that Asn deamidation reactions in peptide chains occur via the five-membered ring succinimide intermediate. Recently, we computationally showed by the B3LYP density functional theory method, that inorganic phosphate and the Arg side chain can catalyze the NGR deamidation using a cyclic peptide, c[CH₂CO–NGRC]–NH₂. In this previous study, the tetrahedral intermediate of the succinimide formation was assumed to be readily protonated at the nitrogen originating from the Asn side chain by the solvent water before the release of an NH₃ molecule. In the present study, we found a new mechanism for the decomposition of the tetrahedral intermediate that does not require the protonation by an external proton source. The computational method is the same as in the previous study. In the new mechanism, the release of an NH₃ molecule occurs after a proton exchange between the peptide and the phosphate and conformational changes. The rate-determining step of the overall reaction course is the previously reported first step, i.e., the cyclization to form the tetrahedral intermediate. Full article

(This article belongs to the Special Issue Cyclic Peptides)

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15 pages, 2522 KiB

Open AccessArticle

Succinimide Formation from an NGR-Containing Cyclic Peptide: Computational Evidence for Catalytic Roles of Phosphate Buffer and the Arginine Side Chain

by Ryota Kirikoshi, Noriyoshi Manabe and Ohgi Takahashi

Int. J. Mol. Sci. 2017, 18(2), 429; https://doi.org/10.3390/ijms18020429 - 16 Feb 2017

Cited by 18 | Viewed by 8459

Abstract

The Asn-Gly-Arg (NGR) motif and its deamidation product isoAsp-Gly-Arg (isoDGR) have recently attracted considerable attention as tumor-targeting ligands. Because an NGR-containing peptide and the corresponding isoDGR-containing peptide target different receptors, the spontaneous NGR deamidation can be used in dual targeting strategies. It is well known that the Asn deamidation proceeds via a succinimide derivative. In the present study, we computationally investigated the mechanism of succinimide formation from a cyclic peptide, c[CH₂CO-NGRC]-NH₂, which has recently been shown to undergo rapid deamidation in a phosphate buffer. An H₂PO₄⁻ ion was explicitly included in the calculations. We employed the density functional theory using the B3LYP functional. While geometry optimizations were performed in the gas phase, hydration Gibbs energies were calculated by the SM8 (solvation model 8) continuum model. We have found a pathway leading to the five-membered ring tetrahedral intermediate in which both the H₂PO₄⁻ ion and the Arg side chain act as catalyst. This intermediate, once protonated at the NH₂ group on the five-membered ring, was shown to easily undergo NH₃ elimination leading to the succinimide formation. This study is the first to propose a possible catalytic role for the Arg side chain in the NGR deamidation. Full article

(This article belongs to the Special Issue Chemical Bond and Bonding 2016)

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