Racemization of Serine Residues Catalyzed by Dihydrogen Phosphate Ion: A Computational Study

Takahashi, Ohgi; Kirikoshi, Ryota; Manabe, Noriyoshi

doi:10.3390/catal7120363

Cited by 13 publications

(15 citation statements)

References 55 publications

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“…The dihydro-phosphate ion may catalyze various reactions in proteins, including the racemization of amino acid residues. Therefore, it may contribute to better cellular membrane permeability [30], as racemization of the amino acids influences the functions of many intracellular, extracellular and membrane-bound proteins, and it is considered as a critical factor of protein conformation [31]. However, the observations made must be confirmed in further studies.…”

Section: Discussionmentioning

confidence: 99%

Topical Photodynamic Therapy with Different Forms of 5-Aminolevulinic Acid in the Treatment of Actinic Keratosis

et al. 2022

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Photodynamic therapy (PDT) is safe and effective in the treatment of patients with actinic keratosis (AK). The aim of the study was to assess the efficacy, tolerability and cosmetic outcome of topical PDT in the treatment of AKs with three forms of photosensitizers: 5-Aminolevulinic acid hydrochloride (ALA-HCl), 5-Aminolevulinate methyl ester hydrochloride (MAL-HCl) and 5-Aminolevulinate phosphate (ALA-P). The formulations were applied onto selected scalp/face areas. Fluorescence was assessed with a FotoFinder Dermoscope 800 attachment. Skin areas were irradiated with Red Beam Pro+, Model APRO (MedLight GmbH, Herford, Germany). Applied treatments were assessed during the PDT as well as 7 days and 12 weeks after its completion. Ninety-four percent of patients rated obtained cosmetic effect excellent. The efficacy of applied PSs did not differ significantly. However, pain intensity during the PDT procedure was significantly lower in the area treated with ALA-P (5.8 on average) in comparison to the areas treated with ALA-HCl or MAL-HCl (7.0 on average on 0–10 scale). Obtained results show that ALA-P may undergo more selective accumulation than ALA-HCl and MAL-HCl. Our promising results suggest that PDT with the use of ALA-P in AK treatment may be an advantageous alternative to the already used ALA-HCl and MAL-HCl.

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Section: Discussionmentioning

confidence: 99%

Topical Photodynamic Therapy with Different Forms of 5-Aminolevulinic Acid in the Treatment of Actinic Keratosis

et al. 2022

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“…In previous studies on Ser-residue enolization, the shortening of the side-chain C α –C β bond and the extension of the side-chain C β –O γ bond were observed with the formation of TSs from the keto-form Ser residues. 25 , 27 These phenomena suggest that the TSs are stabilized by delocalizing the negative charge accumulating on the C α to the antibonding orbital of the C β –O γ bond (i.e., negative hyperconjugation). 25 , 27 Similar changes in the lengths of C α –C β and C β –O γ bonds were observed in Thr-residue enolization and following reketonization.…”

Section: Discussionmentioning

confidence: 99%

“…Previously, quantum chemical calculations showed that the activation energies of Ser-residue stereoinversion via enol intermediates are comparable to those of typical nonenzymatic reactions. 25 , 27 Although Dha residues are potential intermediates of Ser-residue stereoinversion, experimental and computational evidence so far has confirmed the hypothesis that Dha residues are intermediates of stereoinversion. 24 , 25 Therefore, in the present study, d - allo -Thr residue was assumed to be obtained via enolized Thr residues ( Scheme 3 ), as well as Ser-residue stereoinversion.…”

Section: Introductionmentioning

confidence: 93%

“…Previous computational studies showed that a dihydrogen phosphate ion (H 2 PO 4 – ) could catalyze several nonenzymatic modifications of amino acid residues. 25 , 27 , 31 − 40 In these studies, H 2 PO 4 – acts as both a Brønsted acid and base, and the catalyzed proton relays after forming appropriate complexes with amino acid residues. In the present study, to investigate why Thr-residue stereoinversion has not been observed in vivo, computational analysis was performed using quantum chemical calculations to elucidate the mechanisms for the stereoinversion of Thr residues catalyzed by H 2 PO 4 – .…”

Section: Introductionmentioning

confidence: 99%

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Predicting Reaction Mechanisms for the Threonine-Residue Stereoinversion Catalyzed by a Dihydrogen Phosphate Ion

et al. 2022

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The stereoinversion of amino acid residues in proteins is considered to trigger various age-related diseases. Serine (Ser) residues are relatively prone to stereoinversion. It is assumed that threonine (Thr) residues also undergo stereoinversion, which results in the formation of the d - allo -Thr residue, by the same mechanisms as those for Ser-residue stereoinversion; however, d - allo -Thr residues have not been detected in vivo. To date, although Ser-residue stereoinversion has been suggested to progress via enolization, plausible reaction mechanisms for Thr-residue stereoinversion have not been proposed. In this study, we investigated the pathway of Thr-residue enolization and successfully identified the three types of plausible reaction pathways of Thr-residue stereoinversion catalyzed by a dihydrogen phosphate ion. The geometries of reactant complexes, transition states, and enolized product complexes were optimized using B3LYP density functional methods, and single-point calculations were performed for all optimized geometries using Møller–Plesset perturbation theory to obtain reliable energies. As a result, the calculated activation energies of Thr-residue stereoinversion were 105–106 kJ mol –1 , which were comparable with those of Ser-residue stereoinversion reported previously. The infrequency of Thr-residue stereoinversion may be due to other factors, such as the hydrophobicity and/or the steric hindrance of the γ-methyl group, rather than the high activation energies.

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“…Most studied amyloid beta (Aβ) peptides includes Aβ (1-16), Aβ (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19), Aβ (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34), Aβ (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33), Aβ , Aβ (23-34), Aβ (34)(35)(36)(37)…”

Section: Racemization Of the Aβmentioning

confidence: 99%

Chiral Interface of Amyloid Beta (Aβ): Relevance to Protein Aging, Aggregation and Neurodegeneration

2020

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Biochirality is the subject of distinct branches of science, including biophysics, biochemistry, the stereochemistry of protein folding, neuroscience, brain functional laterality and bioinformatics. At the protein level, biochirality is closely associated with various post-translational modifications (PTMs) accompanied by the non-equilibrium phase transitions (PhTs NE ). PTMs NE support the dynamic balance of the prevalent chirality of enzymes and their substrates. The stereoselective nature of most biochemical reactions is evident in the enzymatic (Enz) and spontaneous (Sp) PTMs (PTMs Enz and PTMs Sp ) of proteins. Protein chirality, which embraces biophysics and biochemistry, is a subject of this review. In this broad field, we focus attention to the amyloid-beta (Aβ) peptide, known for its essential cellular functions and associations with neuropathology. The widely discussed amyloid cascade hypothesis (ACH) of Alzheimer's disease (AD) states that disease pathogenesis is initiated by the oligomerization and subsequent aggregation of the Aβ peptide into plaques. The racemization-induced aggregation of protein and RNA have been extensively studied in the search for the contribution of spontaneous stochastic stereo-specific mechanisms that are common for both kinds of biomolecules. The failure of numerous Aβ drug-targeting therapies requires the reconsolidation of the ACH with the concept of PTMs Sp . The progress in methods of chiral discrimination can help overcome previous limitations in the understanding of AD pathogenesis. The primary target of attention becomes the network of stereospecific PTMs that affect the aggregation of many pathogenic agents, including Aβ. Extensive recent experimental results describe the truncated, isomerized and racemized forms of Aβ and the interplay between enzymatic and PTMs Sp . Currently, accumulated data suggest that non-enzymatic PTMs Sp occur in parallel to an existing metabolic network of enzymatic pathways, meaning that the presence and activity of enzymes does not prevent non-enzymatic reactions from occurring. PTMs Sp impact the functions of many proteins and peptides, including Aβ. This is in logical agreement with the silently accepted racemization hypothesis of protein aggregation (RHPA). Therefore, the ACH of AD should be complemented by the concept of PTMs Sp and RHPA.

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Racemization of Serine Residues Catalyzed by Dihydrogen Phosphate Ion: A Computational Study

Cited by 13 publications

References 55 publications

Topical Photodynamic Therapy with Different Forms of 5-Aminolevulinic Acid in the Treatment of Actinic Keratosis

Topical Photodynamic Therapy with Different Forms of 5-Aminolevulinic Acid in the Treatment of Actinic Keratosis

Predicting Reaction Mechanisms for the Threonine-Residue Stereoinversion Catalyzed by a Dihydrogen Phosphate Ion

Chiral Interface of Amyloid Beta (Aβ): Relevance to Protein Aging, Aggregation and Neurodegeneration

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