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Experimental and Theoretical Characterization of Arsenite in Water: Insights into the Coordination Environment of As-O
Abstract
Long-term exposure to arsenic in drinking water has been linked to cancer of the bladder, lungs, skin, kidney, nasal passages, liver, and prostate in humans. It is therefore important to understand the structural aspects of arsenic in water, as hydrated arsenic is most likely the initial form of the metalloid absorbed by cells. We present a detailed experimental and theoretical characterization of the coordination environment of hydrated arsenite. XANES analysis confirms As(III) is a stable redox form of the metalloid in solution. EXAFS analysis indicate, at neutral pH, arsenite has a nearest-neighbor coordination geometry of approximately 3 As-O bonds at an average bond length of 1.77 A, while at basic pH the nearest-neighbor coordination geometry shifts to a single short As-O bond at 1.69 A and two longer As-O bonds at 1.82 A. Long-range ligand scattering is present in all EXAFS samples; however, these data could not be fit with any degree of certainty. There is no XAS detectable interaction between As and antimony, suggesting they are not imported into cells as a multinuclear complex. XAS results were compared to a structural database of arsenite compounds to confirm that a 3 coordinate As-O complex for hydrated arsenite is the predominate species in solution. Finally, quantum chemical studies indicate arsenite in solution is solvated by 3 water molecules. These results indicate As(OH)3 as the most stable structure existing in solution at neutral pH; thus, ionic As transport does not appear to be involved in the cellular uptake process.
... These values are in agreement with those found in the literature for As bound to the surfaceo fa dsorbents (inner-shell complexes). [35][36][37][38] However,t he samples that underwent the calcination process (calcined and calcined-reduced) show similar Debye-Waller factors, whereas the reduced one showedasignificantly higher value,s uggesting that As atoms are in am ore disordered local environment, which can explain its lower AsÀ Of irst-shell contribution intensity at j FT j with respectt ot hose that have undergone ac alcination process. The meaningful DE 0 value is also in agreementw ith those found in the literature for As-based species studied by XAS. ...
... The meaningful DE 0 value is also in agreementw ith those found in the literature for As-based species studied by XAS. [38][39] Finally,t he nature of the Ga speciesp resent in the zeolitic framework was also studied by XAS at the Ga K-edge. The XANESs pectrum of the as-synthesized Ga-MFI (Figures S32 and S33 in the Supporting Information) is similart ot hat reported for Ga-substituted zeoliteB eta, [40] with the absorption edge positioned at 10 372 eV,t ypicalo fG a 3 + .M oreover,n oi ndication of the Ga 2 O 3 phase can be observedi nt he XAS spectrum of the as-made material. ...
Expanding the previously known family of ‐onium (ammonium, phosphonium, and sulfonium) organic structure‐directing agents (OSDAs) for the synthesis of zeolite MFI, a new member, the arsonium cation, is used for the first time. The new group of tetraalkylarsonium cations has allowed the synthesis of the zeolite ZSM‐5 with several different chemical compositions, opening a route for the synthesis of zeolites with a new series of OSDA. Moreover, the use of As replacing N in the OSDA allows the introduction of probe atoms that facilitate the study of these molecules by powder X‐ray diffraction (PXRD), solid‐state nuclear magnetic resonance (MAS NMR), and X‐ray absorption spectroscopy (XAS). Finally, the influence of trivalent elements such as B, Al, or Ga isomorphically replacing Si atoms in the framework structure and its interaction with the As species has been studied. The suitability of the tetraalkylarsonium cation for carrying out the crystallization of zeolites is demonstrated along with the benefit of the presence of As atoms in the occluded OSDA, which allows its advanced characterization as well as the study of its evolution during OSDA removal by thermal treatments.
... EXAFS fitting analysis was performed on raw/unfiltered data. Protein EXAFS data were fit using single-scattering Feff theoretical models calculated for carbon, oxygen, and sulfur coordi-nation to simulate arsenic-ligand environments, with values for the scale factors (Sc) and E 0 calibrated by fitting crystallographically characterized arsenic model compounds, as previously outlined (31). Criteria for judging the best-fit EXAFS simulations utilized both the lowest mean square deviation between data and the fit corrected for the number of degrees of freedom (F=) (32) and reasonable Debye-Waller factors ( 2 Ͻ 0.006 Å 2 ) (33). ...
... X-ray absorption near edge structure (XANES) analysis indicated that arsenic is stably bound as As(III) in MBP-Yap8 (Fig. 1A). The observed value for the first inflection point energy is 11,868 eV, consistent with observed values for As(III) in protein and model systems (31). Extended X-ray absorption fine structure (EXAFS) analysis for MBP-Yap8 is consistent with a three-coordinate As(III)-nearest neighbor coordination system constructed by sulfur-based ligands only at 2.24 Å (Fig. 1B; Table 1). ...
The AP-1 like transcription factor Yap8 is critical for arsenic tolerance in yeast
Saccharomyces cerevisiae
. However, the mechanism by which Yap8 senses the presence of arsenic and activates transcription of detoxification genes is unknown. Here we demonstrate that Yap8 directly binds to trivalent arsenite [As(III)]
in vitro
and
in vivo
, and that approximately one As(III) molecule is bound per molecule of Yap8. As(III) is coordinated by three sulphur atoms in purified Yap8, and our genetic and biochemical data identify the cysteine residues that form the binding site as Cys132, Cys137 and Cys274. As(III) binding by Yap8 does not require an additional yeast protein, and Yap8 is neither regulated at the level of localization nor at the level of DNA binding. Instead, our data are consistent with a model in which a DNA-bound form of Yap8 acts directly as an As(III) sensor. Binding of As(III) to Yap8 triggers a conformational change that in turn brings about a transcriptional response. Thus, As(III) binding to Yap8 acts as a molecular switch that converts inactive Yap8 into an active transcriptional regulator. This is the first report to demonstrate how a eukaryotic protein couples arsenic sensing to transcriptional activation.
... In this model, As(III) was assumed to form covalent bonds with L79C and Q81C, forming L79C-S−AsOH−S-Q81C ( Figure 6a); this configuration is informed by the experimental evidence suggesting that As(OH) 3 has the most stable structure in solution at neutral pH. 29 Such a configuration could be feasible owing to the potential of the cysteines of L79C and Q81C to act as dithiol sites. Generally, dithiol sites, composed of two cysteines separated by a few amino acid residues, can easily be occupied by trivalent arsenicals, exhibiting a K d value ranging from 1 to 20 μM. 30 This range is much lower than the present As(III) concentration of 10 ppm (about 130 μM). ...
The development of a low-cost and user-friendly sensor using microorganisms to monitor the presence of As(III) on earth has garnered significant attention. In conventional research on microbial As(III) sensors, the focus has been on transcription factor ArsR, which plays a role in As(III) metabolism. However, we recently discovered that LuxR, a quorum-sensing control factor in Vibrio fischeri that contains multiple cysteine residues, acted as an As(III) sensor despite having no role in As(III) metabolism. This finding suggested that any protein could be an As(III) sensor if cysteine residues were incorporated. In this study, we aimed to confer As(III) responsiveness to BetI, a transcriptional repressor of the TetR family involved in osmotic regulation of the choline response, unrelated to As(III) metabolism. Based on the BetI structure constructed using molecular dynamics calculations, we generated a series of mutants in which each of the three amino acids not critical for function was substituted with cysteine. Subsequent examination of their response to As(III) revealed that the cysteine-substituted mutant, incorporating all three substitutions, demonstrated As(III) responsiveness. This was evidenced by the fluorescence intensity of the downstream reporter superfolder green fluorescent protein expression regulated by the operator region. Intriguingly, the BetI cysteine mutant maintained its binding responsiveness to the natural ligand choline. We successfully engineered an OR logic gate capable of responding to two orthogonal ligands using a single protein.
... Arsenite may form relatively weak bonds with monothiols, and high intracellular concentrations of As III can deplete glutathione cells. It forms strong bonds with dithiols in small molecules, e.g., lipoic acid cofactor, and with vicinal thiols in proteins, leading to the inactivation of various enzymes and receptors (Ramírez-Solis 2004). In contrast to As V , a negatively charged oxyanion in solution, As III , is the neutral undissociated acid As(OH) 3 at physiological pH. ...
The study used scattered literature to summarize the effects of excess Cd, As, and Pb from contaminated soils on plant secondary metabolites/bioactive compounds (non-nutrient organic substances). Hence, we provided a systematic overview involving the sources and forms of Cd, As, and Pb in soils, plant uptake, mechanisms governing the interaction of these risk elements during the formation of secondary metabolites, and subsequent effects. The biogeochemical characteristics of soils are directly responsible for the mobility and bioavailability of risk elements, which include pH, redox potential, dissolved organic carbon, clay content, Fe/Mn/Al oxides, and microbial transformations. The radial risk element flow in plant systems is restricted by the apoplastic barrier (e.g., Casparian strip) and chelation (phytochelatins and vacuole sequestration) in roots. However, bioaccumulation is primarily a function of risk element concentration and plant genotype. The translocation of risk elements to the shoot via the xylem and phloem is well-mediated by transporter proteins. Besides the dysfunction of growth, photosynthesis, and respiration, excess Cd, As, and Pb in plants trigger the production of secondary metabolites with antioxidant properties to counteract the toxic effects. Eventually, this affects the quantity and quality of secondary metabolites (including phenolics, flavonoids, and terpenes) and adversely influences their antioxidant, antiinflammatory, antidiabetic, anticoagulant, and lipid-lowering properties. The mechanisms governing the translocation of Cd, As, and Pb are vital for regulating risk element accumulation in plants and subsequent effects on secondary metabolites.
... In aqueous solution, As(III) and Sb(III) are mostly found as trihydroxylated uncharged molecules, i.e. As(OH) 3 and Sb(OH) 3 , which are structurally similar to glycerol at neutral pH (Ramírez-Solís et al., 2004;Porquet and Filella, 2007). Therefore, As(III) and Sb(III) are easily transported by the aquaglyceroporins and membrane proteins permeable for water and glycerol (Bhattacharjee et al., 2008) (Fig. 2). ...
Antimony (Sb) is a non-essential element for plants, animals, and humans. With increased anthropogenic inputs from mining and industrial activities, ore processing, vehicle emissions, and shooting activities, elevated Sb levels in the environment have become a growing concern. Despite of its non-essentiality, some plants can take up and accumulate Sb in relatively high concentrations in their organs. At increased concentration in edible plant parts or medicinal herbs it may pose health risks to humans and livestock. Although most of Sb is stored in root tissues, a smaller quantity of this metalloid can be translocated to the shoot depending on the plant species, where it exerts a variety of deleterious effects. Its chemical speciation has an influence on its behavior in the environment and its ecotoxicity. Inhibition of photosynthesis, modified root and leaf anatomy, activation of plant antioxidant system, or disruption of plant membrane system are some of the negative effects of Sb on plant growth and development. Studies on mitigation methods are quite important in order to produce food crops in a safe way. Application of silicon, selenium, biochar, nanoparticles, and microoraginsms are proven to be emerging strategies for reducing the Sb toxicity.
... mechanisms in order to survive and ultimately thrive in arsenic-containing environments, involving arsenic absorption, As(V) reduction, As(III) oxidation, As(III) methylation, and As(III) efflux (9)(10)(11). Furthermore, many genes responsible for arsenic uptake, resistance, and detoxification have been identified and characterized, including the phosphate uptake systems Pit and Pst (12) for arsenate and the glycerol facilitator GlpF (13)(14)(15)(16) for arsenite uptake; ArsA, ArsB, and Acr3 for arsenite and antimonite efflux (17); ArrA and ArrB for arsenate respiratory reduction (18); ArsC and Acr2p for cytoplasmic arsenate reduction (19)(20)(21)(22); ArxAB (23) and AioAB (24)(25)(26) for arsenite oxidation; and, finally, ArsM for methylation (27). Most often, these processes are regulated by the repressor ArsR. ...
The Gram-positive bacterium Paenibacillus taichungensis NC1 was isolated from the Zijin gold-copper mine and shown to display high resistance to arsenic (MICs of 10 mM for arsenite in minimal medium). Genome sequencing indicated the presence of a number of potential arsenic resistance determinants in NC1. Global transcriptomic analysis under arsenic stress showed that NC1 not only directly upregulated genes in an arsenic resistance operon but also responded to arsenic toxicity by increasing the expression of genes encoding antioxidant functions, such as cat, perR, and gpx. In addition, two highly expressed genes, marR and arsV, encoding a putative flavin-dependent monooxygenase and located adjacent to the ars resistance operon, were highly induced by As(III) exposure and conferred resistance to arsenic and antimony compounds. Interestingly, the zinc scarcity response was induced under exposure to high concentrations of arsenite, and genes responsible for iron uptake were downregulated, possibly to cope with oxidative stress associated with As toxicity.
IMPORTANCE Microbes have the ability to adapt and respond to a variety of conditions. To better understand these processes, we isolated the arsenic-resistant Gram-positive bacterium Paenibacillus taichungensis NC1 from a gold-copper mine. The transcriptome responding to arsenite exposure showed induction of not only genes encoding arsenic resistance determinants but also genes involved in the zinc scarcity response. In addition, many genes encoding functions involved in iron uptake were downregulated. These results help to understand how bacteria integrate specific responses to arsenite exposure with broader physiological responses.
... Trivalent inorganic As appears mostly as neutral undissociated acid, As(OH) 3 , at pH 7 (Ramírez- Solis et al. 2004). In 1997, (Sanders et al. 1997) first reported in Escherichia coli that an aquaglyceroporin GlpF (Glycerol uptake facilitator protein) facilitated antimony [Sb(III)] and As(III) intake into the bacterial cells. ...
Arsenic (As), a heavy metalloid, occupies the topmost position in the list of the top ten hazardous chemicals published by the World Health Organization. The contamination of arsenic in groundwater predominantly utilized for irrigation and drinking is responsible for serious public health issues across the globe. The two most common arsenic species, i.e., inorganic arse-nate and arsenite, are toxic and environmental pollutants. The toxicity of arsenic and its speciation are impacted by bacterial biotransformations. Bacteria have evolved several systems to deal with arsenic toxicity in their vicinity through detoxification and metabolism. The knowledge about these processes provides insight into the strategies employed by bacteria for arsenic biotransformation. In this study, we comprehensively discuss the genetics and molecular mechanisms of arsenate reduction, arsenite oxidation, methylation/demethylation, and other arsenic biotransformations. Relatively recent scientific discoveries and the use of molecular approaches have notably enhanced our understanding of these microbial processes present in the environment. The present review intends to focus on the diverse categories of arsenic-transforming and -metabolizing bacte-rial species and their genetics, recent advances in the mechanisms of the microbe-mediated As-biotransformation pathways, and their implications on the biogeochemical cycling of arsenic in nature. This review will further help to develop a better understanding of bacterial response to arsenic, bioremediation strategies, and future research fields.Keywords Arsenic · Bacteria · Biotransformation · Arsenite · Arsenate · Methylation · Demethylation · Bioremediation
(PDF) Decoding the pathways of arsenic biotransformation in bacteria. Available from: https://www.researchgate.net/publication/350003355_Decoding_the_pathways_of_arsenic_biotransformation_in_bacteria [accessed Mar 31 2021].
... [64] This also demonstrates that the As(III)-drug was in the pores in a form of H3AsO3 and not as As2O3 (shown in Figure S1). The existence of the hydrated form, which is usually stable only in a solution, [65] was possible due to the interaction with the framework. It was reported for the MOF MIL-100(Fe) that if As(OH)3 was coordinated to the metal centre via the oxygen donor atom then a band around 800 cm -1 corresponding to the (As−O) vibration was detected. ...
Although arsenic and its compounds are mainly known as a poison, they also found applications as drugs in medicine. However, their distribution in a therapeutic dose is often problematic due to their high toxicity. One possibility how to address this issue is utilizing drug delivery systems. Herein, we report on a metal‐organic framework (MOF) called Zn‐MOF‐74, which comprises Zn(II) ions and 2,5‐dihydroxybenzene‐1,4‐dicarboxylate ligands, as a drug nanocarrier of arsenic trioxide. We synthetized the material in a nanoparticle formulation and showed that due to the open metal sites in Zn‐MOF‐74, it was possible to load the material with a high amount of the As(III)‐drug (in a form of arsenous acid). Moreover, we also investigated the drug release at different pH‐values. Noticeably, we observed that the As(III)‐release was pH‐triggered and was faster at pH 6.0 than at pH 7.4. Therefore, we suggest Zn‐MOF‐74 as a model example of a MOF containing open metal sites for controlled drug loading and delivery.
... In E.coli, As(III) can enter the cell by the aquaglyceroporin channel GlpF (Sanders et al., 1997;Meng et al., 2004). These channels normally transport small uncharged molecules such as glycerol (Heller et al., 1980;Borgnia and Agre, 2001), but also As(III) as non-charged As(OH) 3 under neutral pH (Ramírez-Solís et al., 2012). However, in environments with a pH higher than its pKa of 9.2, As(III) will be mostly present in its ionic form (Smedley and Kinniburgh, 2002). ...
The genus Thioalkalivibrio includes haloalkaliphilic chemolithoautotrophic sulfur-oxidizing bacteria isolated from various soda lakes worldwide. Some of these lakes possess in addition to their extreme haloalkaline environment also other harsh conditions, to which Thioalkalivibrio needs to adapt. An example is arsenic in soda lakes in eastern California, which is found there in concentrations up to 3000 μM. Arsenic is a widespread element that can be an environmental issue, as it is highly toxic to most organisms. However, resistance mechanisms in the form of detoxification are widespread and some prokaryotes can even use arsenic as an energy source. We first screened the genomes of 76 Thioalkalivibrio strains for the presence of known arsenic oxidoreductases and found 15 putative ArxA (arsenite oxidase) and two putative ArrA (arsenate reductase). Subsequently, we studied the resistance to arsenite in detail in Thioalkalivibrio jannaschii ALM2T, and Thioalkalivibrio thiocyanoxidans ARh2T by comparative genomics and by growing them at different arsenite concentrations followed by arsenic species and transcriptomic analysis. Tv. jannaschii ALM2T, which has been isolated from Mono Lake, an arsenic-rich soda lake, could resist up to 5 mM arsenite, whereas Tv. thiocyanoxidans ARh2T, which was isolated from a Kenyan soda lake, could only grow up to 0.1 mM arsenite. Interestingly, both species oxidized arsenite to arsenate under aerobic conditions, although Tv. thiocyanoxidans ARh2T does not contain any known arsenite oxidases, and in Tv. jannaschii ALM2T, only arxB2 was clearly upregulated. However, we found the expression of a SoeABC-like gene, which we assume might have been involved in arsenite oxidation. Other arsenite stress responses for both strains were the upregulation of the vitamin B12 synthesis pathway, which can be linked to antioxidant activity, and the up- and downregulation of different DsrE/F-like genes whose roles are still unclear. Moreover, Tv. jannaschii ALM2T induced the ars gene operon and the Pst system, and Tv. thiocanoxidans ARh2T upregulated the sox and apr genes as well as different heat shock proteins. Our findings for Thioalkalivibrio confirm previously observed adaptations to arsenic, but also provide new insights into the arsenic stress response and the connection between the arsenic and the sulfur cycle.
... Arsenic in solution commonly found as As(OH)3 (Ramírez- Solís et al., 2004) whose structure is similar to glycerol (Porquet & Filella, 2007). Based on the structural similarity, it is suggested that As(OH)3 can be recognized as a substrate by Fps1, a yeast aquagyceroporin, like it is done for glycerol ( Fig. 1). ...
Arsenic is a metalloid member of heavy metals associated with many health problems from various cancers to skin diseases. Due to mankind activities and natural sources, arsenic contamination seen globally. More than 150 million people globally face with arsenic via arsenic polluted ground water. It is well known that speciation of arsenic is important for its actions inside of the exposed organism. Saccharomyces cerevisiae, is one of six model organisms, provides an general answer for the question “What eukaryotes do?”. So assessing some questions on budding yeast gives a general idea about potential results in other eukaryotes including human. One of the issues investigated on this yeast is that impacts and metabolism of arsenic. Arsenic is well studied on Saccharomyces cerevisiae and consequently much data became available. In this review, cellular impacts of arsenic and response of the yeast towards arsenic exposure is covered.
... The specific subfamily of AQPs named aquaglyceroporins (AQP3, AQP7, AQP9, and AQP10) transports larger molecules such as glycerol. It was sown that this subfamily is responsible for transporting arsenite in mammalians [35]. ...
Arsenic is one of the most important environmental pollutants especially in drinking water. The S100B protein is presented as a sensitive biomarker for assessment of the blood-brain barrier integrity previously. The objective of this study was to determine the impact of chronic arsenic exposure in drinking water and serum S100B correlation. Fifty-four male BALB/c mice were randomly divided into three groups. Group I and II subjects were treated with arsenic trioxide (1 ppm and 10 ppm, respectively), while the rest received normal drinking water. Arsenic concentration in serum and brain was measured by an atomic absorption spectrometer (Varian model 220-Z) conjugated with a graphite furnace atomizer (GTA-110). Also, a serum S100B protein concentration was determined using commercial ELISA kit during different times of exposure. It was observed that body weight gain was significantly lower from the 10th week onwards in arsenic-treated subjects. However, it did not induce any visible clinical signs of toxicity. Measured arsenic level in serum and brain was higher in espoused groups as compared to the control subjects (p < 0.001 and p < 0.0001, respectively). In addition, serum S100B content was increased over a period of 3 months and had significant differences as compared to the control and 1-ppm group especially after 3 months of exposure in the 10-ppm group (p < 0.0001). In conclusion, it could be inferred that long-term arsenic exposure via drinking water leads to brain arsenic accumulation with serum S100B elevated concentration as a probable BBB disruption consequence.
... The effective radius of the anion (AsO 3 Þ 3À is about *2.5 Å and is determined by its trigonal geometry, its As-O bond length of 1.77Å , and the large oxygen atom. The ion in the hydrated state As(OH) 3 is suggested by Ramãres Solis et al. (2004) to be the form taken up by cellular processes. Maximum allowed limits (MALs) indicate the safe limits for each substance, according to WHO drinking water standards used in Wasana et al. (2017), i.e., MALs for F = 1.5 mg/l, Cd = 3 lg/l, As = 10 lg/l, Pb = 10 lg/l, secondary standard Al = 200 lg/l, hardness: CaCO 3 = 200 mg/l and MgCO 3 = 185 mg/l Just as ions solvate a layer of water molecules, proteins also from a hydration layer at their charge centers where electrostatic effects and hydrogen bonding come into play. ...
High incidence of chronic kidney disease of unknown etiology (CKDU) prevalent in many countries (e.g., Sri Lanka, equatorial America) is reviewed in the context of recent experimental work and using our understanding of the hydration of ions and proteins. Qualitative considerations based on Hofmeister-type action of these ions, as well as quantitative electrochemical models for the Gibbs free energy change for ionpair formation, are used to explain why (1) fluoride and water hardness due to magnesium ions (but not due to calcium ions) and similarly (2) cadmium ions in the presence of suitable pairing ions can be expected to be more nephrotoxic, while arsenite in the presence of fluoride and hardness may be expected to be less nephrotoxic. No synergy of arsenic with calcium hardness is found. The analysis is applied to a variety of ionic species that may be found in typical water sources to predict their likely combined electrochemical action. These results clarify the origins of chronic kidney disease that has reached epidemic proportions in the North Central Province of Sri Lanka as being most likely due to the joint presence of fluoride and magnesium ions in drinking water. The conclusion is further strengthened by a study of the dietary load of Cd and other toxins in the affected regions and in the healthy regions where the dietary toxin loads and lifestyles are similar, and found to be safe especially when the mitigating effects of micronutrient ionic forms of Zn, Se, as well as corrections for bioavailability are taken into account. The resulting etiological picture is consistent with the views of most workers in the field who have suspected that fluoride and other ions found in the hard water stagnant in shallow household wells were the major causative factors of the disease. Similar incidence of CKDu found in other hot tropical climates is likely to have similar origins.
... The predominant form of arsenite in solution at neutral pH appears to be the polyhydroxylated form As(OH) 3 (Ramirez- Solis et al. 2004). Similarly, the chemical form of Sb(III) recognised by aquaglyceroporins is thought to be Sb(OH) 3 (Baes and Mesmer 1976). ...
... The membrane transport of As III in the body is incompletely understood. Apparently, multidrug resistance-associated protein 2 (MRP2) located in the bile canalicular membrane is responsible for the biliary excretion of glutathione conjugates of As III and MMAs III (Leslie, 2012), while the uncharged form of As III (i.e., As(OH) 3 ) can pass through some aquaglyceroporins (Ramírez-Solís et al., 2004). The potential involvement of glucose transporters (GLUT1 and GLUT2) in the disposition of As III has been suggested (Drobná et al., 2010;Liu et al., 2006). ...
Arsenate (AsV) and arsenite (AsIII) are typical sources of acute and chronic arsenic poisoning. Therefore, reducing inner exposure to these arsenicals is a rational objective. Because AsV mimics phosphate, phosphate binder drugs may decrease the intestinal AsV absorption. Indeed, lanthanum and aluminium salts and sevelamer removed AsV from solution in vitro, especially at acidic pH. In mice gavaged with AsV, lanthanum chloride, lanthanum carbonate and aluminium hydroxide given orally also lowered the urinary excretion and tissue levels of AsV and its metabolites, indicating that they decreased the gastrointestinal AsV absorption. As some glucose transporters may carry AsIII, the effect of the SGLT2 inhibitor dapagliflozin was investigated in AsIII-injected mice. While producing extreme glucosuria, dapagliflozin barely affected the urinary excretion and tissue concentrations of AsIII and its metabolites. Thus, phosphate binders (especially lanthanum compounds) can reduce the gastrointestinal absorption of AsV; however, SGLT2 inhibition cannot diminish the renal reabsorption of AsIII.
... allow the passage of other small neutral molecules including glycerol, urea, and certain species of arsenic across cellular membranes down their concentration gradients (Rojek et al., 2008). In solution at physiological pH, As III exists almost exclusively in the undissociated neutral form As(OH) 3 (pK a 9.2) (Ramirez-Solis et al., 2004). Studies of As III permeability in oocytes of Xenopus laevis injected with water, or cRNA of human AQP3 (hAQP3), hAQP7, hAQP9, or hAQP10 revealed that hAQP3, hAQP7, and hAQP9 can conduct As III across cell membranes, while hAQP10 could not (Liu et al., 2004b) (Table 1). ...
Natural contamination of drinking water with arsenic results in the exposure of millions of people world-wide to unacceptable levels of this metalloid. This is a serious global health problem because arsenic is a Group 1 (proven) human carcinogen and chronic exposure is known to cause skin, lung, and bladder tumors. Furthermore, arsenic exposure can result in a myriad of other adverse health effects including diseases of the cardiovascular, respiratory, neurological, reproductive, and endocrine systems. In addition to chronic environmental exposure to arsenic, arsenic trioxide is approved for the clinical treatment of acute promyelocytic leukemia, and is in clinical trials for other hematological malignancies as well as solid tumors. Considerable inter-individual variability in susceptibility to arsenic-induced disease and toxicity exists, and the reasons for such differences are incompletely understood. Transport pathways that influence the cellular uptake and export of arsenic contribute to regulating its cellular, tissue, and ultimately body levels. In the current review, membrane proteins (including phosphate transporters, aquaglyceroporin channels, solute carrier proteins, and ATP-binding cassette transporters) shown experimentally to contribute to the passage of inorganic, methylated, and/or glutathionylated arsenic species across cellular membranes are discussed. Furthermore, what is known about arsenic transporters in organs involved in absorption, distribution, and metabolism and how transport pathways contribute to arsenic elimination are described.
... EXAFS data indicate an arsenitelike structure (three-coordinated AsO 3 3À moiety with a stereochemically active electron lone pair), but with AsAO bond distances of $1.68-1.70 Å that are similar to AsAO distances in the rigid arsenate group ($1.68 Å ) but shorter than typical As(III)AO distances in crystals (1.77(3) Å ; Ramirez-Solis et al., 2004) or in aqueous complexes (1.75-1.77(1) Å , Testemale et al., 2004). ...
Element substitution that occurs during fluid-rock interaction permits assessment of fluid composition and interaction conditions in ancient geological systems, and provides a way to fix contaminants from aqueous solutions. We conducted a series of hydrothermal mineral replacement experiments to determine whether a relationship can be established between arsenic (As) distribution in apatite and fluid chemistry. Calcite crystals were reacted with phosphate solutions spiked with As(V), As(III), and mixed As(III)/As(V) species at 250 ̊C and water- saturated pressure. Arsenic-bearing apatite rims formed in several hours, and within 48 hours the calcite grains were fully replaced. X-ray Absorption Near-edge Spectroscopy (XANES) data show that As retained the trivalent oxidation state in the fully-reacted apatite grown from solutions containing only As(III). Extended X-ray Fine Spectroscopy (EXAFS) data reveal that these As(III) ions are surrounded by about three oxygen atoms at an As-O bond length close to that of an arsenate group (AsO43-), indicating that they occupy tetrahedral phosphate sites. The three-coordinated As(III)-O3 structure, with three oxygen atoms and one lone electron pair around As(III), was confirmed by geometry optimization using ab initio molecular simulations.
The micro-XANES imaging data show that apatite formed from solutions spiked with mixed As(III) and As(V) retained only As(V) after completion of the replacement reaction; in contrast, partially reacted samples revealed a complex distribution of As(V)/As(III) ratios, with As(V) concentrated in the center of the grain and As(III) towards the rim. Most natural apatites from the Ernest Henry Iron Oxide Copper Gold deposit, Australia, show predominantly As(V), but two grains retained some As(III) in their core. The As-anomalous amphibolite-facies gneiss from Binntal, Switzerland, only revealed As(V), despite the fact that these apatites in both cases formed under conditions where As(III) is expected to be the dominant As form in hydrothermal fluids.
These results show that incorporation of As in apatite is a complicated process, and sensitive to the local fluid composition during crystallization, and that some of the complexity in As zoning in partially reacted apatite may be due to local fluctuations of As(V)/As(III) ratios in the fluid and to kinetic effects during the mineral replacement reaction. Our study shows for the first time that As(III) can be incorporated into the apatite structure, although not as efficiently as As(V). Uptake of As(III) is probably highly dependent on the reaction mechanism. As(III)O33- moieties replace phosphate groups, but cause a high strain on the lattice; as a result, As(III) is easily exchanged (or oxidized) for As(V) during hydrothermal recrystallization, and the fully reacted grains only record the preferred oxidation state (i.e., As(V)) from mixed-oxidation state solutions. Overall this study shows that the observed oxidation state of As in apatite may not reflect the original As(III)/As(V) ratio of the parent fluid, due to the complex nature of As(III) uptake and possible in-situ oxidation during recrystallization.
... These values are very close to the experimental As-O bond length determined for As(OH) 3 (ref. 108) and those for the ionic arsenic-water complexes. 109,110 A comparison between the covalent and ionic bond character provided by NRT also suggests a pAs-O bond for i7 due to its large covalent nature and the large polarization on the arsenic atom. ...
The main goal of this investigation is to understand the reaction pathways and the electronic and spectroscopy properties of AsOHn radicals (n = 0-3), which are some of the simplest compound models with an arsenic-oxygen bond. A CCSD(T) level of theory with a complete basis set limit (CBS) was applied to understand the relative stability and the reaction pathways among the isomers. Several reaction pathways such as the unimolecular rearrangement routes, the internal rotational transition state structures, and the hydrogen release routes were also evaluated among these structures. In the case of oxoarsine isomers, it was seen that the oxoarsine (HAsO) ground state structure presents a singlet state and AsOH possesses a triplet ground one. trans-Hydroxyarsinyl (trans-HAsOH) is the global minimum structure with an energy gap around 20 kcal mol⁻¹ when compared with arsinoyl (H2AsO), and this energy difference is increased two times when compared with AsOH2. Arsinous acid (H2AsOH) is more stable than arsine oxide (H3AsO) based on the relative energy difference, while it is predicted that there is a large energy gap when compared with HAs(H2O) stereoisomers. The heat of formation was also calculated for each isomer. In addition, in the characterization of arsenic-oxygen bond characters, several bond order indexes and different population methods were also applied to understand the influence of different methodologies, as well as the Quantum Theory of Atoms in Molecules (QTAIM) and the Natural Bond Orbital (NBO) method.
... As and Sb can permeate cells using molecular mimicry via transporters that evolved for accumulation of fundamental ions and nutrients. Both trivalent arsenite and antimonite exist in the tri-hydroxylated uncharged forms [As(OH) 3 and Sb (OH) 3 ] which structurally resemble glycerol at the physiological pH in aqueous solution (Ramirez-Solis et al. 2004;Porquet and Filella 2007). The aquaglyceroporins (membrane proteins) that are permeable to water and glycerol also permits accumulation of As(III) and Sb(III) (Bhattacharjee et al. 2008). ...
In natural environments, heavy metals and metalloids are widely dispersed as a consequence of anthropogenic (e.g. mining) and geological (e.g. volcanic eruption) activities. The toxicity of these metals/metalloids could adversely affect the ecosystem as well as causing major human health concerns. Mycoremediation (remediation by fungi) has received attention from many researchers as an alternative to conventional chemical and physical methods in removing toxic metals and metalloids. A number of regulatory mechanisms to control the concentrations and counteract the toxicity of these pollutants have been observed in fungi. These mechanisms include: (i) precipitation or binding to cell surface materials, (ii) intracellular chelation and precipitation, (iii) biotransformation and (iv) control of membrane transport systems. This chapter examines the use of fungi to bioremediate metals and metalloids and their detoxification mechanisms, with special focus on an extremophilic fungus, Acidomyces acidophilus, isolated from a disused tin mine in the UK, to illustrate some of the mechanisms involved. Future biotechnological and nanotechnological prospects of metal/metalloids bioremediation using fungi are also discussed.
... the form of As(OH) 3 [ 7] and quantum calculations support the notion that As III and Sb III in the form of As(OH) 3 and Sb(OH) 3 respectively are highly similar to each other at the structural, thermodynamic and electrostatic levels. [8] In contrast, the pentavalent forms As V and Sb V are dissimilar, the former having a tetrahedral structure whereas the latter has an octahedral structure. ...
Antimony is a toxic metalloid that is naturally present in low amounts in the environment, but can locally reach high concentrations at mining and processing sites. Today, antimony is used in a wide range of modern technology applications and is also an important constituent of pharmacological drugs. The increasing use of antimony has led to concerns about human and environmental exposure. Yet little is known about the biological properties of antimony and its mechanisms of actions in cells. This review will provide a brief summary of how antimony enters and affects cells, and how cells deal with the presence of this metalloid to acquire resistance.
... 2004; Zhao et al., 2009;Zhang et al., 2009;Duester et al., 2011). Inorganic arsenic exists in two forms under physiological conditions, as the reduced form, As(III) (Arsenite) and the oxidised form, As(V) (Arsenate) (Greenwood and Earnshaw, 1984;Ramirez-Solis et al., 2004;Zhao et al., 2009). Under the usual aerobic conditions arsenate is the predominant form as HAsO 4 2 À (pKa 2 ¼6.96). ...
Accumulation of arsenic in plants is a serious Southeast Asian environmental problem. Photosynthesis in the small aquatic angiosperm Wolffia arrhiza is very sensitive to arsenic toxicity, particularly in water below pH 7 where arsenite (As (OH) 3) (AsIII) is the dominant form; at pH 47 AsO 4 2 À (As (V) predominates). A blue-diode PAM (Pulse Amplitude Fluorometer) machine was used to monitor photosynthesis in Wolffia. Maximum gross photosynthesis (Pg max) and not maximum yield (Y max) is the most reliable indicator of arsenic toxicity. The toxicity of arsenite As(III) and arsenate (H 2 AsO 4 2 À) As (V) vary with pH. As(V) was less toxic than As(III) at both pH 5 and pH 8 but both forms of arsenic were toxic (490% inhibition) at below 0.1 mol m À 3 when incubated in arsenic for 24 h. Arsenite toxicity was apparent after 1 h based on Pg max and gradually increased over 7 h but there was no apparent effect on Y max or photosynthetic efficiency (α 0).
... These fit results are consistent with previous studies on aqueous As(III) characterization [12] and As(GS)3 complex formation [13]. It is important to note that EXAFS data provide an averaged picture of the local coordination of As and cannot rule out the possibility of oxygen and sulfur binding simultaneously to As ions. ...
In this study, the chemical reactions between As(III) and As(V) with glutathione, which is a target compound in As biochemistry due to its primordial role in As immobilization and intracellular reduction, in various molar ratios were investigated using As K-edge XAFS spectroscopy. Results showed a gradual substitution of As-O bonds in the coordination of aqueous As(III) and As(V) for three As-S bonds in the As+GSH complex. Moreover, the data showed reduction of As(V) to As(III) prior or concomitant to the As+GSH complex formation.
... As(III) removal potential of Bacillus licheniformis DAS-2 was 100% at lower concentration of supplied As(III) in the media (1 mM), which decreased up to 58% at 5 mM of supplied As(III). As(III)/Arsenite (AsO 2 À ) occurs in its hydroxide form as As(OH) 3 at neutral pH, which is an inorganic equivalent of non-ionized glycerol, hence As(III) might uses glycerol membrane transport system to move across the cell Ramirez-Solis et al., 2004). There was no biotransformation of As(III) observed. ...
... (Zhu et al., 1999b) When grown on polluted soil b , shoots showed 1.5 higher Cd and Zn levels. (Bennett et al., 2003 to have high levels of endogenous root arsenate reductase and arsenate conversion to arsenite sequestered in the roots as As(III)thiol prevents the translocation of arsenic species to aboveground tissues, making it unsuitable for phytoextraction (Pickering et al., 2000;Dhankher et al., 2002;Ramírez-Solís et al., 2004). To promote arsenate mobilization to the shoots, Dhankher et al. (2006) employed the RNA interference approach to silence the arsenate reductase ARS2 gene in A. thaliana. ...
Environmental pollution by heavy metals is an actual problem. Their cytotoxic, mutagenic and carcinogenic effects have been discovered recently. Phyto or bioremediation are environmental-friendly methods for metals removal from water and soils. Plant phytoremediation potential is limited by their tolerance to heavy metals, other benefits are metal accumulation in shoots and production of high amount of biomass. To increase the binding capacity of heavy metals transgenic plants expressing a fusion protein combining CUP1 gene encoding yeast metallothionein and gene for polyhistidine tag from commercial plasmid pTrc-HisA (HisCUP), which was transformed via A. tumefaciens into tobacco plants. The aim of this article was to determine metallothionein content in transgenic tobacco plants exposed to 250 μM CdCl2. A marked MT induction was found in the whole plant, especially in stem. Change in MT content corresponded to change of low-molecular thiol compounds. The obtained results indicate that MT is in experimental plants induced by heavy metal and it is involved in plant detoxication mechanisms.
... Many investigators have used sodium arsenite rather than ATO for in vitro studies. Chemically, these agents are both converted to arsenous acid and exist as arsenous acid [As(OH) 3 ] in neutral solution [24]. Indeed, Trisenox®, the pharmacological formulation of ATO used in the clinic to treat APL, is prepared by dissolution of ATO in 30 mM NaOH followed by titration with HCl to near neutral pH (http://www.trisenox.com/hcp/trisenoxprescribing-information.pdf). ...
Arsenic is an enigmatic xenobiotic that causes a multitude of chronic diseases including cancer and also is a therapeutic with promise in cancer treatment. Arsenic causes mitotic delay and induces aneuploidy in diploid human cells. In contrast, arsenic causes mitotic arrest followed by an apoptotic death in a multitude of virally transformed cells and cancer cells. We have explored the hypothesis that these differential effects of arsenic exposure are related by arsenic disruption of mitosis and are differentiated by the target cell’s ability to regulate or modify cell cycle checkpoints. Functional p53/CDKN1A axis has been shown to mitigate the mitotic block and to be essential to induction of aneuploidy. More recent preliminary data suggest that microRNA modulation of chromatid cohesion also may play a role in escape from mitotic block and in generation of chromosomal instability. Other recent studies suggest that arsenic may be useful in treatment of solid tumors when used in combination with other cytotoxic agents such as cisplatin.
In the soil of Bihar (latitudes N25-40.997' and E84-52.288'), a new type of bacteria resistant to arsenic was found. Bacillus stratosphericus was identified as the isolate using phylogenetic analysis and 16S rRNA sequencing. The isolated strain was also registered as Bacillus stratosphericus MKS under accession numbers OM841514, according to IMTECH, Chandigarh. The isolated strain can eliminate 99.9% of arsenate at 50 mM As(V) concentrations and 90% of Arsenite at 2 mM As (III) concentrations, according to the batch experiment's impressive results. The strain's ability to withstand high arsenite and arsenate concentrations, with minimum inhibitory values of 10 mM and 250 mM, respectively, is also noteworthy. A bacterium species called Bacillus stratosphericus is well known for its capacity to endure harsh conditions like the stratosphere. It may have evolved special adaptations to deal with this deadly metalloid given that it was discovered in soil that was contaminated with arsenic. In conclusion, this work offers insightful information about the possible application of Bacillus stratosphericus MKS for arsenic remediation in contaminated areas. As well as examining the underlying processes of this strain's tolerance to arsenic, future studies might concentrate on improving the circumstances for its growth and elimination of arsenic.
Background: Realgar, a traditional mineral medicine containing arsenic, has been utilized for a long time in Asian nations like China and India. Realgar is primarily excreted in proto-form, and its active components are believed to be the soluble portion. The biological events involved in absorption, transportation, metabolism, and excretion are poorly understood. Objective: In this review, we attempt to systematically elaborate the in vivo process of realgar from absorption to excretion and investigate its possible mechanism, so that people can gain a better understanding of the chemical substance basis of realgar and serve as a reference for realgar efficacy, toxicity research, and clinical application. Methods: The relevant information and literature were extracted and retrieved from the National Library of Medicine (PubMed), Elsevier, the National Knowledge Infrastructure (CNKI), Wiley Analytical Science, Springer Link, the Web of Science, the Science Guide Chinese Pharmacopoeia, and other databases, using realgar, arsenic, absorption, transport, distribution, metabolism, excretion, intestinal flora, and anticancer as keywords. The process and possible mechanisms of realgar from absorption to excretion in vivo were summarized. Results: Realgar has a low bioavailability and only soluble arsenic is dissolved in the gastrointestinal tract. Arsenic is mostly absorbed by ion and molecular mimicry, transported to the bloodstream by carrier proteins, and distributed throughout the body's organs. The metabolism of arsenic in realgar includes reduction, oxidation, methylation, and mercaptan. Arsenic and its metabolites are mainly distributed in the blood and various organs, among which the blood is the highest level of arsenic distribution. Ultimately, the majority of arsenic and its metabolites are removed in the urine, whereas unabsorbed realgar is eliminated in the feces. Conclusion: The main ingredient of realgar (As4S4) is mainly found in its primary form in the gastrointestinal tract and excreted with feces in vivo, where it has little to no therapeutic effect. Realgar's efficacy and toxicity may be attributed to the soluble arsenic it contains, which includes inorganic arsenic such as AsIII and AsV as well as organic arsenic such as MMA and DMA, which are metabolites of inorganic arsenic. In vivo, soluble arsenic is absorbed, distributed, metabolized, accumulated, and excreted, and there is hepatoenteric circulation.
Arsenic contamination in food and groundwater constitutes a public health concern for more than 200 million people worldwide. Individuals chronically exposed to arsenic through drinking and ingestion exhibit a higher risk of developing cancers and cardiovascular diseases. Nevertheless, the underlying mechanisms of arsenic toxicity are not fully understood. Arsenite is known to bind to and deactivate RING finger E3 ubiquitin ligases; thus, we reason that a systematic interrogation about how arsenite exposure modulates global protein ubiquitination may reveal novel molecular targets for arsenic toxicity. By employing liquid chromatography-tandem mass spectrometry, in combination with stable isotope labeling by amino acids in cell culture (SILAC) and immunoprecipitation of di-glycine-conjugated lysine-containing tryptic peptides, we assessed the alterations in protein ubiquitination in GM00637 human skin fibroblast cells upon arsenite exposure at the entire proteome level. We observed that arsenite exposure led to altered ubiquitination of many proteins, where the alterations in a large majority of ubiquitination events are negatively correlated with changes in expression of the corresponding proteins, suggesting their modulation by the ubiquitin-proteasomal pathway. Moreover, we observed that arsenite exposure confers diminished ubiquitination of a rate-limiting enzyme in cholesterol biosynthesis, HMGCR, at Lys248. We also revealed that TRC8 is the major E3 ubiquitin ligase for HMGCR ubiquitination in HEK293T cells, and the arsenite-induced diminution of HMGCR ubiquitination is abrogated upon genetic depletion of TRC8. In summary, we systematically characterized arsenite-induced perturbations in a ubiquitinated proteome in human cells and found that the arsenite-elicited attenuation of HMGCR ubiquitination in HEK293T cells involves TRC8.
Zirconium clusters of UiO-66 have been hydroxylated with NaOH to generate strong binding sites for As(III) species in wastewater treatment. Hydroxylated UiO-66 provides high adsorption capacity over a wide range of pH from 1 to 10 with a maximum uptake of 204 mg g-1, which is significantly enhanced compared to those of pristine UiO-66, acid-modulated UiO-66, and other adsorbents for use in a wide pH range of treatment processes. The local structure of hydroxylated sites and As(III) adsorption mechanism are determined by extended X-ray absorption fine structure combined with density functional theory calculations.
Antimony complexation with organic ligands dominates its biotoxicity and mobility in the environment, drawing extensive concerns. Structure resolution and pertinently quantitative analysis of those complexes in diversified matrix become significant...
Oxyanions are pollutants that pose health risks to humans, impact organisms negatively and can cause environmental hazard like eutrophication. Their removal from aqua systems is therefore expedient. Although conventional chemical and physical treatments exist and have been well-exploited, the biotreatment option is the way forward as they are eco-friendly, cheaper and less technical. There are available scientific studies on the use of biological agents for the removal of oxyanions from water which ranges from the use of plants through to organisms. However, a only a few of these studies focus on the use of microorganisms for oxyanion removal in water. This chapter, therefore, focuses on the use of microorganisms for the removal of oxyanions from water. It provides a collection of reports on the laboratory and field applications of microorganism removal of oxyanions in water either singly or as a consortium and highlights their successes and weaknesses. This chapter also gives a rare insight into genes responsible for arsenic-resistant bacteria that allows them to effectively accumulate arsenate and arsenite from aqua systems. We present future perspectives that will aid further research in this area of study.
This study aims to determine the bioremediation potential of bioengineered Shewanella oneidensis as a cost-effective alternative for arsenic (As) removal from groundwater, as opposed to the current complex and hazardous chemical and physical methods. Herein we present a novel filtration method, by bioengineering a bacterium with bioremediation potential, S. oneidensis MR-1, to express As-binding protein, ArsR, as it adopts a biofilm lifestyle. The recombinant S. oneidensis (M) was compared to its wild-type MR-1 (WT) across a range of As concentrations (0–800 µM) and time (0–48 h) in its planktonic and biofilm form. Analyses of As-sorption in the wild-type MR-1 and recombinant indicated significant sequestration which increased with time incubated, while As-sorption did not plateau even at high As concentrations of 800 μM. The recombinant displayed significantly higher As sequestration than the wild type (p < 0.0001; cohen’s d = 122.4), with higher sequestration observed in the planktonic compared to the biofilm form (p < 0.0001; cohen’s d = 4.262). Filtration efficiencies of 87% and 94% were obtained for As(III) and As(V) respectively using our system, showing a significant improvement over current commercial systems. With applications in potable water and industrial wastewater filtration, especially for rural and underdeveloped countries given the lack of reliance on specialized equipment, this system represents a powerful potential next-generation Arsenic filtration method.
Nephrotoxicity is within the recognized toxic effects of arsenic. In this study we assessed the effect of arsenite on the renal capacity to metabolize and handle arsenicals in rats exposed to drinking water with 0, 1, 5, or 10 ppm sodium arsenite for ten days. Arsenite treatment did not affect the gene expression of the main enzyme catalyzing methylation of arsenite, As3mt, while it reduced the expression of GSTO1 mRNA and protein. Arsenite decreased the expression of Aqp3, Mrp1, Mrp4, and Mdr1b (i.e., transporters and channels used by arsenic), but not that of Aqp7, Glut1, Mrp2, and Mdr1a. The protein abundance of AQP3 was also reduced by arsenite. Arsenite increased urinary NGAL and FABP3 and decreased Klotho plasma levels, without alteration of creatinine, which evidenced early tubular damage. Renal Klotho mRNA and protein expressions were also downregulated, which may exacerbate renal damage. No effect was observed in selected miRNAs putatively associated with renal injury. Plasma PTH and FGF23 were similar between groups, but arsenite decreased the renal expression of Fgfr1 mRNA. In conclusion, exposure to arsenite alters the gene expression of proteins involved in the cellular handling of arsenical species and elicits tubular damage.
Minerals/water interfaces affect the transport and fate of arsenic and are effective to control arsenic contamination. Dispersion-corrected p-DFT calculations are conducted to unravel the mechanisms of As(III) and As(V) adsorption at gibbsite surfaces (both anhydrous and hydrated). The possibility for As(III) and As(V) anion formation is explored by studying the proton transfers to gibbsite surfaces and water molecules, and electron transfers are calculated to facilitate the understanding of adsorption mechanisms. Anhydrous and hydrated surfaces prefer to adsorb H3AsO4 and As(OH)3, respectively. (100) surface is superior for adsorption and produces direct Al-OAs bonds, in addition to H-bonded structures as (001) surface. Reservation of surface/water interactions is critical to maintain the stabilities of outer-sphere complexes, especially for (100) surface. H2AsO4⁻ is always ready to form, and H2AsO3⁻ does exist for (100) surface as characterized by the small reaction energy and activation barrier. Mineral surfaces are more important than water for formation and stabilization of As(III) and As(V) anions. Electron transfers are significant for both inner- and outer-sphere complexes, and mineral surfaces rather than water play a larger role during electron transfers. Nature of electron transfers for water layers is reversed by H3AsO4 adsorption, which may interpret the inferior adsorption than As(OH)3.
Arsenite is a highly toxic compound present in many water sources around the world. The removal of arsenite from water requires its oxidation to arsenate which is much more amenable to treatment using well attested technologies. Prior research has shown that the oxidation of arsenite by hydroxyl radicals is significantly accelerated in the presence of carbonate ions but the intrinsic mechanisms of the acceleration have not yet been established. The main goal of the present work was to examine the oxidation of arsenite in the framework of the density functional theory, to establish a detailed microscopic level mechanism of interactions between arsenite and hydroxyl radicals and to elucidate the nature of the catalytic effect of carbonate ions. Results of this study demonstrate that the [As(OH)2CO3]- complex is the thermodynamically most stable species formed in the system H3AsO3-CO32-/HCO3--H2O. Interactions of the hydroxyl radical with the [As(OH)2CO3]- complex yield the pre-reaction complex [As(OH)3CO3]-∗ in the reaction of subsequent oxidation of arsenite. The structures of the reactants, products and transition states, as well as pre- and post-reaction complexes corresponding to several possible mechanisms of the first stage of As(III) oxidation to As(IV) intermediate using hydroxyl radicals in the absence and in the presence of [As(OH)2CO3]-, were determined in this study. The data demonstrate that the arsenite-carbonate complexes [As(OH)2CO3]- are characterized by a significantly lower activation energy of the first oxidation stage under the action of a hydroxyl radical (2.8 kcal/mol) compared to that for the free arsenite H3AsO3 (13.6 kcal/mol).
Leishmania parasites rely heavily upon membrane transport proteins to deliver essential nutrients from their hosts to the interior of the parasite. Some of these transporters also serve as routes for uptake of drugs used for treatment of leishmaniasis or experimental drugs with potential for development of novel anti-leishmanial therapies. Hence, mutations within the coding regions of such permeases or alterations in the expression of the carrier proteins can confer drug resistance upon the parasites. This chapter reviews the current level of knowledge regarding several classes of membrane transporters known to play roles in uptake or sensitivity to drugs. The increasing knowledge of the “permeome,” provided by complete genome sequences of several Leishmania species, has advanced considerably our knowledge of how nutrients and drugs or other cytotoxic compounds enter these pathogenic protozoa. Recent genome-wide approaches to functional analysis promise to further our understanding of transporters as determinants of drug sensitivity and resistance.
While arsenous acid, As(OH)3, has been the subject of a plethora of studies due to its worldwide ubiquity and its toxicity, pentavalent As in the form of arsenic acid, AsO(OH)3, has recently been found in rivers in central Mexico as the most abundant naturally occurring arsenic species. In order to better understand the solvation pattern differences of these toxic species at the molecular level, we report the results of Born-Oppenheimer molecular dynamics (BOMD) simulations on the aqueous solvation of the AsO(OH)3 and As(OH)3 molecules at room temperature using the cluster microsolvation approach including 30 water molecules. The electronic structure calculations were done using the M062X hybrid exchange-correlation functional in conjunction with the 6-31G** basis sets for oxygen and hydrogen atoms. For As the Stuttgart-Köln relativistic effective-core potential was utilized with its associated valence basis set. Starting from the optimized geometry of the arsenic and arsenous acids embedded in the microsolvation environment, we find that the average per-molecule water binding energy is ca. 1 kcal/mol larger for the As(V) species as compared to the As(III) one. The total As-O radial distribution functions (RDF) reveal radically different solvation patterns. In spite that similar first As(V)-As(III) solvation shells from 3.1 to 4.42 Å are found, their integration leads to 10 and 14 oxygen atoms implying coordination numbers of 6 and 11 water molecules for AsO(OH)3 and As(OH)3, respectively. A careful structural analysis of the upper and lower-hemispheres RDF also reveals very different angular solvation patterns for As(V) vs. As(III). Theoretical EXAFS spectra were obtained and are in very good agreement with experimental spectra for As(III) and As(V) in liquid water. Proton transfer processes are also addressed, and we find that singly and even doubly deprotonated AsO4H3-x forms are very frequent for the As(V) species.
The use of arsenic has been restricted to acute promyelocytic leukemia (APL), although a significant number of investigations have the potential to broaden the clinical setting for arsenic trioxide and develop new arsenicals with enhanced efficacy. Arsenic exists in several states in nature, but the majority of its applications in cancer are as arsenic oxides. Arsenic trioxide and tetraarsenic oxide are inorganic arsenic compounds that show antitumor properties, although the mechanisms have yet to be fully elucidated. Any arsenic compound with similar chemotherapeutic effects that could be given orally will favor patient compliance to treatment and improve the long-term consolidation therapy. Numerous organic arsenicals have been explored, and some have shown promising effects in vitro against both APL and non-APL cell lines. These include phenylarsonous acid and S-dimethylarsino-thiosuccinic acid (MER1). Other arsenicals with improved therapeutic index are in development, such as darinaparsin, dipropil-S-glycerol arsenic (GMZ27), and 4-(N-(S-glutathionylacetyl)amino) phenylarsenous acid (GSAO).
Reactive mineral–water interfaces exert control on the bioavailability of contaminant arsenic species in natural aqueous systems. However, the ability to accurately predict As surface complexation is limited by the lack of molecular-level understanding of As−water−mineral interactions. In the present study, we report the structures and properties of the adsorption complexes of arsenous acid (As(OH)3) on hydrated mackinawite (FeS) surfaces, obtained from density functional theory (DFT) calculations. The fundamental aspects of the adsorption, including the registries of the adsorption complexes, adsorption energies, and structural parameters are presented. The FeS surfaces are shown to be stabilized by hydration, as is perhaps to be expected because the adsorbed water molecules stabilize the low-coordinated surface atoms. As(OH)3 adsorbs weakly at the water−FeS(001) interface through a network of hydrogen-bonded interactions with water molecules on the surface, with the lowest-energy structure calculated to be an As−up outer-sphere complex. Compared to the water−FeS(001) interface, stronger adsorption was calculated for As(OH)3 on the water−FeS(011) and water−FeS(111) interfaces, characterized by strong hybridization between the S-p and O-p states of As(OH)3 and the surface Fe-d states. The As(OH)3 molecule displayed a variety of chemisorption geometries on the water−FeS(011) and water−FeS(111) interfaces, where the most stable configuration at the water−FeS(011) interface is a bidentate Fe−AsO−Fe complex, but on the water−FeS(111) interface, a monodentate Fe−O−Fe complex was found. Detailed information regarding the adsorption mechanisms has been obtained via projected density of states (PDOS) and electron density difference iso-surface analyses and vibrational frequency assignments of the adsorbed As(OH)3 molecule.
The adsorption of arsenic species on magnetite has been studied by first principles calculations. From the considered anionic species, a higher adsorption energy was found for the complexation of Fe3O4(0 0 1) with As(III) being 1.3 eV higher than the adsorption energy for As(V). In the case of As(III), a large partial band charge density was found, which was associated to the OFe bond formation, while more delocalized electron density was found in the adsorption of As(V) subspecies, with the formation of two FeO bonds. A comparison with sorption of neutral arsenic atoms and O2 molecule was also considered. As(V) is mainly adsorbed on the surface with a double OFe bond formation, similar to the case of O2 in the most stable configuration.
The ATP-binding cassette (ABC) transporter MRP1 (ABCC1) is responsible for the cellular export of a chemically diverse array of xenobiotics and endogenous compounds. Arsenic, a human carcinogen, is a high affinity MRP1 substrate as arsenic triglutathione [As(GS)3]. In this study, marked differences in As(GS)3 transport kinetics were observed between MRP1-enriched membrane vesicles prepared from HEK293 (Km 3.8 μM and Vmax 307 pmol/mg/min) and HeLa (Km 0.32 μM and Vmax 42 pmol/mg/min) cells. Mutant MRP1 lacking N-linked glycosylation [Asn19/23/1006Gln; sugar-free (SF)-MRP1] expressed in either HEK293 or HeLa cells had low Km and Vmax values for As(GS)3, similar to HeLa-WT-MRP1. When prepared in the presence of phosphatase inhibitors, both WT- and SF-MRP1-enriched membrane vesicles had a high Km for As(GS)3 (3-6 µM), regardless of the cell line. Kinetic parameters of As(GS)3 for HEK-Asn19/23Gln-MRP1 were similar to HeLa/HEK-SF-MRP1 and HeLa-WT-MRP1, while those of single glycosylation mutants were like HEK-WT-MRP1. Mutation of 19 potential MRP1 phosphorylation sites revealed that HEK-Tyr920Phe/Ser921Ala-MRP1 transported As(GS)3 like HeLa-WT-MRP1, while individual HEK-Tyr920Phe and -Ser921Ala mutants were similar to HEK-WT-MRP1. Together these results suggest that Asn19/Asn23 glycosylation and Tyr920/Ser921 phosphorylation are responsible for altering the kinetics of MRP1-mediated As(GS)3 transport. The kinetics of As(GS)3 transport by HEK-Asn19/23Gln/Tyr920Glu/Ser921Glu were similar to HEK-WT-MRP1 indicating that the phosphorylation-mimicking substitutions abrogated the influence of Asn19/23Gln glycosylation. Overall these data suggest that cross-talk between MRP1 glycosylation and phosphorylation occurs, and that phosphorylation of Tyr920 and Ser921 can switch MRP1 to a lower affinity, higher capacity As(GS)3 transporter, allowing arsenic detoxification over a broad concentration range.
Aquaporins (AQPs) have been proved to be important physiological ‘partners’ for metal and metalloid compounds, either as their transporters or as targets for inhi- bition. Here, we summarize the key findings on how AQP channels contribute to the accumulation of metalloids in cells. Specifically, the elucidation of the mechanisms of met- alloids uptake by aquaporins provides an understanding of (1) inorganic elements toxic- ity and (2) how the delivery of arsenic and antimony-containing drugs is crucial in the
treatment of certain forms of leukaemia and chemotherapy of diseases caused by patho- genic protozoa. Moreover, a description of the state-of-the-art progresses in the discovery of new metal-based inhibitors, after mercurial compounds and other transition metal ions, is provided. Among them, coordination gold(III) complexes as aquaglyceroporins inhibi- tors are presented with special focus on their mechanism of action at a molecular level, and with indication of their possible applications. Overall, the potential of coordination chemistry in providing compounds to modulate the activity of ‘elusive’ drug targets, such as the aquaporins, will be discussed.
Arsenic (As) is a moderately toxic, naturally abundant element with no known nutritional or metabolic roles. The chemical form of As in surface waters is dependent on redox potential, pH, and biological processes; however, the thermodynamically stable arsenate predominates in both freshwaters and saltwaters. Arsenic concentrations are much more variable in freshwaters than in estuaries and oceans. Natural and anthropogenic sources can cause high concentrations of As in freshwaters without apparent effects on fish. Arsenite is generally more toxic than arsenate. Chronic effects on fish are primarily linked to increased maintenance due to inhibited energy-linked functions. Effects appear to occur when fish tissue concentrations reach 2-5mgkg -1 wet weight. Marine fish accumulate much more As than freshwater fish, presumably because of the higher levels of arsenobetaine in their prey. Biomagnification does not occur; rather, As concentrations decrease as trophic level increases. Approximately 90% of As in fish is organic As, with arsenobetaine being the dominant species in marine fish; speciation in freshwater fish is much more variable. Few environmental situations invoke homeostatic control mechanisms by fish, except those involving uncommonly high inorganic waterborne and dietary exposure.
The presence of arsenic in water bodies depends on pH, the redox condition of the solution, sorption, and exchange reactions. The World Health Organization (WHO) has established a guideline value of a maximum of 10 μg/L for arsenic in drinking water. Historically, arsenic has been used in fertilizers and medicines, and as a wood preservative; however, exposure to it over time may lead to skin diseases, impaired biochemical process, and various types of cancer. Bangladesh and West Bengal in India are the worst affected regions in terms of arsenic levels in water bodies and the magnitude of resultant health problems. In order to prevent arsenic pollution it is essential to understand the geochemical interactions of arsenic with its environment. The mechanism of arsenic release and mobility and its natural attenuation process are the key factors to elucidate the risk of arsenic contamination and to design and implement safe and effective treatment and remediation technologies.
Efflux is by far the most common means of arsenic detoxification. Another mechanism is methylation catalyzed by a family of As(III) S-adenosylmethionine (SAM) methyltransferases (MTs) enzymes designated ArsM in microbes or AS3MT in higher eukaryotes. The protein sequence of more than 5000 AS3MT/ArsM orthologues were deposited in the NCBI database, primarily in prokaryotic and eukaryotic microbes. As(III) SAM MTs are members of a large superfamily of MTs involved in numerous physiological functions. ArsMs detoxify arsenic by conversion of inorganic trivalent arsenic (As(III)) into mono-, di- and trimethylated species that may be more toxic and carcinogenic than inorganic arsenic. The pathway of methylation remains controversial. Several hypotheses are examined in this review.
The budding yeast
Saccharomyces cerevisiae is a powerful eukaryotic model organism for elucidating arsenic detoxification and tolerance acquisition mechanisms. The discovery of key yeast proteins involved in arsenite
accumulation and efflux, arsenate
reduction, and the use of complementation assays where a yeast protein is replaced by a homologous protein from another organism, has accelerated the identification of arsenic tolerance genes in fungi, plants, animals, and humans. In this chapter, we review the molecular biology of arsenic tolerance in budding yeast, focusing on arsenic sensing, signalling and detoxification mechanisms, how these pathways are regulated, and on the importance of yeast as a model for understanding fundamental aspects of arsenic tolerance in eukaryotes.
Leishmania parasites rely heavily upon membrane transport proteins to deliver essential nutrients from their hosts to the interior of the parasite. Some of these transporters also serve as routes for uptake of drugs used for treatment of leishmaniasis or experimental drugs with potential for development of novel anti-leishmanial therapies. Hence, mutations within the coding regions of such permeases or alterations in the expression of the carrier proteins can confer drug resistance upon the parasites. This chapter reviews the current level of knowledge regarding several classes of membrane transporters known to play roles in uptake or sensitivity to drugs. The increasing knowledge of the “permeome,” provided by complete genome sequences of several Leishmania species, has advanced considerably our knowledge of how nutrients and drugs or other cytotoxic compounds enter these pathogenic protozoa.
Ingestion of arsenic, both from water supplies and medicinal preparations, is known to cause skin cancer. The evidence assessed here indicates that arsenic can also cause liver, lung, kidney, and bladder cancer and that the population cancer risks due to arsenic in U.S. water supplies may be comparable to those from environmental tobacco smoke and radon in homes. Large population studies in an area of Taiwan with high arsenic levels in well water (170-800 micrograms/L) were used to establish dose-response relationships between cancer risks and the concentration of inorganic arsenic naturally present in water supplies. It was estimated that at the current EPA standard of 50 micrograms/L, the lifetime risk of dying from cancer of the liver, lung, kidney, or bladder from drinking 1 L/day of water could be as high as 13 per 1000 persons. It has been estimated that more than 350,000 people in the United States may be supplied with water containing more than 50 micrograms/L arsenic, and more than 2.5 million people may be supplied with water with levels above 25 micrograms/L. For average arsenic levels and water consumption patterns in the United States, the risk estimate was around 1/1000. Although further research is needed to validate these findings, measures to reduce arsenic levels in water supplies should be considered.
The arsenical resistance (ars) operon of the conjugative R-factor R773 confers resistance to arsenical and antimonial compounds in Escherichia coli, where resistance results from active extrusion of arsenite catalyzed by the products of the arsA and arsB genes. Previous in vivo studies on the energetics of arsenite extrusion showed that expression of both genes produced an ATP-coupled arsenite extrusion system that was independent of the electrochemical proton gradient. In contrast, in cells expressing only the arsB gene, arsenite extrusion was coupled to electrochemical energy and independent of ATP, suggesting that the Ars transport system exhibits a dual mode of energy coupling depending on the subunit composition. In vitro the ArsA-ArsB complex has been shown to catalyze ATP-coupled uptake of 73AsO2(-1) in everted membrane vesicles. However, transport catalyzed by ArsB alone has not previously been observed in vitro. In this study we demonstrate everted membrane vesicles prepared from cells expressing only arsB exhibit uptake of 73AsO2(-1) coupled to electrochemical energy.
In a search for genes responsible for the accumulation of antimonite in Escherichia coli, TnphoA was used to create a pool of random insertional mutants, from which one antimonite-resistant mutant was isolated. Sequence analysis showed that the TnphoA insertion was located in the glpF gene, coding for the glycerol facilitator GlpF. The mutant was shown to be defective in polyol transport by GlpF. These results suggest that in solution Sb(III) is recognized as a polyol by the glycerol facilitator.
Quasi-relativistic energy-adjusted ab initio pseudopotentials for the elements of groups 13-17 up to atomic number 53 (I) are presented together with corresponding energy-optimized valence basis sets. Test calculations for atomic excitation and ionization energies show the reliability of the derived pseudopotentials and basis sets.
Reactions of Ph2P(O)(OH) and t-BuP(O)(OSiMe3)(OH) with Ti(O-i-Pr)4 in equimolar ratios gave titanium phosphonates of the type [(O-i-Pr)3Ti(μ-O)2PR1R2]2 (1, R1 = R2 = Ph; 2, R1 = t-Bu, R2 = OSiMe3) as colorless crystalline solids in moderate yields. Reactions of Ph2P(O)(OH) and the isopropoxides of zirconium and hafnium resulted in products of the composition [(O-i-Pr)3M(μ-O-i-Pr)2(μ-OPOPh2)M(O-i-Pr)2]Ph2P(O)(OH) (M = Zr (3), Hf (4)) in high yields. The compounds were characterized by 1H, 31P, and 29Si NMR, infrared (IR), and mass spectroscopic (MS) techniques. The molecular structures of 2 and 3 were confirmed by X-ray crystallography.
Tri L12C and Tri L16C are amphiphilic peptides composed of 30 amino acids with cysteine in either the 12 or 16 position of the sequence. In the absence of metal, the peptides form two- (pH < 5.5) and three-helix bundles (pH > 7). The preference of As(III) for trigonal-pyramidal geometry and thiol coordination is used to direct folding of the peptide to form three-helix bundles under all conditions studied. These observations are contrasted with previous Hg(II) complexation in which both linear Hg(II) bis thiolate (two-helix bundle) and trigonal tris thiolate (three-helix bundle) binding motifs were observed.
Much is known about the transport of arsenite and antimonite into microbes, but the identities of mammalian transport proteins are unknown. The Saccharomyces cerevisiae FPS1 gene encodes a membrane protein homologous to the bacterial aquaglyceroporin GlpF and to mammalian aquaglyceroporins AQP7 and AQP9. Fps1p mediates glycerol uptake and glycerol efflux in response to hypoosmotic shock. Fps1p has been shown to facilitate uptake of the metalloids arsenite and antimonite, and the Escherichia coli homolog, GlpF, facilitates the uptake and sensitivity to metalloid salts. In this study, the ability of mammalian aquaglyceroporins AQP7 and AQP9 to substitute for the yeast Fps1p was examined. The fps1Delta strain of S. cerevisiae exhibits increased tolerance to arsenite and antimonite compared to a wild-type strain. Introduction of a plasmid containing AQP9 reverses the metalloid tolerance of the deletion strain. AQP7 was not expressed in yeast. The fps1Delta cells exhibit reduced transport of (73)As(III) or (125)Sb(III), but uptake is enhanced by expression of AQP9. Xenopus laevis oocytes microinjected with either AQP7 or AQP9 cRNA exhibited increased transport of (73)As(III). These results suggest that AQP9 and AQP7 may be a major routes of arsenite uptake into mammalian cells, an observation potentially of large importance for understanding the action of arsenite as a human toxin and carcinogen, as well as its efficacy as a chemotherapeutic agent for acute promyelocytic leukemia.
All living organisms have systems for arsenic detoxification. The common themes are (a) uptake of As(V) in the form of arsenate by phosphate transporters, (b) uptake of As(III) in the form of arsenite by aquaglyceroporins, (c) reduction of As(V) to As(III) by arsenate reductases, and (d) extrusion or sequestration of As(III). While the overall schemes for arsenic resistance are similar in prokaryotes and eukaryotes, some of the specific proteins are the products of separate evolutionary pathways.
Particulate methane monooxygenase (pMMO) is a membrane-bound enzyme that catalyzes the oxidation of methane to methanol in methanotropic bacteria. Understanding how this enzyme hydroxylates methane at ambient temperature and pressure is of fundamental chemical and potential commercial importance. Difficulties in solubilizing and purifying active pMMO have led to conflicting reports regarding its biochemical and biophysical properties, however. We have purified pMMO from Methylococcus capsulatus (Bath) and detected activity. The purified enzyme has a molecular mass of approximately 200 kDa, probably corresponding to an alpha(2)beta(2)gamma(2) polypeptide arrangement. Each 200-kDa pMMO complex contains 4.8 +/- 0.8 copper ions and 1.5 +/- 0.7 iron ions. Electron paramagnetic resonance spectroscopic parameters corresponding to 40-60% of the total copper are consistent with the presence of a mononuclear type 2 copper site. X-ray absorption near edge spectra indicate that purified pMMO is a mixture of Cu(I) and Cu(II) oxidation states. Finally, extended x-ray absorption fine structure data are best fit with oxygennitrogen ligands and a 2.57-A Cu-Cu interaction, providing direct evidence for a copper-containing cluster in pMMO.
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