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Aluminum's preferential binding site in proteins: Sidechain of amino acids versus backbone interactions
Abstract
The interaction of aluminum ion Al(III) with polypeptides is a subject of paramount importance, since it is a central feature to understand its deleterious effects in biological systems. Various drastic effects have been attributed to aluminum in its interaction with polypeptides and proteins. These interactions are thought to be established mainly through the binding of aluminum to phosphorylated and non-phosphorylated amino acid sidechains. However, a new structural paradigm has recently been proposed, in which aluminum interacts directly with the backbone of the proteins, provoking drastic changes in their secondary structure and leading ultimately to their denaturation. In the present paper, we use computational methods to discuss the possibility of aluminum to interact with the backbone of peptides and compare it with the known ability of aluminum to interact with amino acid sidechains. To do so, we compare the thermodynamics of formation of prototype aluminum-backbone structures with prototype aluminum-sidechain structures, and compare these results with previous data generated in our group in which aluminum interacts with various types of polypeptides and known aluminum biochelators. Our results clearly points to a preference of aluminum towards amino acid sidechains, rather than towards the peptide backbone. Thus, structures in which aluminum is interacting with the carbonyl group are only slightly exothermic, and they become even less favorable if the interaction implies additionally the peptide nitrogen. However, structures in which aluminum is interacting with negatively-charged sidechains like aspartic acid, or phosphorylated serines are highly favored thermodynamically.
... In this range of Al 3+ concentrations, the potential of BSA particles is close to zero, which promotes the aggregation of protein molecules. These particles can be formed by denatured protein aggregates 41 , which are also condensation centers for part of the native protein in the dispersion. ...
... www.nature.com/scientificreports/ trations of iron and aluminum salts can be explained by the effects associated with the metastable state of the protein solution-due to the influence of pH change caused by the hydrolysis of metal salts and the inversion of the protein charge 2 , and also, in the case of solutions with aluminum ions, due to interaction with main and side chains with possible denaturation 41 . ...
... mM AlCl 3 is not great enough to violate the crystallization conditions). The addition of 0.025 and 0.05 mM AlCl 3 also leads to an increase in the intensity of BSA fluorescence by 10-30% (Fig. 4a), which may be due AlCl 3 hydrolysis, as well as due to interaction with the protein backbone and amino acid side chains 10,41 . ...
The relationships between the structural and aggregational state of bovine serum albumin (BSA) and the specific length and total number of zigzag pattern segments of the film textures formed upon drying biopolymer solutions with aluminum and iron chlorides have been shown. To obtain films, saline solutions of BSA were dried in a glass cuvette under thermostatically controlled conditions. It is shown that the formation of zigzag structures is sensitive to the influence of aluminum chlorides Al³⁺ and iron chlorides Fe³⁺ and depend on the concentration of AlCl3 and FeCl3. This may be due to a change in the charge and size of BSA particles and due to a change in conformation or a violation of the structure of BSA. These factors, in turn, affect the hydration of the solution components and the structural state of free water in solution, which presumably also affects the formation of zigzag structures. It is established that the analysis of the specific length and the number of segments of zigzag patterns makes it possible to evaluate changes in the state of biopolymers in the initial solution during structural changes and aggregation.
... The first simulates the near-neutral lung-lining fluid, and the second mimics the acidic fluid that inhaled particles are exposed to after phagocytosis by alveolar macrophages [16,33]. The complexity of biologically relevant media (e.g., simulated lung fluids or cell culture media) may influence dissolution results due to the interaction of the dissolved fraction with specific media components [65][66][67] by increasing or inhibiting dissolution. The presence of ligands such as phosphate was shown to inhibit the dissolution of nano-MnO 2 [45] and nano-CeO 2 [44,55]. ...
... Consequently, the dissolved fraction measured for those specific combinations of analyte and media may be an underestimation of solubility; that is, an "apparent solubility" that represents the fraction not matrix-bound under the experimental conditions employed in the study. For example, released Al can interact either with proteins (their phosphate cofactor [66]) or with phosphate in the media [67], followed by aluminium phosphate precipitation, which may account for the observed losses by sedimentation. Similarly, in the case of nano-CeO 2 in PSF and Gamble, losses may be related to the presence of ligands, as phosphate has been shown to inhibit the dissolution of nano-CeO 2 by complexation with Ce ions, followed by precipitation [44,55]. ...
... In general, losses of analyte by sedimentation appears to be related to complexation of the dissolved fraction by specific media components [65][66][67]. Further research would be needed to identify the precise mechanism(s) causing these analyte losses. ...
Toxicological effects of metal-oxide-engineered nanomaterials (ENMs) are closely related to their distinct physical–chemical properties, especially solubility and surface reactivity. The present study used five metal-oxide ENMs (ZnO, MnO2, CeO2, Al2O3, and Fe2O3) to investigate how various biologically relevant media influenced dissolution behaviour. In both water and cell culture medium (DMEM), the metal-oxide ENMs were more soluble than their bulk analogues, with the exception that bulk-MnO2 was slightly more soluble in water than nano-MnO2 and Fe2O3 displayed negligible solubility across all tested media (regardless of particle size). Lowering the initial concentration (10 mg/L vs. 100 mg/L) significantly increased the relative solubility (% of total concentration) of nano-ZnO and nano-MnO2 in both water and DMEM. Nano-Al2O3 and nano-CeO2 were impacted differently by the two media (significantly higher % solubility at 10 mg/L in DMEM vs. water). Further evaluation of simulated interstitial lung fluid (Gamble’s solution) and phagolysosomal simulant fluid (PSF) showed that the selection of aqueous media significantly affected agglomeration and dissolution behaviour. The solubility of all investigated ENMs was significantly higher in DMEM (pH = 7.4) compared to Gamble’s (pH 7.4), attributable to the presence of amino acids and proteins in DMEM. All ENMs showed low solubility in Gamble’s (pH = 7.4) compared with PSF (pH = 4.5), attributable to the difference in pH. These observations are relevant to nanotoxicology as increased nanomaterial solubility also affects toxicity. The results demonstrated that, for the purpose of grouping and read-across efforts, the dissolution behaviour of metal-oxide ENMs should be evaluated using aqueous media representative of the exposure pathway being considered.
... En general, se encontró que la distancia O-Al(III) en los enlaces tipo Ph-O -(1,70Ǻ-1,75Ǻ) es menor en comparación con los tipos C=O y COO -(1,83Ǻ-1,95Ǻ), sugiriendo que la interacción con el aminoácido Tyr10 es más fuerte con respecto a otros ligandos oxigenados, lo cual es consistente con trabajos computacionales previos (Mujika et al., 2014;Mujika et al., 2017). Mujika et al. (2018), ya había sugerido que las estructuras en las que el aluminio interactúa con cadenas laterales cargadas negativamente como el ácido aspártico son altamente favorecidas termodinámicamente. Por otra parte, las interacciones N-Al(III) son más frecuentes en complejos pentacoordinados (CP) debiéndose principalmente a ligandos imidazólicos (ImN) con distancias de enlace que varían entre 1,88Ǻ y 2,03Ǻ y ligandos amínicos (RN), con distancias de 2,01Ǻ a 2,13Ǻ, respectivamente. ...
... Ahora bien, aunque en la literatura científica se reportan estudios experimentales de la interacción de Al(III) con βA, las investigaciones computacionales para estos sistemas moleculares son escasas(Strodel y Coskuner-Weber, 2019). Una serie de estudios basados en la teoría de los funcionales de la densidad (DFT, por sus siglas en inglés) examinaron la capacidad del aluminio(III) para unirse con algunas biomoléculas(Mujika et al., 2014), y también su actividad pro-oxidante(Mujika et al., 2011).En un estudio reciente,Mujika et al. (2018), plantearon que las interacciones se establecen principalmente mediante la unión del aluminio a cadenas laterales de aminoácidos fosforiladas y no fosforiladas. Sin embargo, recientemente se ha propuesto un nuevo paradigma estructural, en el que el aluminio interactúa directamente con la columna vertebral de las proteínas, provocando cambios drásticos en su estructura secundaria y conduciendo finalmente a su desnaturalización. ...
... Sin embargo, recientemente se ha propuesto un nuevo paradigma estructural, en el que el aluminio interactúa directamente con la columna vertebral de las proteínas, provocando cambios drásticos en su estructura secundaria y conduciendo finalmente a su desnaturalización. En dicho estudio, los resultados muestran la preferencia de aluminio(III) hacia las cadenas laterales de aminoácidos, en lugar del esqueleto peptídico(Mujika et al., 2018).Otras investigaciones recientes basadas en la DFT, buscan caracterizar el entorno de coordinación de Al(III) con βA, ya que esto es una pieza clave para entender las interacciones que ocurren en detalle molecular del metal con el péptido(Thaís et al., 2013). En este sentido, la química computacional surge como una valiosa herramienta que complementa los resultados experimentales, y al mismo tiempo provee de un conocimiento adicional sobre la unión entre el péptido βA con el ion metálico Al(III). ...
This research study examined computationally the geometric, electronic, and thermodynamic properties of a group of complexes formed by aluminum(III) and some amino acids present in the βA peptide, which are involved in the development of Alzheimer's disease. Density Functional Theory (DFT) was used for modeling complexes at the level of theory B3LYP/6-31+G(d,p) resulting in five-coordinated (CP) and four-coordinated (CT) compounds. There were aluminum(III) interactions with O and N ligands: phenolate (Ph-O-), carboxylate (COO-), carbonyl (C=O), amino (RN), and imidazole (ImN). The interactions with greater strength were phenolate and imidazole. In conclusion, the thermodynamic analyses of the structures examined showed that the five-coordinated complexes tend to be more stable than the four-coordinated complexes.
... Based on the Lewis acidbase theory, an aluminum ion can form a coordination bond with active sites of ligands, resulting in a distorted octahedral monodentate complex structure [37], an example of which is shown in Figure 1. Other forms of ligand-complexes [37,38] have previously been presented. ...
... Based on the Lewis acid-base theory, an aluminum ion can form a coordination bond with active sites of ligands, resulting in a distorted octahedral monodentate complex structure [37], an example of which is shown in Figure 1. Other forms of ligand-complexes [37,38] have previously been presented. Multiple types of physical and chemical interaction between protein and metal ions can take place simultaneously, some of which facilitate the formation of metallocomplexes. ...
Sustainable coating solutions that function as a fire retardant for wood are still a challenging topic for the academic and industrial sectors. In this study, composite coatings of casein protein mixed with mica and aluminum trihydroxide (ATH) were tested as fire retardants for wood and plywood; coating degradation and fire retardancy performance were assessed with a cone calorim-eter, and a thermogravimeter was used for the thermal stability measurement. The results indicated that casein-mica composites were beneficial as coatings. The heat release rate (HRR) and the total heat released (THR) of the sample coated with casein-mica composite were reduced by 55% and 37%, respectively; the time to ignition was increased by 27% compared to the untreated sample. However, the TTI of the sample coated with the casein-mica-ATH composite was increased by 156%; the PHR and THR were reduced by 31% and 28%, respectively. This is attributed to the yielded insulating surface layer, active catalytic sites, and the crosslink from mica and endothermic decomposition of ATH and casein producing different fragments which create multiple modes of action, leading to significant roles in suppressing fire spread. The multiple modes of action involved in the prepared composites are presented in detail. Coating wear resistance was investigated using a Taber Abrader, and adhesion interaction between wood and a coated composite were investigated by applying a pull-off test. While the addition of the three filler types to casein caused a decrease in the pull-off adhesion strength by up to 38%, their abrasion resistance was greatly increased by as much as 80%.
... On the other hand, once it has been internalized (Liu et al. 2019), Al will bind with biomolecules (Exley and Mold 2015). The Al-binding biomolecules would be difficult to dissociate and decompose, because Al can form strong bonds and structures with a diversity of biomolecules (Song et al. 2014;Exley and Mold 2015;Mujika et al. 2018). In a summary of these various factors, our recent review paper suggested that Al may play an important role in the ocean carbon cycle and climate change, by enhancing carbon fixation in the upper ocean and by facilitating carbon export and sequestration in ocean depths by reducing the decomposition and decay of organic matter (Zhou et al. 2018b). ...
... This incorporation can reduce the dissolution rate of the frustule, and potentially reduce the degradation rate of the frustule-associated organic carbon (Abramson et al. 2009). Second, Al can react with biomolecules in biological systems to form strong bonds and structures (Song et al. 2014;Exley and Mold 2015;Mujika et al. 2018), which are potentially difficult to dissociate and decompose (Zhou et al. 2018b). As a result, Al could delay the breaking down (or lysis) of diatom cells and decrease the decomposition rate of the diatom-produced POC. ...
Recent studies indicate that aluminum (Al) could play an important role in the ocean carbon cycle by increasing phytoplankton carbon fixation and reducing organic carbon decomposition. However, how Al may influence the decomposition of organic carbon has not yet been explicitly examined. Here we report the effects of Al on carbon fixation by marine diatoms and their subsequent decomposition. By using radiocarbon as a tracer, the carbon fixation and decomposition of three model marine diatoms were examined in Aquil* media at different concentrations (0, 40, 200, and 2000 nM) of dissolved Al. Addition of Al enhanced net carbon fixation by the diatoms in the declining growth phase (by 9%–29% for Thalassiosira pseudonana, 15%–20% for T. oceanica, 15%–23% for T. weissflogii). Under axenic conditions the decomposition rates (d−1) of the diatom‐produced particulate organic carbon (POC) significantly decreased (by 21%–57% for T. pseudonana, 0%–41% for T. oceanica, 29%–58% for T. weissflogii) in the Al‐enriched treatments. In the presence of bacteria, the decomposition rates of T. weissflogii‐produced POC were still 37%–38% lower in Al‐enriched treatments compared to the control. Significant increases in cell size, cellular carbon content (pmol C/cell) and cellular carbon density (pmol C/μm3) of T. weissflogii were also observed in the Al‐enriched treatments compared to the control. The Al‐related increase in net carbon fixation and cell size, and the decrease in POC decomposition rate may facilitate carbon export to ocean depths. The study provides new evidence for the iron–aluminum hypothesis, which suggests that Al could increase phytoplankton uptake of atmospheric CO2 and influence climate change.
... A series of studies from Mujika et al. used density functional theory (DFT) to examine the pro-oxidant activity of Al [19], its binding to biomolecules [23] including metal-transport proteins [24,25] and neurotransmitters [26]. Most relevant for this work, the same group showed that Al(III) has a clear preference for anionic sidechains of peptides over backbone carbonyl or water [27], and that coordination numbers of 5 or 6 are preferred over lower values [28]. The latter study also sets out a template-based method for location of likely binding modes of Aβ, identifying Glu3, Asp7 and Glu11 as the preferred sites of interaction. ...
... It is important to assess the suitability of the GFN2-XTB method for the description of Al-peptide binding. To do so, we adopt two model systems previously used by Mujika et al. [27], namely Asp-Al(H 2 O) 5 and Ala-Ala-Asp(Al(H 2 O) 5 -Ala-Ala, denoted Al-A and Al-AADAA, respectively. Both were fully optimized at DFT and GFN2-XTB level, within implicit aqueous solvent. ...
We report semi-empirical tight-binding simulations of the interaction between Al(III) and biologically relevant peptides. The GFN2-XTB method is shown to accurately reproduce previously reported and density functional theory (DFT)-calculated geometries of model systems. Molecular dynamics simulations based on this method are able to sample peptide flexibility over timescales of up to nanoseconds, but these timescales are insufficient to explore potential changes in metal-peptide binding modes. To achieve this, metadynamics simulations using root mean square deviation as a collective variable were employed. With suitably chosen biasing potentials, these are able to efficiently explore diverse coordination modes, for instance, through Glu and/or Asp residues in a model peptide. Using these methods, we find that Al(III) binding to the N-terminal sequence of amyloid-β is highly fluxional, with all acidic sidechains and several backbone oxygens participating in coordination. We also show that such simulations could provide a means to predict a priori possible binding modes as a precursor to longer, atomistic simulations.
... However, it should be always taken into account that, despite the presence of this small but yet important covalent character, the Al-ligand bond is mainly ionic/electrostatic driven, a factor that shifts the preferential binding of Al(III) to negatively charged donors such as the carboxylate donors of protein siechains 24 . It is important to emphasize that the above discussion is mainly the fruit of some of the results achieved in this thesis dissertation, that will be presented and more deeply discussed in chapters 3-7. ...
... This is due to the fact that H + is also a hard acid according to the HSAB principle 20 (Table 1.1). Such a situation is reflected by the increase of the protonation constants of the INTRODUCTION such as those that can be found in the backbone of proteins, are not competitive Al(III) binders when compared to carboxylates that are found in the sidechains of peptides 24 (see chapter 5). ...
... Aluminum found in the granule fraction in the diatom might be bound to polyphosphate bodies, given that Al is classified as a "hard" cation, a Class A metal, with a strong preference for ligands with oxygen donor atoms (e.g., phosphate) (Mujika et al., 2018). Polyphosphate-bound Fe has been identified as a potential vacuolar Fe storage pool in T. weissflogii (Nuester et al., 2012). ...
... Metal-rich granules are associated with metal tolerance in many organisms and are considered to play an important role in the detoxification of many trace metals (Crémazy et al., 2013b;Vijver et al., 2004). The presence of Al in the HSP and HDP subcellular components in the diatom is consistent with the findings that oxygen-containing amino acids are the preferential coordination site of Al, and that Al can complex with amino acids (Mujika et al., 2018). ...
Aluminum (Al) is widespread in the environment including the ocean. The effects of Al on marine organisms have attracted more and more attention in recent years. However, the mechanisms of uptake of Al by marine organisms and the subcellular distribution of Al once assimilated are unknown. Here we report the uptake and subcellular distribution of Al in a marine diatom Thalassiosira weissflogii. Short-term (< 120 min) uptake experiments showed that the Al uptake rate by the diatom was 0.033 ± 0.013 fmol-1 cell-1 min-1 (internalization flux normalized to the exposure Al concentration of 2 µM = 0.034 ± 0.013 nmol m −2 min −1 nM −1). Subcellular fractionation experiments showed that the internalized Al was partitioned to subcellular components in the following order: granules (69 ± 5%) > debris (17 ± 4%) > organelles (12 ± 2%) > heat-stable peptides (HSP) (~2%) > heat-denaturable proteins (HDP) (< 1%), indicating that the majority of intracellular Al was detoxified and stored in inorganic forms. The subcellular distribution of Al in the diatom is different from that of Al in freshwater green algae, in which most of the internalized Al is partitioned to organelles. We also evaluated an artificial seawater-based EDTA rinse solution to remove Al adsorbed on the diatom cell surface. Overall, our study provides new information to understand the mechanisms of uptake of Al by marine diatoms, and the mechanisms responsible for the biological effects (both toxic and beneficial) of Al on the growth of marine phytoplankton, especially diatoms.
... Aluminum found in the granule fraction in the diatom might be bound to polyphosphate bodies, given that Al is classified as a "hard" cation, a Class A metal, with a strong preference for ligands with oxygen donor atoms (e.g., phosphate) (Mujika et al., 2018). Polyphosphate-bound Fe has been identified as a potential vacuolar Fe storage pool in T. weissflogii (Nuester et al., 2012). ...
... Metal-rich granules are associated with metal tolerance in many organisms and are considered to play an important role in the detoxification of many trace metals (Crémazy et al., 2013b;Vijver et al., 2004). The presence of Al in the HSP and HDP subcellular components in the diatom is consistent with the findings that oxygen-containing amino acids are the preferential coordination site of Al, and that Al can complex with amino acids (Mujika et al., 2018). ...
Aluminum (Al) is widespread in the environment including the ocean. The effects of Al on marine organisms have attracted more and more attention in recent years. However, the mechanisms of uptake of Al by marine organisms and the subcellular distribution of Al once assimilated are unknown. Here we report the uptake and subcellular distribution of Al in a marine diatom Thalassiosira weissflogii. Short-term (< 120 min) uptake experiments showed that the Al uptake rate by the diatom was 0.033 ± 0.013 fmol⁻¹ cell⁻¹ min⁻¹ (internalization flux normalized to the exposure Al concentration of 2 µM = 0.034 ± 0.013 nmol m⁻² min⁻¹ nM⁻¹). Subcellular fractionation experiments showed that the internalized Al was partitioned to subcellular components in the following order: granules (69 ± 5%) > debris (17 ± 4%) > organelles (12 ± 2%) > heat-stable peptides (HSP) (~2%) > heat-denaturable proteins (HDP) (< 1%), indicating that the majority of intracellular Al was detoxified and stored in inorganic forms. The subcellular distribution of Al in the diatom is different from that of Al in freshwater green algae, in which most of the internalized Al is partitioned to organelles. We also evaluated an artificial seawater-based EDTA rinse solution to remove Al adsorbed on the diatom cell surface. Overall, our study provides new information to understand the mechanisms of uptake of Al by marine diatoms, and the mechanisms responsible for the biological effects (both toxic and beneficial) of Al on the growth of marine phytoplankton, especially diatoms.
... Third, Al can substitute for other cations (e.g., Mg) in biological systems, reacting with biomolecules to form strong bonds that are slow to dissociate (Exley and Mold 2015;Williams 1996). In addition, Al can induce the formation of strong structures in a wide range of peptides, through binding amino acid sidechains (Mujika et al. 2018). Binding to the peptide backbone has also been considered (Mujika et al. 2014;Song et al. 2014) but is less favored (Mujika et al. 2018). ...
... In addition, Al can induce the formation of strong structures in a wide range of peptides, through binding amino acid sidechains (Mujika et al. 2018). Binding to the peptide backbone has also been considered (Mujika et al. 2014;Song et al. 2014) but is less favored (Mujika et al. 2018). As a result, Al may make organic carbon more difficult to decompose, again leading to greater and longer sequestration in the ocean depths. ...
In contrast to substantial studies and established knowledge of aluminum (Al) effects (mainly toxicity) on freshwater organisms and terrestrial plants, and even on human health, only a few studies of Al effects on marine organisms have been reported, and our understanding of the role of Al in marine biogeochemistry is limited. In this paper, we review the results of both field and laboratory experiments on the effects of Al on marine organisms, including Al toxicity to marine phytoplankton and the beneficial effects of Al on marine phytoplankton growth, and we discuss possible links of Al to the biological pump and the global carbon cycle. We propose a revised Iron (Fe) Hypothesis, i.e., the Fe–Al Hypothesis that introduces the idea that Al as well as Fe play an important role in the glacial-interglacial change in atmospheric CO2 concentrations and climate change. We propose that Al could not only facilitate Fe utilization, dissolved organic phosphorus utilization and nitrogen fixation by marine phytoplankton, enhancing phytoplankton biomass and carbon fixation in the upper oceans, but also reduce the decomposition and decay of biogenic matter. As a result, Al allows potentially more carbon to be exported and sequestered in the ocean depths through the biological pump. We also propose that Al binds to superoxide to form an Al-superoxide complex, which could catalyze the reduction of Fe(III) to Fe(II) and thus facilitate Fe utilization by marine phytoplankton and other microbes. Further ocean fertilization experiments with Fe and Al are suggested, to clarify the role of Al in the stimulation of phytoplankton growth and carbon sequestration in the ocean depths.
... Due to its strong pro-oxidative nature, Al can cause oxidative damage in tissue exposed to it. 5 Physiologically the negative effects of ROS are effectively prevented by the body's efficient antioxidant system. Both enzymatic antioxidants like Superoxide Dismutase (SOD), Catalase, Glutathione Peroxidase (GPx), and Glutathione Reductase (GR) and nonenzymatic antioxidants like reduced Glutathione (GSH), ascorbic acid and tocopherol are involved in the removal of ROS. 6 However, aluminium exposure can also lead to a reduction in cell level antioxidant handling capacity directly or indirectly and create a state of oxidative stress. ...
... Los efectos tóxicos del Al surgen principalmente de su prooxidante actividad que resulta en estrés oxidativo, radicales libres ataque y oxidación de proteínas y lípidos celulares. Los polipéptidos de proteínas se transforman en estructuras secundarias cuando los iones de Al interactúan con ellos a través de aminoácidos que contienen oxígeno, cadenas laterales y el esqueleto de la proteína, lo que conduce a la desnaturalización final o alteración conformacional o estructural (Mujika & Torre, 2018). ...
El aluminio es uno de los metales más utilizados a nivel doméstico y comercial, debido a esto se ha observado un incremento notorio en personas con intoxicación por aluminio representando un problema de salud mundial que afecta a muchos órganos. El cloruro de aluminio es un compuesto de aluminio y cloro utilizado como catalizador en la industria petrolera además de sus usos en la industria farmacéutica, química, cosmética, textil, entre otros. Es una sustancia corrosiva para los ojos, la piel y el tracto respiratorio, por lo que se considera una sustancia nociva cuando se dispersa en el aire alcanzando concentraciones que afectan la salud humana. Los residuos de compuestos de aluminio se pueden encontrar en el agua potable, los alimentos, el aire, los medicamentos, los desodorantes, los cosméticos, los envases, muchos electrodomésticos y equipos, los edificios, las industrias del transporte, entre otros. La intoxicación por cloruro de aluminio puede afectar el contenido de la sangre, el sistema musculoesquelético, los riñones, el hígado, el sistema respiratorio y el sistema nervioso, El alcance de la intoxicación se puede diagnosticar analizando los compuestos de aluminio en la sangre, la orina, el cabello, las uñas y el sudor. Tomando en consideración los efectos complejos y multidimensionales que la intoxicación por aluminio produce debido a la exposición de altos niveles de compuestos de aluminio, se presenta una revisión de bibliografía donde se exponen los efectos que produce en personas del ámbito ocupacional.
... However, recent studies indicated that chronic ingestion of synthetic metal chelators can lead to other chronic toxicities in animals (Samal et al., 2016). For instance, aluminum has been shown to induce oxidative stress (Exley, 2013), immunological perturbations (Mujika et al., 2018), genotoxicity (Nam et al., 2014), and metabolic dysregulation. Moreover, it had shown pathological conditions associated with aluminum such as pulmonary alveolar proteinosis (Iijima et al., 2017), granulomatosis and fibrosis (Igbokwe et al., 2019), toxicmyocarditis (El Hangouche et al., 2017), infertility (Malekshah et al., 2005), neurodegenerative, and hepatorenal disease in animals (Igbokwe et al., 2019). ...
In Morocco, ruminant breeding is a sector with significant socioeconomic value. It contributes to the red meat national production and also provides jobs for a large rural population as well as being the main source of income for most livestock breeders. However, in phosphate areas, this sector is facing environmental poisoning due to an excess of fluoride. The chronic ingestion and/or inhalation of this element by ruminants exerts various toxic effects influencing the animal's performance and thus leading to significant socioeconomic consequences. Data from previous studies concerning the geographic distribution of fluorosis in Morocco, the metabolism of fluoride in ruminants, and its harmful effects, namely dental, skeletal, and non-skeletal fluorosis in ruminants (sheep, goats, cattle) is clearly summarized in this review. Moreover, the socioeconomic impact and the updated progress in the prevention or reducing fluorosis are reviewed. This review highlights the need to further investigate endemic fluorosis in ruminants.
... It has no physiological role of Al in metabolic processes but it can be toxic to humans and animals when the metal's body burden is elevated after natural or unnatural exposure. Currently, the provisional tolerable weekly intake (PTWI) is set at 2 mg/kg/wk [1,2] Al induce numerous toxic effects such as immunological alterations, genotoxicity, pro-in ammatory effect, peptide denaturation or transformation, enzymatic dysfunction, metabolic derangement, amyloidogenesis, membrane perturbation, iron dyshomeostasis, apoptosis, necrosis and dysplasia but the major toxic action of Al is to generate oxidative stress by producing reactive free radicals that may overwhelm the cell's antioxidant defenses to perpetrate cell damage [3][4][5][6]. ...
Aluminum (Al) is one of the more widespread metals in the environment used in various fields and the most abundant known for its neurotoxicity in both humans and animals and could be a potential factor inducing behavioral changes, oxidative stress (OS) and loss of synapses and neurons in the hippocampal and cerebral cortical areas. The main objective of this study is to determine the short-term impact of a single 2 μl intracerebral injection of AlCl 3 at different doses on the right hippocampus on affective and cognitive behaviour, on levels of oxidative stress and morphological changes in male Wistar rats. Rats were treated with a single intrahippocampal injection of 2 μL of NaCl (0.9%) (Control) or successively with 2 μL of AlCl 3 at 0.5 mg/Kg (Al-0.5), 1 mg/Kg (Al-1) and 2 mg/Kg (Al-2). Five days following surgical procedures, neurobehavioral tests were performed for all groups (OFT, EPM, FST, Y-maze and MWM) and the brain were taken to isolate the hippocampus from adjacent tissues to prepare homogenates for the determination of oxidative stress markers and to examine the morphological change in CA3 hippocampal area. The results clearly demonstrate that Al induced anxiety and depressive-like behaviours, cognitive deficit, increased lipid peroxidation (LPO), nitric oxide (NO) levels, decreased superoxide dismutase (SOD) activity in the hippocampus and mediates progressive alterations characterized by disorganization in the pyramidal cellular arrangement and a decrease in neuronal density in the CA3 hippocampal area. In conclusion, a single intrahippocampal injection of Al induced anxiety-like, depression-like, memory impairment, OS and morphological alterations in the hippocampus.
... In a recently proposed paradigm, it has been suggested that Al can interact directly with the backbone of proteins. In this study, it was suggested that Al coordinates directly to the carbonyl oxygen and protonated peptide nitrogen, occurring in stable structures with a 5-membered ring that forms strong covalent bonds, and can interact directly with the backbone of proteins [22]. It was reported that the patients affected by Al intoxication were treated successfully with the ethylenediaminetetraacetic acid (EDTA) as chelating agent over a short period (Table 1) [23]. ...
Heavy metals are essential for a wide range of biological processes, including the growth and reproduction of cells, synthesis of biomolecules, many enzymatic reactions, and the body’s immunity, but their excessive intake is harmful. Specifically, they cause oxidative stress (OS) and generate free radicals and reactive oxygen species (ROS) in metabolism. In addition, the accumulation of heavy metals in humans can cause serious damage to different organs, especially respiratory, nervous and reproductive and digestive systems. Biologically, metal chelation therapy is often used to treat metal toxicity. This process occurs through the interaction between the ligand and a central metal atom, forming a complex ring-like structure. After metals are chelated with appropriate chelating agents, their damage in metabolism can be prevented and efficiently removed from the body. On the other hand, heavy metals, including Zn, Fe and Cu, are necessary for the suitable functioning of different proteins including enzymes in metabolism. However, when the same metals accumulate at levels higher than the optimum level, they can easily become toxic and have harmful effects toward biomolecules. In this case, it induces the formation of ROS and nitrogen species (RNS) resulting in peroxidation of biological molecules such as lipids in the plasma membrane. Antioxidants have an increasing interest in many fields due to their protective effects, especially in food and pharmaceutical products. Screening of antioxidant properties of compounds needs appropriate methods including metal chelating assay. In this study, a general approach to the bonding and chelating properties of metals is described. For this purpose, the basic principles and chemical principles of metal chelation methods, both in vivo and in vitro, are outlined and discussed. Hence, in the main sections of this review, the descriptions related to metal ions, metal chelating, antioxidants, importance of metal chelating in biological system and definitions of metal chelating assays as widely used methods to determine antioxidant ability of compounds are provided. In addition, some chemical properties, technical and critical details of the used chelation methods are given.
... Nevertheless, recent toxicological studies report that the daily intake of aluminum derived from food ranges from 3.4 to 9 mg/day, thus continuing to pose a serious concern to public health due to an overdosage [1,12]. In fact, several reports highlight the toxic role of aluminum, including, but not limited to, the induction of oxidative stress [13], organ inflammation [14], immunosuppression [13], protein denaturation and transformation [15], apoptosis [13] and endocrine disruption [16]. ...
Aluminum is the second most widely used metal worldwide. It is present as an additive in cosmetics, pharmaceuticals, food, and food contact materials (FCM). In this study, we confirm the bactericidal effect of a special anodizing method, based on TiO2 nanoparticles (DURALTI®) deposited on aluminum disks with different roughness and subjected to two sanitizing treatments: UV and alcohol 70%. Consequently, we perform a time-course evaluation against both Gram-negative and
Gram-positive bacteria to better frame the time required to achieve the best result. Approximately 106 CFU/mL of Escherichia coli ATCC 25922; Salmonella Typhimurium ATCC 1402; Yersinia enterocolitica ATCC 9610; Pseudomonas aeruginosa ATCC 27588; Staphylococcus aureus ATCC 6538; Enterococcus faecalis ATCC 29212; Bacillus cereus ATCC 14579 and Listeria monocytogenes NCTT 10888 were inoculated onto each aluminum surface and challenged with UV and alcohol 70% at 0, 15”, 30”, 1', 5', 15', 30',1, 2, 4 and 6 h. DURALTI® coating already confirmed its ability to induce a 4-logarithmic decrease (from 106 to 102 CFU/mL) after 6 h. Once each sanitizing treatment was applied, an overall bacterial
inhibition occurred in a time ranging from 15'' to 1'. The results are innovative in terms of preventing microbial adhesion and growth in the food industry.
... Although there can be other donors to hard metal ions, such as backbone carbonyl and amide groups of proteins, by virtue of the partial covalent nature of the coordination bond, these donors are less competitive. Indeed, we recently demonstrated, from a thermodynamic perspective, that the preferred binding sites of Al 3+ in proteins are the negatively charged side chains of amino acids rather than the backbone carbonyl and amide groups [28]. ...
Thymosin β4 (Tβ4) was extracted forty years agofrom calf thymus. Since then, it has been identified as a G-actin binding protein involved in blood clotting, tissue regeneration, angiogenesis, and anti-inflammatory processes. Tβ4 has also been implicated in tumor metastasis and neurodegeneration. However, the precise roles and mechanism(s) of action of Tβ4 in these processes remain largely unknown, with the binding of the G-actin protein being insufficient to explain these multi-actions. Here we identify for the first time the important role of Tβ4 mechanism in ferroptosis, an iron-dependent form of cell death, which leads to neurodegeneration and somehow protects cancer cells against cell death. Specifically, we demonstrate four iron2+ and iron3+ binding regions along the peptide and show that the presence of Tβ4 in cell growing medium inhibits erastin and glutamate-induced ferroptosis in the macrophage cell line. Moreover, Tβ4 increases the expression of oxidative stress-related genes, namely BAX, hem oxygenase-1, heat shock protein 70 and thioredoxin reductase 1, which are downregulated during ferroptosis. We state the hypothesis that Tβ4 is an endogenous iron chelator and take part in iron homeostasis in the ferroptosis process. We discuss the literature data of parallel involvement of Tβ4 and ferroptosis in different human pathologies, mainly cancer and neurodegeneration. Our findings confronted with literature data show that controlled Tβ4 release could command on/off switching of ferroptosis and may provide novel therapeutic opportunities in cancer and tissue degeneration pathologies.
... That is, the oxidation state +3 of aluminum in a biological system is maintained unaltered in different biochemical environments, as demonstrated recently. 15 However, this does not imply that aluminum can not alter important redox cycles 16 in vitro and in vivo. The early hypothesis of the possibility of forming an aluminum-superoxide complex, 14 which would augment the lifetime of this radical species, has been proven computationally. ...
The increased bioavailability of aluminum has led to a concern about its toxicity on living systems. Among the most important toxic effects, it has been proven that aluminum increases oxidative stress in biological systems, a controversial fact, however, due to its non-redox nature. In the present work, we characterize in detail how aluminum can alter redox equilibriums by analyzing its effects on the thermodynamics of the redox scavenging reaction between DPPH . , a radical compound often used as a reactive oxygen species model, and hydroquinones, a potent natural antioxidant. For the first time, theoretical and experimental redox potentials within aluminum biochemistry are directly compared. Our results fully agree with experimental reduction and oxidation potentials, unequivocally revealing how aluminum alters the spontaneity of the reaction by stabilizing the reduction of DPPH· to DPPH − and promoting a proton transfer to the diazine moiety, leading to the production of a DPPH-H species. The capability of aluminum to modify redox potentials shown here confirms previous experimental findings on the role of aluminum to interfere with free radical scavenging reactions, affecting the natural redox processes of living organisms.
... After its deposition, aluminum-induced toxicity is achieved through many diverse pathways; the following being the most studied: oxidant/antioxidant/apoptosis [8], pro-inflammatory [9], immunosuppression [10], and interference with enzymes, proteins and metabolism [11]. ...
Introduction/Objective. Research has demonstrated the toxicant potential of aluminum, but no therapeutic options have been suggested. The aim of the study was to investigate the extent of the aluminum-induced toxicity, evaluated by hematological/biochemical disarrangements, hepcidin concentration and tissue accumulation after chronic aluminum exposure and to determine possible protection with Ca2+-channel blockage, verapamil. Methods. Experimental animals (36 rats) were treated with different doses of AlCl3 during 8 weeks and after that their blood and tissues were analyzed. Results. The significant differences, regardless of the aluminum dose administered, were documented in all evaluated hematological (p
... No essential function of aluminium in any biochemical system or in any organism is known [47], although aluminium ions, as many other metal ions, have the potential of interacting with biomolecules and biological pathways. In vitro, Al 3+ has been shown to form complexes with biomolecules such as carboxylates, phosphates, nucleotides [48], and it may interact with proteins altering the 3D structure [49,50] and thus inhibit or modulate enzyme activity [51]. Also, Al 3+ can compete with biologically relevant metal ions such as Ca 2+ , Mg 2+ , Zn 2+ , Fe 2+ , and Fe 3+ . ...
Aluminium salts have been used as adjuvants in vaccines for almost a century, but still no clear understanding of the mechanisms behind the immune stimulating properties of aluminium based adjuvants is recognized. Aluminium adjuvants consist of aggregates and upon administration of a vaccine, the aggregates will be recognized and phagocytosed by sentinel cells such as macrophages or dendritic cells. The adjuvant aggregates will persist intracellularly, maintaining a saturated intracellular concentration of aluminium ions over an extended time. Macrophages and dendritic cells are pivotal cells of the innate immune system, linking the innate and adaptive immune systems, and become inflammatory and antigen-presenting upon activation, thus mediating the initiation of the adaptive immune system. Both types of cell are highly adaptable, and this review will discuss and highlight how the occurrence of intracellular aluminium ions over an extended time may induce the polarization of macrophages into inflammatory and antigen presenting M1 macrophages by affecting the: endosomal pH; formation of reactive oxygen species (ROS); stability of the phagosomal membrane; release of damage associated molecular patterns (DAMPs); and metabolism (metabolic re-programming). This review emphasizes that a persistent intracellular presence of aluminium ions over an extended time has the potential to affect the functionality of sentinel cells of the innate immune system, inducing polarization and activation. The immune stimulating properties of aluminium adjuvants is presumably mediated by several discrete events, however, a persistent intracellular presence of aluminium ions appears to be a key factor regarding the immune stimulating properties of aluminium based adjuvants.
... Aluminum is known to bind to the microtubuleassociated protein tau and especially upon its hyperphosphorylation forming aberrant insoluble NFTs [48]. Intraneuronal NFTs are frequently observed in the cerebral cortex of fAD, PD, and epilepsy patients, collectively prompting our study to probe their intracellular presence [7,14,17,27]. ...
Background:
Protein misfolding disorders are frequently implicated in neurodegenerative conditions. Familial Alzheimer’s disease (fAD) is an early-onset and aggressive form of Alzheimer’s disease (AD), driven through autosomal dominant mutations in genes encoding the amyloid precursor protein and presenilins 1 and 2. The incidence of epilepsy is higher in AD patients with shared neuropathological hallmarks in both disease states, including the formation of neurofibrillary tangles. Similarly, in Parkinson’s disease, dementia onset is known to follow neurofibrillary tangle deposition.
Objective:
Human exposure to aluminum has been linked to the etiology of neurodegenerative conditions and recent studies have demonstrated a high level of co-localization between amyloid-β and aluminum in fAD. In contrast, in a donor exposed to high levels of aluminum later developing late-onset epilepsy, aluminum and neurofibrillary tangles were found to deposit independently. Herein, we sought to identify aluminum and neurofibrillary tangles in fAD, Parkinson’s disease, and epilepsy donors.
Methods:
Aluminum-specific fluorescence microscopy was used to identify aluminum in neurofibrillary tangles in human brain tissue.
Results:
We observed aluminum and neurofibrillary-like tangles in identical cells in all respective disease states. Co-deposition varied across brain regions, with aluminum and neurofibrillary tangles depositing in different cellular locations of the same cell.
Conclusion:
Neurofibrillary tangle deposition closely follows cognitive-decline, and in epilepsy, tau phosphorylation associates with increased mossy fiber sprouting and seizure onset. Therefore, the presence of aluminum in these cells may exacerbate the accumulation and misfolding of amyloidogenic proteins including hyperphosphorylated tau in fAD, epilepsy, and Parkinson’s disease.
... [28] To date, several simulation studies on the interaction of aluminium with Aβ have been reported, focussing on the binding modes of Al(III) with Aβ and the resulting morphology of Al-Aβ aggregates. [29,30] Recently, Mujika et al used a computational approach to generate 3D models of Al(III) bound to the N-terminal Aβ16 fragment of Aβ in a 1:1 stoichiometry. [31] Here, Al shows a clear preference for coordination by carboxylate groups (Glu3, Asp7 and Glu11) with the remaining coordination sites occupied by backbone carbonyl moieties or water molecules. ...
Multiple microsecond-length molecular dynamics simulations of complexes of Al(III) with amyloid-β (Aβ) peptides of varying length are reported, employing a non-bonded model of Al-coordination to the peptide, which is modelled using the AMBER ff14SB forcefield. Individual simulations reach equilibrium within 100 to 400 ns, as determined by root mean square deviations, leading to between 2.1 and 2.7 μs of equilibrated data. These reveal a compact set of configurations, with radius of gyration similar to that of the metal free peptide but larger than complexes with Cu, Fe and Zn. Strong coordination through acidic residues Glu3, Asp7 and Glu11 is maintained throughout all trajectories, leading to average coordination numbers of approximately 4 to 5. Helical conformations predominate, particularly in the longer Al-Aβ40 and Al-Aβ42 peptides, while β-strand forms are rare. Binding of the small, highly charged Al(III) ion to acidic residues in the N-terminus strongly disrupts their ability to engage in salt bridges, whereas residues outside the metal binding region engage in salt bridges to similar extent to the metal-free peptide, including the Asp23-Lys28 bridge known to be important for formation of fibrils. High helical content and disruption of salt bridges leads to characteristic tertiary structure, as shown by heat maps of contact between residues as well as representative clusters of trajectories.
The nitrogen atom of 2,6-di-tert-butyl-N,N-diethylpyridin-4-amine (DEAP) is not available for non-covalent interactions. This molecule has been used to define the reference 15N NMR absolute chemical shielding (σref) required to convert between the chemical shift scale used in experiments and the absolute shielding scale used in theoretical calculations. The accuracy of the obtained σref was tested for solid samples of acetanilide-15N, the protonated homodimer of pyridine-15N, and poly(4-vinylpyridine-15N). Experimental 15N NMR chemical shift tensors were compared to 15N NMR shielding tensors calculated using the TPSSh, B3LYP, and ωB97XD functionals and the polarizable continuum model approximation. General recommendations are given for the smallest reliable basis set size. The reported structure of DEAP can be used to calculate σref for any other calculation method.
Some anthropogenic pollutants, such as heavy metals and nanoparticles (NPs), are widely distributed and a major threat to environmental safety and public health. In particular, lead (Pb), cadmium (Cd), chromium (Cr), arsenic (As), and mercury (Hg) have systemic toxicity even at extremely low concentrations, so they are listed as priority metals in relation to their significant public health burden. Aluminum (Al) is also toxic to multiple organs and is linked to Alzheimer’s disease. As the utilization of many metal nanoparticles (MNPs) gradually gain traction in industrial and medical applications, they are increasingly being investigated to address potential toxicity by impairing certain biological barriers. The dominant toxic mechanism of these metals and MNPs is the induction of oxidative stress, which subsequently triggers lipid peroxidation, protein modification, and DNA damage. Notably, a growing body of research has revealed the linkage between dysregulated autophagy and some diseases, including neurodegenerative diseases and cancers. Among them, some metals or metal mixtures can act as environmental stimuli and disturb basal autophagic activity, which has an underlying adverse health effect. Some studies also revealed that specific autophagy inhibitors or activators could modify the abnormal autophagic flux attributed to continuous exposure to metals. In this review, we have gathered recent data about the contribution of the autophagy/mitophagy mediated toxic effects and focused on the involvement of some key regulatory factors of autophagic signaling during exposure to selected metals, metal mixtures, as well as MNPs in the real world. Besides this, we summarized the potential significance of interactions between autophagy and excessive reactive oxygen species (ROS)-mediated oxidative damage in the regulation of cell survival response to metals/NPs. A critical view is given on the application of autophagy activators/inhibitors to modulate the systematic toxicity of various metals/MNPs.
Toxic and metabolic diseases of the nervous system generally result in acute neurological signs and bilateral, usually symmetrical, lesions involving specific localization of the brain and/or spinal cord. This group of neurological disorders can be caused by toxins, deficiencies (e.g., inadequate intake of minerals or vitamins), or intoxications (e.g., organic or inorganic compounds, plant, microbial, animal poisons). Failure of metabolically important organs such as the liver or kidney may result in endogenous intoxications or deficiencies. Most common examples of toxic and metabolic diseases of the nervous system are provided herein.
The increased bioavailability of aluminum has led to a concern about its toxicity on living systems. Among the most important toxic effects, it has been proven that aluminum increases oxidative stress in biological systems, a controversial fact, however, due to its non-redox nature. In the present work, we characterize in detail how aluminum can alter redox equilibriums by analyzing its effects on the thermodynamics of the redox scavenging reaction between DPPH., a radical compound often used as a reactive oxygen species model, and hydroquinones, a potent natural antioxidant. For the first time, theoretical and experimental redox potentials within aluminum biochemistry are directly compared. Our results fully agree with experimental reduction and oxidation potentials, unequivocally revealing how aluminum alters the spontaneity of the reaction by stabilizing the reduction of DPPH ⋅ to DPPH⁻ and promoting a proton transfer to the diazine moiety, leading to the production of a DPPH-H species. The capability of aluminum to modify redox potentials shown here confirms previous experimental findings on the role of aluminum to interfere with free radical scavenging reactions, affecting the natural redox processes of living organisms.
Thymosin β4 (Tβ4) was extracted forty years ago ¹ from calf thymus. Since then, it has been identified as a G-actin binding protein involved in blood clothing, tissue regeneration, angiogenesis, and anti-inflammatory processes. Tβ4 has also been implicated in tumor metastasis and neurodegeneration. However, the precise roles and mechanism(s) of action of Tβ4 in these processes remain largely unknown, with the binding of the G-actin protein being insufficient to explain these multi-actions. Here we identify for the first time the important part of Tβ4 mechanism in ferroptosis, an iron-dependent form of cell death, which leads to neurodegeneration and somehow protects cancer cells against cell death. Specifically, we demonstrate four iron ²⁺ and iron ³⁺ binding regions along the peptide and show that the presence of Tβ4 in cell growing medium inhibits erastin and glutamate-induced ferroptosis in macrophage cell line. Moreover, Tβ4 increases the expression of oxidative stress-related genes, namely BAX, hem oxygenase-1, Heat shock protein 70 and Thioredoxin reductase 1, which are downregulated during ferroptosis. We state the hypothesis that Tβ4 is an endogenous iron chelator and take part of iron homeostasis in ferroptosis process. We discuss the literature data of parallel involvement of Tβ4 and ferroptosis in different human pathologies, mainly cancer and neurodegeneration. Our findings confronted with literature data shows that controlled Tβ4 release could command on/off switching of ferroptosis, and may provide novel therapeutic opportunities in pathologies of cancer and tissue degeneration.
Nucleation of minerals in the presence of additives is critical for achieving control over the formation of solids in biomineralization processes or during syntheses of advanced hybrid materials. Herein, we investigated the early stages of Fe(III) (oxy)(hydr)oxide formation with/without polyglutamic acid (pGlu) at low driving force for phase separation (pH 2.0 to 3.0). We employed an advanced pH-constant titration assay, X-ray diffraction, thermal analysis with mass spectrometry, Fourier Transform infrared spectroscopy, and scanning electron microscopy. Three stages were observed: initial binding, stabilization of Fe(III) pre-nucleation clusters (PNCs), and phase separation, yielding Fe(III) (oxy)(hydr)oxide. The data suggest that organic–inorganic interactions occurred via binding of olation Fe(III) PNC species. Fourier Transform Infrared Spectroscopy (FTIR) analyses revealed a plausible interaction motif and a conformational adaptation of the polypeptide. The stabilization of the aqueous Fe(III) system against nucleation by pGlu contrasts with the previously reported influence of poly-aspartic acid (pAsp). While this is difficult to explain based on classical nucleation theory, alternative notions such as the so-called PNC pathway provide a possible rationale. Developing a nucleation theory that successfully explains and predicts distinct influences for chemically similar additives like pAsp and pGlu is the Holy Grail toward advancing the knowledge of nucleation, early growth, and structure formation.
Classical molecular dynamic simulations and density functional theory are used to unveil the interaction of aluminum with various phosphorylated derivatives of the fragment KSPVPKSPVEEKG (NF13), a major multiphosphorylation domain of human neurofilament medium (NFM). Our calculations reveal the rich coordination chemistry of the resultant structures with a clear tendency of aluminum to form multidentate structures, acting as a bridging agent between different sidechains and altering the local secondary structure around the binding site. Our evaluation of binding energies allows us to determine that phosphorylation has an increase in the affinity of these peptides towards aluminum, although the interaction is not as strong as well-known chelators of aluminum in biological systems. Finally, the presence of hydroxides in the first solvation layer has a clear damping effect on the binding affinities. Our results help in elucidating the potential structures than can be formed between this exogenous neurotoxic metal and key sequences for the formation of neurofilament tangles, which are behind of some of the most important degenerative diseases.
Aluminium (Al) is frequently accessible to animal and human populations to the extent that intoxications may occur. Intake of Al is by inhalation of aerosols or particles, ingestion of food, water and medicaments, skin contact, vaccination, dialysis and infusions. Toxic actions of Al induce oxidative stress, immunologic alterations, genotoxicity, pro-inflammatory effect, peptide denaturation or transformation, enzymatic dysfunction, metabolic derangement, amyloidogenesis, membrane perturbation, iron dyshomeostasis, apoptosis, necrosis and dysplasia. The pathological conditions associated with Al toxicosis are desquamative interstitial pneumonia, pulmonary alveolar proteinosis, granulomas, granulomatosis and fibrosis, toxic myocarditis, thrombosis and ischemic stroke, granulomatous enteritis, Crohn’s disease, inflammatory bowel diseases, anemia, Alzheimer’s disease, dementia, sclerosis, autism, macrophagic myofasciitis, osteomalacia, oligospermia and infertility, hepatorenal disease, breast cancer and cyst, pancreatitis, pancreatic necrosis and diabetes mellitus. The review provides a broad overview of Al toxicosis as a background for sustained investigations of the toxicology of Al compounds of public health importance.
The bio-relevant metals (and derived compounds) of the Periodic Table of the Elements ( PTE ) are in the focus. The bulk elements sodium (Na), potassium (K), magnesium (Mg), and calcium (Ca) from the s -block, which are essential for all kingdoms of life, and some of their bio-activities are discussed. The trace elements of the d -block of the PTE as far as they are essential for humans (Mn, Fe, Co, Cu, Zn, Mo) are emphasized, but V, Ni, Cd, and W, which are essential only for some forms of life, are also considered. Chromium is no longer classified as being essential. From the p -block metals only the metalloid (half-metal) selenium (Se) is essential for all forms of life. Two other metalloids, silicon and arsenic, are briefly mentioned, but they have not been proven as being essential for humans. All metals of the PTE and a plethora of their compounds are used in industry and many of them are highly toxic, like lead (Pb), which is discussed as a prime example. Several metals of the PTE , that is, their ions and complexes, are employed in medicine and we discuss the role of lithium, gallium, strontium, technetium, silver, gadolinium (the only f -block element), platinum, and gold.
In the field of cultural heritage, a growing interest is focused on the UV photo-degradation of organic binders induced by mineral pigments. But the effect of alum on the UV photo-degradation of gelatin binder remains unclear, which are two of the most common materials in traditional Chinese painting and calligraphy. This paper investigated alterations in composition, the secondary structure and morphology of gelatin under the individual or compound action of UV light and alum. Results showed that alum can obviously accelerate the alterations in the secondary structure and morphology of gelatin. The results of FTIR, XPS and DFT calculation confirmed that alum can directly or indirectly provide active hydrogen atom and O2· radicals, so the initiation and propagation process of gelatin photodegradation were promoted. The paper discovered the mechanism of the degradation of protein binders in Chinese traditional cultural heritage, and provided important theoretical basis for find suitable treatments for conservation or targeted materials for protection.
What are the molecular basis of the detrimental role of the aluminum ion within the catecholamine biosynthesis pathway?
Senile plaques are extracellular deposits found in patients with Alzheimer’s’ Disease (AD) and are mainly constituted by insoluble fibrils of β-amyloids (Aβ) peptides. The mechanistic details about how AD develops are not fully understood yet, but metals such as Cu, Zn or Fe are proposed to have a non-innocent role. Many studies have also linked the non biological metal aluminum with AD; a species whose concentration in the environment and food has been constantly increasing since the industrial revolution. Gaining a molecular picture of how Al(III) interacts with an Aβ peptide is of primordial interest to understand the many variables evolution of AD. So far, no consensus has been reached on how this metal interacts with Aβ, partially due to the experimental complexity detecting and quantifying the resulting Al(III)-Aβ complexes. Computational chemistry rises as a powerful alternative to investigate how Al(III) can interact with the Aβ peptides, as convenient strategies could shed light on the metal-peptide description at molecular level. However, the absence of any reliable template which could be used for the modeling of the metallopeptide structure makes computational insight extremely difficult. Here, we present a novel strategy to generate accurate 3D models of the Al(III)-Aβ which still circumvents first principle simulations of metal binding to peptides of Aβ. The key of the approach consists in the identification of experimental structures of the isolated peptide well pre-organized for the binding of a given metal in configurations of the first coordination sphere that were previously identified as the most stable with amino acids models. This approach greatly solves the absence of clear structural templates for novel metallopeptide constructs. The posterior refinement of the structures by QM/MM and MD calculations allows us to provide for the first time with physically sound models for Al(III)-Aβ complexes with a 1:1 stoichiometry, where up to three carboxylic groups are involved in the metal binding, with a clear preference towards Glu3, Asp7 and Glu11.
The interaction of aluminum with glucose 6-phosphate (Al-G6P) is thought to disrupt key processes of the glucide metabolism in cells. In this article, a Density Functional Theory study on the interaction of aluminum with D-glucose 6-phoshate is presented, combined with polarizable continuum models to account for bulk solvent effects. 143 aluminum–G6P complexes with different binding modes and various total charges are characterized comprising mononuclear (1:1, 1:2, 1:3, 1:1:1 (with citrate)) and dinuclear (2:1, 2:2) species. This large Al-G6P interaction dataset, the largest theoretical characterization of an aluminum–biophosphate interaction, gives insight into the diversity and complex picture of the interaction of aluminum with phosphate metabolites. We have found that charge and binding mode are driving factors in the binding affinity of glucose 6-phosphate. In addition, our calculations points to a tendency to form dicoordinated binding motifs, in which aluminum is bound to two functional groups of glucose 6-phosphate ligand. This tendency gives rise to a capacity of aluminum to act as a bridging agent in the coordination of several metabolites, a behavior that can be linked to the suspected tendency of aluminum to form aggregates that could induce various toxic effects in biological systems.
The interaction of aluminum with 2,3-diphosphoglyceric acid (2,3-DPG) is thought to be one of the strongest interactions of aluminium with a biophosphate molecule. In this article, the affinity energies for a family of Al-(2,3-DPG) complexes are calculated at the DFT level of theory. The study includes a total of 26 structures that vary from 1:1 complexes, 1:2 stoichiometry and ternary complexes with citrate, considering different coordination modes and protonation states. Our results demonstrate that in the case of 1:1 complexes, 2,3-DPG ligand could compete with citrate for complexation with aluminum, at physiological pH. However, for the rest of the complexes there is a clear preference for Al(Citr)2} > Al(2,3-DPG)(Citr) ternary complex > Al(2,3-DPG)2} complexes. For each of these groups the charge of the ligand determines the affinity but at a lower extent that the nature of the Citr/2,3-DPG ligand. In summary, our results point to a high variety of possible complexation modes of 2,3-DPG to aluminum, showing higher preference towards the formation of ternary complexes.
The interaction of aluminum with biomolecular building blocks is a topic of interest as a first step to understand the potential toxic effects of aluminum in biosystems. Among the different molecules that aluminum can bind in a biological environment, phosphates are the most likely ones, due to their negatively charged nature. In the present paper, we combined DFT quantum mechanical calculations with the implicit solvent effect in order to characterize the interaction of Al(iii) with these molecules. An extended set composed of a total of 59 structures was investigated, which includes various types of phosphates (monoester, diester, triester-phosphates) and various phosphate units (mono-, di- and tri-phosphate), considering various charge and protonation states, and different binding modes. The goal is to unveil the preferential interaction mode of Al(iii) with phosphates in 1 : 1 complexes. Our results reveal that Al(iii) prefers to form dicoordinated complexes with two phosphates, in which the interaction with each of the phosphates is of monodentate character. Our results also suggest a high affinity for binding basic phosphate groups, pointing to ATP, phosphorylated peptides, and basic diphosphates (such as 2,3-DPG) as strong aluminum chelators.
The increased availability of aluminium in biological environments, due to human intervention in the last century, raises concerns on the effects that this so far "excluded from biology" metal might have on living organisms. Consequently, the bioinorganic chemistry of aluminium has emerged as a very active field of research. This review will focus on our contributions to this field, based on computational studies that can yield an understanding of the aluminum biochemistry at a molecular level. Aluminium can interact and be stabilized in biological environments by complexing with both low molecular mass chelants and high molecular mass peptides. The speciation of the metal is, nonetheless, dictated by the hydrolytic species dominant in each case and which vary according to the pH condition of the medium. In blood, citrate and serum transferrin are identified as the main low molecular mass and high molecular mass molecules interacting with aluminium. The complexation of aluminium to citrate and the subsequent changes exerted on the deprotonation pathways of its tritable groups will be discussed along with the mechanisms for the intake and release of aluminium in serum transferrin at two pH conditions, physiological neutral and endosomatic acidic. Aluminium can substitute other metals, in particular magnesium, in protein buried sites and trigger conformational disorder and alteration of the protonation states of the protein's sidechains. A detailed account of the interaction of aluminium with proteic sidechains will be given. Finally, it will be described how alumnium can exert oxidative stress by stabilizing superoxide radicals either as mononuclear aluminium or clustered in boehmite. The possibility of promotion of Fenton reaction, and production of hydroxyl radicals will also be discussed.
Citrate is the main low mass molecule chelator of aluminum in serum, and knowledge of the interaction mode of this organic molecule with this cation is necessary to understand aluminum speciation in biosystems. However, the 1:1 complexation of citric acid to Al(III) is a complex process due to the myriad of coordination sites and protonation states of this molecule. Moreover, due to the acidic character of the complex, its entire experimental characterization is elusive. The system is also challenging from a computational point of view, due to the difficulties in getting a balanced estimation of the large range of solvation free energies encountered for the different protonation states of a multiprotic acid in both situations, complexed and uncomplexed with a trivalent cation. Herein, the deprotonation process of the free citric acid in solution and that interacting with Al(III) have been investigated considering all possible coordination modes and protonation states of the citric acid. All the structures were optimized in solution combining the B3LYP density function method with the polarizable continuum IEFPCM model. In addition, different schemes have been employed to obtain reliable solvation energies. Taking into account the most stable isomer of each protonation state, the pK(a) values were computationally estimated for the free citric acid and that interacting with Al(III), showing a good agreement with the experimental data. All these results shed light on how the deprotonation process of the citric acid takes place, and show that Al(III) not only increases the acidity of the molecule, but also changes qualitatively the deprotonation pattern of the citric acid. This information is highly relevant to understand aluminum speciation in biological environments, for which citrate is the main low molecular weight chelator, and responsible for its cellular in-take.
The brain is a highly compartmentalized organ exceptionally susceptible to accumulation of metabolic errors. Alzheimer's disease (AD) is the most prevalent neurodegenerative disease of the elderly and is characterized by regional specificity of neural aberrations associated with higher cognitive functions. Aluminum (Al) is the most abundant neurotoxic metal on earth, widely bioavailable to humans and repeatedly shown to accumulate in AD-susceptible neuronal foci. In spite of this, the role of Al in AD has been heavily disputed based on the following claims: 1) bioavailable Al cannot enter the brain in sufficient amounts to cause damage, 2) excess Al is efficiently excreted from the body, and 3) Al accumulation in neurons is a consequence rather than a cause of neuronal loss. Research, however, reveals that: 1) very small amounts of Al are needed to produce neurotoxicity and this criterion is satisfied through dietary Al intake, 2) Al sequesters different transport mechanisms to actively traverse brain barriers, 3) incremental acquisition of small amounts of Al over a lifetime favors its selective accumulation in brain tissues, and 4) since 1911, experimental evidence has repeatedly demonstrated that chronic Al intoxication reproduces neuropathological hallmarks of AD. Misconceptions about Al bioavailability may have misled scientists regarding the significance of Al in the pathogenesis of AD. The hypothesis that Al significantly contributes to AD is built upon very solid experimental evidence and should not be dismissed. Immediate steps should be taken to lessen human exposure to Al, which may be the single most aggravating and avoidable factor related to AD.
Aluminum, the third most abundant element in the earth crust and one key industrial components of our everyday life, has been associated with several neurodegenerative diseases due to its ability to promote neurofilament tangle and β-amyloid peptide aggregation. However, the experimental characterization of aluminum speciation in vivo is a difficult task. In the present paper, we develop a theoretical protocol that combines molecular dynamics simulations, clustering of structures, and Density Functional Theory, for the characterization of the binding of Aluminum to the synthetic neurofilament analogue octapeptide GEGEGSGG and its phosphorylated variant. Our protocol is tested with respect to previous NMR experimental data, which allows for a full interpretation of experimental information available and its relation with key thermodynamic quantities. Our results demonstrate the importance of phosphorylation in the ability of a peptide to bind aluminum. Thus, phosphorylation changes: i) the binding pattern of aluminum to GEGEGSGG, shifting the preferential binding site from C-terminal to S6(P); ii) increases the binding affinity by a factor of around 15 kcal/mol in free energy; and iii) may cause significant changes in secondary structure and stiffness of the polypeptide chain, specially in the case of bidentate binding modes. Our results shed light on the possibility of aluminum to induce aggregation of β-amyloid proteins and neurofilament tangles.
Nicotinamide adenine dinucleotide (NADH) is one of the most abundant cofactor employed by proteins and enzymes. The molecule is formed by two nucleotides that can lead to two main conformations: folded/closed and unfolded/open. Experimentally, it has been determined that the closed form is about 2kcal/mol more stable than the open formed. Computationally, a correct description of the NADH unfolding process is challenging due to different reasons: 1) The unfolding process shows a very low energy difference between the two conformations 2) The molecule can form a high number of internal hydrogen bond interactions 3) Subtle effects such as dispersion may be important. In order to tackle all these effects, we have employed a number of different state of the art computational techniques, including: a) well-tempered metadynamics, b) geometry optimizations, and c) Quantum Theory of Atoms in Molecules (QTAIM) calculations, to investigate the conformational change of NADH in solution and interacting with aluminum. All the results indicate that aluminum indeed favors the closed conformation of NADH, due mainly to the formation of a more rigid structure through key hydrogen bond interactions.
A combination of ab initio calculations, circular dichroism, nuclear magnetic resonance, and X-ray photoelectron spectroscopy has shown that aluminum ions can induce the formation of backbone ring structures in a wide range of peptides, including neurodegenerative disease related motifs. These ring structures greatly destabilize the protein and result in irreversible denaturation. This behavior benefits from the ability of aluminum ions to form chemical bonds simultaneously with the amide nitrogen and carbonyl oxygen atoms on the peptide backbone.
The coordination chemistry of a metal ion defines its optimal association with a biomolecule such that its binding by specific ligands on that molecule confers function and biological purpose. Aluminium is a non-essential metal with no known biological role which means that its coordination neurochemistry defines aluminium's putative role in a number of neurodegenerative diseases. In examining this chemistry it is found that very little is known about the complexes formed and ligands involved in aluminium's interactions with neurochemically-relevant ligands. Aluminium's action as a pro-oxidant as well as an excitotoxin are highlighted while the evidence for its interactions with amyloid beta, tau and DNA are discussed and it is concluded that it is too early to discount these ligands as targets for the neurotoxicity of aluminium.
Metal–metal bonds belong, from the topological point of view, to the wide class of the closed shell interactions proposed by Bader. Such a simple classification is, however, not satisfying in the description of these bonds and the nature of the metal–metal bond, in particular in polynuclear complexes, is debated. Using some topological and energy parameters, a comparison is made between polynuclear complexes and bulk metals and indicates the similar nature of these bonds.
This chapter presents a study on the structures of complexes in solution measurements derived from X-ray diffraction. The chapter presents a survey on the structures of the complexes derived from solution diffraction data. The methods used and the approximations involved are discussed in this chapter. Structure determinations of aqua complexes of metal ions in aqueous solutions are discussed only when they are of interest for the structures of complexes containing other ligands. A commonly used instrument for measuring the large-angle X-ray scattering from a solution is the ϴ-ϴ goniometer. The Bragg–Brentano parafocusing geometry is used in which the incoming X-ray beam and the measured diffracted beam form the same angle, ϴ, with the horizontal surface of the liquid sample. X-ray diffraction measurements can give direct structural information on complexes in solution that cannot be obtained by other methods. Comparison of diffraction curves for different solutions can give information on structural changes caused by the changes in concentration of a particular atomic species. For a dominant complex in a solution, precise determinations of the intramolecular distances can usually be made. Derivations of coordination numbers and geometries will depend on the specific characteristics of the system investigated.
The paper gives a review on the importance of distribution of Al in biological fluids, primarily in the lights of the works of the author in Al chemistry. It starts with studies of interactions of Al(III) with small biomolecules, such as aliphatic and aromatic hydroxycarboxylic acids, and inorganic and organic phosphates. A significant part of this review deals with the problems of description of the biospeciation of Al(III) in serum, where besides the thermodynamic conditions the role of time is also considered in the case of this sluggish metal ion. The Al(III) complexes of the other large group of biomolecules, proteins and their building blocks (oligo)peptides and amino acids are also discussed, where the role of the type of the side chain donors and the extent of preorganisation are considered in the efficiency of metal ion binding. The application of low molecular mass chelator molecules in restoring the dysfunctioning metal ion (including Al(III)) homeostasis in the treatment of Alzheimer's disease is also discussed in the paper.
The hydration reaction is defined as the transfer of an ion or neutral chemical species from the gaseous phase into water, M
In order to determine the optimal methodology for evaluation of the magnitude of intermolecular charge transfer, several methods have been examined: Mulliken population, natural population analysis, atoms in molecules AIM as well as charges from electrostatic potentials using a grid-based method Chelp and Chelpg procedures using a series of correlation consistent cc-pVXZ XD, T, Q basis sets within LCAO MO SCF, MP2, DFT, and coupled cluster theory levels. In contrast to previous nonconclusive comparative studies, the present calculations reveal close matching of the recently available experimental data for six Lewis acid-base adducts with theoretical values derived from the Chelpg approach, whereas for the remaining methods relative errors are almost doubled. On the other hand, AIM and Chelpg results display the best linear correlation coefficients with the experimental data. Since reasonably accurate Chelpg results could be already obtained with SCF or DFT B3LYP methods using cc-pVDZ, such an approach opens the way to study intermolecular charge transfer in larger molecular systems. Preliminary results obtained within cc-pVDZ basis set and B3LYP functional for pyridine-SO 3 complex do not exceed relative error limits observed for other smaller complexes. Analysis of corresponding interaction energy components calculated consistently in the dimer basis set indicates significant role of electrostatic, exchange and delocalization contributions, with rather negligible correlation term. In contrast to previous findings, the experimentally observed amount of transferred charge seems not to correlate with any interaction energy term.
We have used circular dichroism spectroscopy to confirm that, in a membrane-mimicking solvent, AβP(1–40) adopts a partially helical conformation and we have demonstrated the loss of this structure in the presence of physiologically relevant concentrations of aluminium. This is the first evidence of a direct biochemical interaction between aluminium and β-amyloid and may have important implications for the pathogenesis of Alzheimer's disease.
Supermolecule density functional calculations were performed on the hydrolysis of aluminum(III) and prediction of pK(a) in aqueous solution. The optimization results showed that the most stable structures for the first, second and third hydrolysis products were hexacoordinate, hexacoordinate and pentacoordinate, respectively. The different coordination geometries could easily transform into each other due to the small energy gaps (within 2.5 kcal mol(-1)). The calculated value of 4.6 for the first hydrolysis constant agreed well with the experimental value of 5.0. The results from the different thermodynamic cycles have been compared, which revealed that the cycle involving the solvation of H(2)O and H(3)O(+) could reasonably predict the first hydrolysis constant, while the other cycle involving the solvation of H(+) acquired a fairly good correlation of the hydrolysis reaction free energies and the experimental pK(a).
The aluminum content of muscle, bone and brain was measured in control subjects and in uremic patients on dialysis who had been maintained on phosphate-binding aluminum gels. The mean muscle aluminum was 14.8 ppm, and the trabecular-bone aluminum 98.5 ppm in the patients on dialysis, as compared with 1.2 and 2.4 in control subjects (P less than 0.05). Brain gray-matter aluminum values in a group of uremic patients on dialysis who died of a neurologic syndrome of unknown cause were 25 ppm as compared with 6.5 ppm in a group of uremic patients on dialysis who died of other causes and 2.2 ppm in control subjects. The fact that brain gray-matter aluminum was higher in all patients with the dialysis-associated encephalopathy syndrome than any of the control subjects or other uremic patients on dialysis suggests that this syndrome may be due to aluminum in intoxication.
The increasing number of roles discovered for Al3+ in physiological processes demands an understanding of how Al3+ interacts with compounds in biological systems. Al3+ is expected to complex with oxygen donor ligands, especially phosphates, and it does so in soils, in the gastrointestinal tract, and in cells. The stability of Al3+ complexes has generally been misjudged because of lack of recognition that free, aqueous Al3+ is not the dominant form in neutral solutions and that the solubility of Al(OH)3 limits the free Al3+ at the plasma pH 7.4 to less than 10(-11) mol/L. In the presence of inorganic phosphate, the permitted free Al3+ is decreased further, through formation of insoluble aluminum phosphate. This precipitate facilitates the elimination of Al3+ from the body. In contrast, citrate solubilizes Al3+, and an appreciable fraction occurs as a neutral complex that may pass through membranes and provide a vehicle for Al3+ absorption into the body. In the blood plasma the most likely small-molecule complex is that with citrate, while the only competitive protein complex is that with transferrin, a protein built to transport Fe3+ but whose sites are only 30% occupied.
Aluminum ion has been proposed to be a factor contributing to the toxicity of aquatic acidification caused by acid rain, and to the etiology of a variety of neurological and skeletal disorders in man. The biological processes and molecular mechanisms that underlie these pathological processes are beginning to be identified. This review outlines the current state of our knowledge concerning the significant factors associated with aluminum ion in biological systems.
Aluminum inhibited both the cytosolic and mitochondrial hexokinase activities in rat brain. The IC50 values were between 4 and 9 microM. Aluminum was effective at mildly acidic (pH 6.8) or slightly alkaline (pH 7.2-7.5) pH, in the presence of a physiological level of magnesium (0.5 mM). However, saturating (8 mM) magnesium antagonized the effect of aluminum on both forms of hexokinase activity. Other enzymes examined were considerably less sensitive to inhibition by aluminum. The IC50 of aluminum for phosphofructokinase was 1.8 mM and for lactate dehydrogenase 0.4 mM. At 10-600 microM, aluminum actually stimulated pyruvate kinase. Aluminum also inhibited lactate production by rat brain extracts: this effect was much more marked with glucose as substrate than with glucose-6-phosphate. However, the IC50 for inhibiting lactate production using glucose as substrate was 280 microM, higher than that required to inhibit hexokinase. This concentration of aluminum is comparable to those reportedly found in the brains of patients who had died with dialysis dementia and in the brains of some of the patients who had died with Alzheimer disease. Inhibition of carbohydrate utilization may be one of the mechanisms by which aluminum can act as a neurotoxin.
Current gradient-corrected density-functional approximations for the exchange energies of atomic and molecular systems fail to reproduce the correct 1/r asymptotic behavior of the exchange-energy density. Here we report a gradient-corrected exchange-energy functional with the proper asymptotic limit. Our functional, containing only one parameter, fits the exact Hartree-Fock exchange energies of a wide variety of atomic systems with remarkable accuracy, surpassing the performance of previous functionals containing two parameters or more.
A correlation-energy formula due to Colle and Salvetti [Theor. Chim. Acta 37, 329 (1975)], in which the correlation energy density is expressed in terms of the electron density and a Laplacian of the second-order Hartree-Fock density matrix, is restated as a formula involving the density and local kinetic-energy density. On insertion of gradient expansions for the local kinetic-energy density, density-functional formulas for the correlation energy and correlation potential are then obtained. Through numerical calculations on a number of atoms, positive ions, and molecules, of both open- and closed-shell type, it is demonstrated that these formulas, like the original Colle-Salvetti formulas, give correlation energies within a few percent.
The aluminum and yeast hexokinase interaction was studied. Structural changes were correlated with variations in protein functionality. Results show two different behaviors: At low metal concentrations preferential adsorption of metal (and water exclusion) induces aggregate formation. No significant changes in the protein structure occur, but there is a continuous loss of activity (from the first concentration). At large salt concentrations a monomerization process and a conformational change in the secondary structure as well as in the three-dimensional structure take place. This change reduces the percentage of alpha-helix conformation, gives thermal stability to the protein, and allows the exposure of some tryptophan residue and hydrophobic regions. The protein inhibition increases. Conformational change and monomerization may allow access of the metal to the substrate site, mainly the ATP site. The inhibition in any case is of mixed type with a competitive component.
The elaboration of biogeochemical cycles for elements which are known to be essential for life has enabled a broad appreciation of the homeostatic mechanisms which underlie element essentiality. In particular they can be used effectively to identify any part played by human activities in element cycling and to predict how such activities might impact upon the lithospheric and biospheric availability of an element in the future. The same criteria were the driving force behind the construction of a biogeochemical cycle for aluminium, a non-essential element which is a known ecotoxicant and a suspected health risk in humans. The purpose of this exercise was to examine the concept of a biogeochemical cycle for aluminium and not to review the biogeochemistry of this element. The cycle as presented is rudimentary and qualitative though, even in this nascent form, it is informative and predictive and, for these reasons alone, it is deserving of future quantification. A fully fledged biogeochemical cycle for aluminium should explain the biospheric abundance of this element and whether we should expect its (continued) active involvement in biochemical evolution.