scholarly journals Molecular Mechanisms of Succinimide Formation from Aspartic Acid Residues Catalyzed by Two Water Molecules in the Aqueous Phase

2021 ◽  
Vol 22 (2) ◽  
pp. 509
Author(s):  
Tomoki Nakayoshi ◽  
Koichi Kato ◽  
Shuichi Fukuyoshi ◽  
Ohgi Takahashi ◽  
Eiji Kurimoto ◽  
...  
Keyword(s):  
Gas Phase ◽  
Aspartic Acid ◽  
Aqueous Phase ◽  
Molecular Mechanisms ◽  
Model Compound ◽  
Reaction Pathway ◽  
Single Point ◽  
Water Molecules ◽  
Age Related ◽  
Optimized Geometries

Aspartic acid (Asp) residues are prone to nonenzymatic isomerization via a succinimide (Suc) intermediate. The formation of isomerized Asp residues is considered to be associated with various age-related diseases, such as cataracts and Alzheimer’s disease. In the present paper, we describe the reaction pathway of Suc residue formation from Asp residues catalyzed by two water molecules using the B3LYP/6-31+G(d,p) level of theory. Single-point energies were calculated using the MP2/6-311+G(d,p) level of theory. For these calculations, we used a model compound in which an Asp residue was capped with acetyl and methylamino groups on the N- and C-termini, respectively. In the aqueous phase, Suc residue formation from an Asp residue was roughly divided into three steps, namely, iminolization, cyclization, and dehydration, with the activation energy estimated to be 109 kJ mol−1. Some optimized geometries and reaction modes in the aqueous phase were observed that differed from those in the gas phase.

On the stabilization of the carbonate dianion by sulfur dioxide

2010 ◽  
Vol 88 (11) ◽  
pp. 1125-1135 ◽  
Author(s):  
Friedrich Grein ◽  
Justin K. Chan ◽  
Idlir Liko
Keyword(s):  
Sulfur Dioxide ◽  
Oxygen Atom ◽  
Gas Phase ◽  
Single Point ◽  
Basis Set ◽  
Water Molecules ◽  
Electron Detachment ◽  
Optimized Geometries

The stabilization in the gas phase of the carbonate dianion [Formula: see text] by SO2 molecules is being investigated. The geometries of various isomers of [Formula: see text] (SO2)n and [Formula: see text] (SO2)n, for n = 1–4, have been optimized by the B3PW91/6−311+G(3df) method. Single-point CCSD and CCSD(T) energies at the DFT-optimized geometries were obtained for n = 1–3, using the 6−311+G(d) basis set. For n = 1 and 2, the monoanionic clusters are adiabatically more stable than the dianionic ones. However, starting at n = 3, they become less stable. The CCSD adiabatic electron detachment energy of the dianionic cluster switches from −0.39 eV for n = 2 to +0.20 eV for n = 3. The vertical electron detachment energy turns positive at n = 2, with a CCSD value of 1.35 eV. Several of the less stable dianionic, and most of the monoionic clusters, are characterized by the transfer of an oxygen atom from CO3 to SO2, forming [Formula: see text] or [Formula: see text] units, owing to [Formula: see text] + CO2 being more stable than [Formula: see text] + SO2. For the stabilization of the sulfate dianion by stepwise hydration, studied both experimentally and theoretically by other groups, a minimum of three water molecules was required.

scholarly journals Computational Study of the Dissociation Reactions of Secondary Ozonide

Atmosphere ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 100 ◽  
Author(s):  
Mansour H. Almatarneh ◽  
Shefa’ F. Alrebei ◽  
Mohammednoor Altarawneh ◽  
Yuming Zhao ◽  
Abd Al-Aziz Abu-Saleh
Keyword(s):  
Barrier Height ◽  
Computational Study ◽  
Reaction Pathway ◽  
Single Point ◽  
Water Dimer ◽  
Basis Set ◽  
Basis Sets ◽  
Water Molecules ◽  
Point Energy ◽  
Secondary Ozonide

This contribution presents a comprehensive computational study on the reactions of secondary ozonide (SOZ) with ammonia and water molecules. The mechanisms were studied in both a vacuum and the aqueous medium. All the molecular geometries were optimized using the B3LYP functional in conjunction with several basis sets. M06-2X, APFD, and ωB97XD functionals with the full basis set were also used. In addition, single-point energy calculations were performed with the G4MP2 and G3MP2 methods. Five different mechanistic pathways were studied for the reaction of SOZ with ammonia and water molecules. The most plausible mechanism for the reaction of SOZ with ammonia yields HC(O)OH, NH3, and HCHO as products, with ammonia herein acting as a mediator. This pathway is exothermic and exergonic, with an overall barrier height of only 157 kJ mol−1 using the G3MP2 method. All the reaction pathways between SOZ and water molecules are endothermic and endergonic reactions. The most likely reaction pathway for the reaction of SOZ with water involves a water dimer, in which the second water molecule acts as a mediator, with an overall barrier height of only 135 kJ mol−1 using the G3MP2 method. Solvent effects were found to incur a significant reduction in activation energies. When the second H2O molecule acts as a mediator in the reaction of SOZ with water, the barrier height of the rate-determining step state decreases significantly.

scholarly journals Theoretical Inversion of Amino Acids (Alanine and Aspartic Acid) by Semi-Empirical Methods

2013 ◽  
Vol 12 ◽  
pp. 37-44
Author(s):  
Musa E. Mohamed
Keyword(s):  
Activation Energy ◽  
Amino Acids ◽  
Transition State ◽  
Gas Phase ◽  
Aspartic Acid ◽  
Aqueous Phase ◽  
Free Amino ◽  
Membered Ring ◽  
Empirical Methods ◽  
Semi Empirical

The inversion reaction coordinate of free amino acids (alanine, aspartic acid) have been computationally calculated by semi-empirical methods AM1. A transition state for free alanine and aspartic acid were obtained as a three membered ring in which the α-C-H and α-C-CH3 are slightly elongated, 1.2 and 2.17 Å respectively in the alanine transition state. The activation energy of alanine is 77.52 kcal/mol in the gas phase and 76.66 kcal/mol in aqueous phase, and for aspartic acid is 54.87 kcal/mol in the gas phase and 50.86 kcal/mol in aqueous phase.

scholarly journals Computational Studies on Water-Catalyzed Mechanisms for Stereoinversion of Glutarimide Intermediates Formed from Glutamic Acid Residues in Aqueous Phase

2019 ◽  
Vol 20 (10) ◽  
pp. 2410
Author(s):  
Tomoki Nakayoshi ◽  
Shuichi Fukuyoshi ◽  
Koichi Kato ◽  
Eiji Kurimoto ◽  
Akifumi Oda
Keyword(s):  
Glutamic Acid ◽  
Gas Phase ◽  
Aqueous Phase ◽  
Density Functional ◽  
Activation Barrier ◽  
Lower Probability ◽  
Activation Barriers ◽  
Functional Methods ◽  
Age Related ◽  
Calculated Activation

Aspartic acid (Asp) residues are prone to non-enzymatic stereoinversion, and Asp-residue stereoinversion is believed to be mediated via a succinimide (SI) intermediate. The stereoinverted Asp residues are believed to cause several age-related diseases. However, in peptides and proteins, few studies have reported the stereoinversion of glutamic acid (Glu) residues whose structures are similar to that of Asp. We previously presumed that Glu-residue stereoinversion proceeds via a glutarimide (GI) intermediate and showed that the calculated activation barriers of SI- and GI-intermediate stereoinversion are almost equivalent in the gas phase. In this study, we investigated the stereoinversion pathways of the l-GI intermediate in the aqueous phase using B3LYP density functional methods. The calculated activation barrier of l-GI-intermediate stereoinversion in the aqueous phase was approximately 36 kcal·mol−1, which was much higher than that in the gas phase. Additionally, as this activation barrier exceeded that of Asp-residue stereoinversion, it is presumed that Glu-residue stereoinversion has a lower probability of proceeding under physiological conditions than Asp-residue stereoinversion.

Crystallins and hereditary cataracts: molecular mechanisms and potential for therapy

2006 ◽  
Vol 8 (25) ◽  
pp. 1-19 ◽  
Author(s):  
Usha P. Andley
Keyword(s):  
Molecular Mechanisms ◽  
Single Point ◽  
Point Mutations ◽  
Major Protein ◽  
Ageing Population ◽  
Age Related ◽  
Genes Encoding ◽  
Mechanisms Of Formation ◽  
Variable Morphology ◽  
Protein Components

Hereditary childhood cataracts can arise from single-point mutations in genes encoding crystallins, the major protein components of the lens. The cataracts are most commonly inherited by an autosomal dominant mechanism. The nature of the changes in the lens resulting from these point mutations in crystallin genes has not been fully characterised. While aggregation and light scattering associated with expression of the mutant crystallin protein may be an end point, it is also necessary to determine the progression of changes induced at the level of development and differentiation. A key finding in recent work is that cell death or cytotoxicity is associated with mutations in αA-crystallin. The variable morphology or localisation of the cataract in different pedigrees, even with the identical crystallin gene mutation, has led to the idea that other environmental or genetic factors interact to give the final lens phenotype. The study of mechanisms of formation of hereditary cataracts may lead to a greater understanding of the mechanisms that lead to age-related cataracts, a very common cause of blindness in the ageing population.

The Role of Vascular Aging in Atherosclerotic Plaque Development and Vulnerability

2019 ◽  
Vol 25 (29) ◽  
pp. 3098-3111 ◽  
Author(s):  
Luca Liberale ◽  
Giovanni G. Camici
Keyword(s):  
Atherosclerotic Plaque ◽  
Molecular Mechanisms ◽  
Driving Forces ◽  
Plaque Burden ◽  
Vascular Aging ◽  
Age Related ◽  
Plaque Development ◽  
Increased Risk ◽  
The Impact ◽  
Over Time

Background: The ongoing demographical shift is leading to an unprecedented aging of the population. As a consequence, the prevalence of age-related diseases, such as atherosclerosis and its thrombotic complications is set to increase in the near future. Endothelial dysfunction and vascular stiffening characterize arterial aging and set the stage for the development of cardiovascular diseases. Atherosclerotic plaques evolve over time, the extent to which these changes might affect their stability and predispose to sudden complications remains to be determined. Recent advances in imaging technology will allow for longitudinal prospective studies following the progression of plaque burden aimed at better characterizing changes over time associated with plaque stability or rupture. Oxidative stress and inflammation, firmly established driving forces of age-related CV dysfunction, also play an important role in atherosclerotic plaque destabilization and rupture. Several genes involved in lifespan determination are known regulator of redox cellular balance and pre-clinical evidence underlines their pathophysiological roles in age-related cardiovascular dysfunction and atherosclerosis. Objective: The aim of this narrative review is to examine the impact of aging on arterial function and atherosclerotic plaque development. Furthermore, we report how molecular mechanisms of vascular aging might regulate age-related plaque modifications and how this may help to identify novel therapeutic targets to attenuate the increased risk of CV disease in elderly people.

Molecular Mechanisms of Complement System Proteins and Matrix Metalloproteinases in the Pathogenesis of Age-Related Macular Degeneration

2019 ◽  
Vol 19 (10) ◽  
pp. 705-718 ◽  
Author(s):  
Naima Mansoor ◽  
Fazli Wahid ◽  
Maleeha Azam ◽  
Khadim Shah ◽  
Anneke I. den Hollander ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Macular Degeneration ◽  
Complement System ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Age Related Macular Degeneration ◽  
Genetic Changes ◽  
Complement System Proteins ◽  
Age Related ◽  
Common Genetic Variants

: Age-related macular degeneration (AMD) is an eye disorder affecting predominantly the older people above the age of 50 years in which the macular region of the retina deteriorates, resulting in the loss of central vision. The key factors associated with the pathogenesis of AMD are age, smoking, dietary, and genetic risk factors. There are few associated and plausible genes involved in AMD pathogenesis. Common genetic variants (with a minor allele frequency of >5% in the population) near the complement genes explain 40–60% of the heritability of AMD. The complement system is a group of proteins that work together to destroy foreign invaders, trigger inflammation, and remove debris from cells and tissues. Genetic changes in and around several complement system genes, including the CFH, contribute to the formation of drusen and progression of AMD. Similarly, Matrix metalloproteinases (MMPs) that are normally involved in tissue remodeling also play a critical role in the pathogenesis of AMD. MMPs are involved in the degradation of cell debris and lipid deposits beneath retina but with age their functions get affected and result in the drusen formation, succeeding to macular degeneration. In this review, AMD pathology, existing knowledge about the normal and pathological role of complement system proteins and MMPs in the eye is reviewed. The scattered data of complement system proteins, MMPs, drusenogenesis, and lipofusogenesis have been gathered and discussed in detail. This might add new dimensions to the understanding of molecular mechanisms of AMD pathophysiology and might help in finding new therapeutic options for AMD.

Review of the Literature Examining the Association of Serum Uric Acid with Osteoporosis and Mechanistic Insights into Its Effect on Bone Metabolism

2019 ◽  
Vol 19 (3) ◽  
pp. 259-273 ◽  
Author(s):  
Neelam Kaushal ◽  
Divya Vohora ◽  
Rajinder K Jalali ◽  
Sujeet Jha
Keyword(s):  
Risk Factors ◽  
Bone Mineral Density ◽  
Uric Acid ◽  
Bone Metabolism ◽  
Serum Uric Acid ◽  
Bone Mineral ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Mineral Density ◽  
Age Related

Background And Objective:Osteoporosis is a common bone disorder that increases susceptibility to fragility bone fractures. The clinical and public health repercussions of osteoporosis are huge due to the morbidity, mortality, and cost of medical care linked with fragility fractures. Clinical assessment of osteoporotic risk factors can help to identify candidates at an early stage that will benefit from medical intervention and potentially lowering the morbidity and mortality seen with fractures and complications. Given this, research is ongoing to evaluate the association of osteoporosis with some novel or less well-studied risk factors/bio-markers such as uric acid (UA).Discussion:Uric acid’s antioxidant activity has been proposed to be one of the factors responsible for increasing longevity and lowering rates of age-related cancers during primate evolution, the level of which increased markedly due to loss of uricase enzyme activity (mutational silencing). Accumulated evidence shows that oxidative stress is the fundamental mechanism of age-related bone loss and acts via enhancing osteoclastic activity and increasing bone resorption. Antioxidant substances such as ascorbic acid scavenge free radicals are positively related to bone health. Thus, it is hypothesized that uric acid holds bone-protective potential owing to its potent antioxidative property. Several correlation studies have been conducted globally to investigate the relationship between serum uric acid with bone mineral density and osteoporosis. Few pre-clinical studies have tried to investigate the interaction between uric acid and bone mineral density and reported important role played via Runt-related transcription factor 2 (RUNX2)/core-binding factor subunit alpha-1 (CBF-alpha-1), Wingless-related integration site (Wnt)-3a/β-catenin signaling pathway and 11β Hydroxysteroid Dehydrogenase type 1.Conclusion:In this review, the authors provided a comprehensive summary of the literature related to association studies reported in humans as well work done until date to understand the potential cellular and molecular mechanisms that interplay between uric acid and bone metabolism.

scholarly journals The Senescence-Associated Secretory Phenotype (SASP) in the Challenging Future of Cancer Therapy and Age-Related Diseases

Biology ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 485
Author(s):  
Lorenzo Cuollo ◽  
Fabrizio Antonangeli ◽  
Angela Santoni ◽  
Alessandra Soriani
Keyword(s):  
Cancer Therapy ◽  
Molecular Mechanisms ◽  
Therapeutic Strategies ◽  
Senescent Cell ◽  
Pharmacological Intervention ◽  
Tissue Microenvironment ◽  
Age Related ◽  
Secretory Phenotype ◽  
Novel Therapeutic Strategies ◽  
Novel Therapeutic

Cellular senescence represents a robust tumor-protecting mechanism that halts the proliferation of stressed or premalignant cells. However, this state of stable proliferative arrest is accompanied by the Senescence-Associated Secretory Phenotype (SASP), which entails the copious secretion of proinflammatory signals in the tissue microenvironment and contributes to age-related conditions, including, paradoxically, cancer. Novel therapeutic strategies aim at eliminating senescent cells with the use of senolytics or abolishing the SASP without killing the senescent cell with the use of the so-called “senomorphics”. In addition, recent works demonstrate the possibility of modifying the composition of the secretome by genetic or pharmacological intervention. The purpose is not to renounce the potent immunostimulatory nature of SASP, but rather learning to modulate it for combating cancer and other age-related diseases. This review describes the main molecular mechanisms regulating the SASP and reports the evidence of the feasibility of abrogating or modulating the SASP, discussing the possible implications of both strategies.

scholarly journals Crosstalk between Long-Term Sublethal Oxidative Stress and Detrimental Inflammation as Potential Drivers for Age-Related Retinal Degeneration

Antioxidants ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 25
Author(s):  
Lara Macchioni ◽  
Davide Chiasserini ◽  
Letizia Mezzasoma ◽  
Magdalena Davidescu ◽  
Pier Luigi Orvietani ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Age Related Macular Degeneration ◽  
Inflammasome Activation ◽  
Related Factor ◽  
Nuclear Factor ◽  
Rpe Cells ◽  
Age Related ◽  
Oxidative Insult

Age-related retinal degenerations, including age-related macular degeneration (AMD), are caused by the loss of retinal pigmented epithelial (RPE) cells and photoreceptors. The pathogenesis of AMD, deeply linked to the aging process, also involves oxidative stress and inflammatory responses. However, the molecular mechanisms contributing to the shift from healthy aging to AMD are still poorly understood. Since RPE cells in the retina are chronically exposed to a pro-oxidant microenvironment throughout life, we simulated in vivo conditions by growing ARPE-19 cells in the presence of 10 μM H2O2 for several passages. This long-term oxidative insult induced senescence in ARPE-19 cells without affecting cell proliferation. Global proteomic analysis revealed a dysregulated expression in proteins involved in antioxidant response, mitochondrial homeostasis, and extracellular matrix organization. The analyses of mitochondrial functionality showed increased mitochondrial biogenesis and ATP generation and improved response to oxidative stress. The latter, however, was linked to nuclear factor-κB (NF-κB) rather than nuclear factor erythroid 2–related factor 2 (Nrf2) activation. NF-κB hyperactivation also resulted in increased pro-inflammatory cytokines expression and inflammasome activation. Moreover, in response to additional pro-inflammatory insults, senescent ARPE-19 cells underwent an exaggerated inflammatory reaction. Our results indicate senescence as an important link between chronic oxidative insult and detrimental chronic inflammation, with possible future repercussions for therapeutic interventions.

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