Kinetics and mechanism of succinimide ring formation in the deamidation process of asparagine residues

Capasso, Sante; Mazzarella, L.; Sica, F.; Zagari, Adriana; Salvadori, Severo

doi:10.1039/p29930000679

Cited by 77 publications

(124 citation statements)

References 9 publications

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“…In solution, the mechanism for deamidation of Asn is known to proceed by formation of cyclic succinic species [2][3][4][5][6][7][8][9][10][11], which corresponds to a-SA for the isolated amino acid [15]. As discussed further below, the mechanism elucidated here parallels that discovered for sodiated Asn [15], and furthermore, the theoretical energetics for the mechanism match experiment nicely (see below).…”

Section: Theoretical Results For H ϩ (Asn) Deamidationsupporting

confidence: 55%

Thermodynamics and mechanism of protonated asparagine decomposition

Heaton

Armentrout

2009

J. Am. Soc. Mass Spectrom.

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Deamidation of the amino acid asparagine (Asn) is a primary route for spontaneous posttranslational protein modification biologically and is a pH dependent process. Here we present a full molecular description of the deamidation and (H 2 O ϩ CO) loss reactions of protonated asparagine, H ϩ (Asn), by studying its collision-induced dissociation (CID) with Xe using a guided ion beam (GIB) tandem mass spectrometer. Analysis of the kinetic energy-dependent CID cross sections provides the 0 K barriers for the deamidation and (H 2 O ϩ CO) loss reactions after accounting for unimolecular decay rates, internal energy of reactant ions, multiple ion-molecule collisions, and competition among the decay channels. Relaxed potential energy surface scans performed at the B3LYP/6-31G(d) level identify the transition-state (TS) and intermediate reaction species for these processes, structures that are further optimized at the B3LYP/6-311ϩG(d,p) level. Intrinsic reaction coordinate (IRC) calculations are also performed at this level on the rate-limiting reaction TSs to validate the molecular details and energy dependence of these species. Single point energies of the key optimized TSs and intermediates are calculated at B3LYP, B3P86, and MP2(full) levels using a 6-311ϩG(2d,2p) basis set. A number of alternative high-energy mechanisms for (H 2 O ϩ CO) loss from H ϩ (Asn) are also investigated. Combining both experimental work and quantum chemical calculations allows for a complete characterization of the elementary steps of these reactions as well as a comprehensive evaluation of the complex behavior of the deamidation reaction. (J Am Soc Mass Spectrom 2009, 20, 852-866)

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Section: Theoretical Results For H ϩ (Asn) Deamidationsupporting

confidence: 55%

Thermodynamics and mechanism of protonated asparagine decomposition

Heaton

Armentrout

2009

J. Am. Soc. Mass Spectrom.

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“…The rate of formation of Asu is dependent upon factors which increase the deprotonation of the peptide nitrogen. These factors include high pH, (Capasso et al 1992(Capasso et al , 1993, high ionic strength (Capasso et al 1991;TylerCross & Schirch 1991), high dielectric constant (Brennan & Clarke 1993) and conformational £exibility within the residues (Kossiako¡ 1988;Lura & Schirch 1988;Bongers et al 1992;Stevenson et al 1993;Tomizawa et al 1995).…”

Section: An Alternative Approach To Asx Kineticsmentioning

confidence: 99%

Predicting protein decomposition: the case of aspartic–acid racemization kinetics

Collins

Waite

Duin

1999

Phil. Trans. R. Soc. Lond. B

154

107

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The increase in proportion of the non-biological (D-) isomer of aspartic acid (Asp) relative to the Lisomer has been widely used in archaeology and geochemistry as a tool for dating. The method has proved controversial, particularly when used for bones. The non-linear kinetics of Asp racemization have prompted a number of suggestions as to the underlying mechanism(s) and have led to the use of mathematical transformations which linearize the increase in D-Asp with respect to time. Using one example, a suggestion that the initial rapid phase of Asp racemization is due to a contribution from asparagine (Asn), we demonstrate how a simple model of the degradation and racemization of Asn can be used to predict the observed kinetics. A more complex model of peptide bound Asx (Asn + Asp) racemization, which occurs via the formation of a cyclic succinimide (Asu), can be used to correctly predict Asx racemization kinetics in proteins at high temperatures (95^140 8C). The model fails to predict racemization kinetics in dentine collagen at 37 8C. The reason for this is that Asu formation is highly conformation dependent and is predicted to occur extremely slowly in triple helical collagen. As conformation strongly in£uences the rate of Asu formation and hence Asx racemization, the use of extrapolation from high temperatures to estimate racemization kinetics of Asx in proteins below their denaturation temperature is called into question.In the case of archaeological bone, we argue that the D:L ratio of Asx re£ects the proportion of nonhelical to helical collagen, overlain by the e¡ects of leaching of more soluble (and conformationally unconstrained) peptides. Thus, racemization kinetics in bone are potentially unpredictable, and the proposed use of Asx racemization to estimate the extent of DNA depurination in archaeological bones is challenged.

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“…This enzyme catalyzes the methyl esterification of l-isoaspartyl (and with less affinity d-aspartyl) residues using S-adenosyl-l-methionine as the methyl group donor, and this reaction can initiate its conversion back into the normal l-aspartyl forms Clarke, 1991, 1992;Brennan et al, 1994). The substrates for this enzyme are generally considered to arise from the deamidation, racemization, and isomerization of l-asparaginyl and l-aspartyl residues, which give rise to l-aspartyl, d-aspartyl, and d-and l-isoaspartyl residues (Geiger and Clarke, 1987;Patel and Borchardt, 1990;TylerCross and Schirch, 1991;Clarke et al, 1992;Capasso et al, 1993). However, l-isoaspartyl residues can also possibly arise as the result of the incorporation of mischarged aspartyl residues during protein synthesis (Momand and Clarke, 1990).…”

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confidence: 99%

Distinct Patterns of Expression But Similar Biochemical Properties of Protein l-Isoaspartyl Methyltransferase in Higher Plants

Thapar

Kim²,

Clarke

2001

Plant Physiology

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Protein l-isoaspartyl methyltransferase is a widely distributed repair enzyme that initiates the conversion of abnormal l-isoaspartyl residues to their normal l-aspartyl forms. Here we show that this activity is expressed in developing corn (Zea mays) and carrot (Daucus carota var. Danvers Half Long) plants in patterns distinct from those previously seen in winter wheat (Triticum aestivum cv Augusta) and thale cress (Arabidopsis thaliana), whereas the pattern of expression observed in rice (Oryza sativa) is similar to that of winter wheat. Although high levels of activity are found in the seeds of all of these plants, relatively high levels of activity in vegetative tissues are only found in corn and carrot. The activity in leaves was found to decrease with aging, an unexpected finding given the postulated role of this enzyme in repairing age-damaged proteins. In contrast with the situation in wheat and Arabidopsis, we found that osmotic or salt stress could increase the methyltransferase activity in newly germinated seeds (but not in seeds or seedlings), whereas abscisic acid had no effect. We found that the corn, rice, and carrot enzymes have comparable affinity for methyl-accepting substrates and similar optimal temperatures for activity of 45°C to 55°C as the wheat and Arabidopsis enzymes. These experiments suggest that this enzyme may have specific roles in different plant tissues despite a common catalytic function.

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Kinetics and mechanism of succinimide ring formation in the deamidation process of asparagine residues

Cited by 77 publications

References 9 publications

Thermodynamics and mechanism of protonated asparagine decomposition

Thermodynamics and mechanism of protonated asparagine decomposition

Predicting protein decomposition: the case of aspartic–acid racemization kinetics

Distinct Patterns of Expression But Similar Biochemical Properties of Protein l-Isoaspartyl Methyltransferase in Higher Plants

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