Isomerization of aspartyl residues in crystallins and its influence upon cataract

Fujii, Nobutaka; Takata, Takumi; Fujii, Norihiko; Aki, Kenzo

doi:10.1016/j.bbagen.2015.08.001

Cited by 49 publications

(41 citation statements)

References 42 publications

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“…Succinimide intermediates can also be formed from asparagine (Asn) residues (this is irreversible because of the release of an ammonia molecule) [1,2,10,11,12,13,14]; therefore, in proteins and peptides, there can be d -Asp and d -β-Asp residues originating from l -Asn residues. The formation of the biologically uncommon l -β-Asp, d -Asp, and d -β-Asp residues have been paid considerable attention due to the relevance to aging and pathologies, especially those of age-related diseases such as cataract and Alzheimer’s disease [5,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42]. …”

Section: Introductionmentioning

confidence: 99%

Racemization of the Succinimide Intermediate Formed in Proteins and Peptides: A Computational Study of the Mechanism Catalyzed by Dihydrogen Phosphate Ion

Takahashi

Kirikoshi

Manabe

2016

IJMS

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In proteins and peptides, d-aspartic acid (d-Asp) and d-β-Asp residues can be spontaneously formed via racemization of the succinimide intermediate formed from l-Asp and l-asparagine (l-Asn) residues. These biologically uncommon amino acid residues are known to have relevance to aging and pathologies. Although nonenzymatic, the succinimide racemization will not occur without a catalyst at room or biological temperature. In the present study, we computationally investigated the mechanism of succinimide racemization catalyzed by dihydrogen phosphate ion, H2PO4−, by B3LYP/6-31+G(d,p) density functional theory calculations, using a model compound in which an aminosuccinyl (Asu) residue is capped with acetyl (Ace) and NCH3 (Nme) groups on the N- and C-termini, respectively (Ace–Asu–Nme). It was shown that an H2PO4− ion can catalyze the enolization of the Hα–Cα–C=O portion of the Asu residue by acting as a proton-transfer mediator. The resulting complex between the enol form and H2PO4− corresponds to a very flat intermediate region on the potential energy surface lying between the initial reactant complex and its mirror-image geometry. The calculated activation barrier (18.8 kcal·mol−1 after corrections for the zero-point energy and the Gibbs energy of hydration) for the enolization was consistent with the experimental activation energies of Asp racemization.

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Section: Introductionmentioning

confidence: 99%

Racemization of the Succinimide Intermediate Formed in Proteins and Peptides: A Computational Study of the Mechanism Catalyzed by Dihydrogen Phosphate Ion

Takahashi

Kirikoshi

Manabe

2016

IJMS

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“…The dissociation of αA-crystallin is also significantly affected by the structural alteration of Asp residues [30]. The results obtained from two types of crystallins clearly show that structural alteration of Asx residues affects the function of the proteins [31]. Functional disorder, caused by Asn deamidation, is also reported in the case of calcium-modulated protein, calmodulin: specifically, the deamidation of two specific Asn residues caused a 90% reduction in activity of calmodulin [32].…”

Section: Asparagine Deamidation and Its Biological Significancementioning

confidence: 99%

Implications of Metal Binding and Asparagine Deamidation for Amyloid Formation

Sadakane

Kawahara

2018

IJMS

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Increasing evidence suggests that amyloid formation, i.e., self-assembly of proteins and the resulting conformational changes, is linked with the pathogenesis of various neurodegenerative disorders such as Alzheimer’s disease, prion diseases, and Lewy body diseases. Among the factors that accelerate or inhibit oligomerization, we focus here on two non-genetic and common characteristics of many amyloidogenic proteins: metal binding and asparagine deamidation. Both reflect the aging process and occur in most amyloidogenic proteins. All of the amyloidogenic proteins, such as Alzheimer’s β-amyloid protein, prion protein, and α-synuclein, are metal-binding proteins and are involved in the regulation of metal homeostasis. It is widely accepted that these proteins are susceptible to non-enzymatic posttranslational modifications, and many asparagine residues of these proteins are deamidated. Moreover, these two factors can combine because asparagine residues can bind metals. We review the current understanding of these two common properties and their implications in the pathogenesis of these neurodegenerative diseases.

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“…Several recent studies by Fujii and coworkers developed assays with LC-MS to study Asp/isoAsp residues in cataracts [30,34,37,[68][69][70][71][72]. For the generation of therapeutic proteins such as antibodies, the presence of Asp especially in the complementary-determining region poses stability risks; the spontaneous isomerization the residue could undergo may alter the folding and as a result the binding properties.…”

Section: Asp/isoasp ( -Asp/ -Asp)mentioning

confidence: 99%

Strategies for analysis of isomeric peptides

Jansson

2017

J of Separation Science

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This review presents an overview and recent progress of strategies for detecting isomerism in peptides, with focus on d/l epimerization and the various isomers that the presence of an aspartic acid residue may yield in a protein or peptide. While mass spectrometry has become a majorly used method of choice within proteomics, isomerism is inherently difficult to analyze because it is a modification that does not yield any change in mass of the analyte. Here, several techniques used for analysis of peptide isomerism are discussed, including enzymatic assays, liquid chromatography, and capillary electrophoresis. Recent progress in method development using mass spectrometry is also discussed, including labeling strategies, fragmentation techniques, and ion-mobility spectrometry.

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Isomerization of aspartyl residues in crystallins and its influence upon cataract

Cited by 49 publications

References 42 publications

Racemization of the Succinimide Intermediate Formed in Proteins and Peptides: A Computational Study of the Mechanism Catalyzed by Dihydrogen Phosphate Ion

Racemization of the Succinimide Intermediate Formed in Proteins and Peptides: A Computational Study of the Mechanism Catalyzed by Dihydrogen Phosphate Ion

Implications of Metal Binding and Asparagine Deamidation for Amyloid Formation

Strategies for analysis of isomeric peptides

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