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PubMed2004

Crystal structure of the YffB protein from Pseudomonas aeruginosa suggests a glutathione-dependent thiol reductase function.

BACKGROUND: The yffB (PA3664) gene of Pseudomonas aeruginosa encodes an uncharacterized protein of 13 kDa molecular weight with a marginal sequence similarity to arsenate reductase from Escherichia coli. The crystal structure determination of YffB was undertaken as part of a structural genomics effort in order to assist with the functional assignment of the protein. RESULTS: The structure was determined at 1.0 A resolution by single-wavelength anomalous diffraction. The fold is very similar to that of arsenate reductase, which is an extension of the thioredoxin fold. CONCLUSION: Given the conservation of the functionally important residues and the ability to bind glutathione, YffB is likely to function as a GSH-dependent thiol reductase.

Arsenite Transporting ATPases↗
PubMed2002

T-brain homologue (HpTb) is involved in the archenteron induction signals of micromere descendant cells in the sea urchin embryo.

Signals from micromere descendants play a crucial role in sea urchin development. In this study, we demonstrate that these micromere descendants express HpTb, a T-brain homolog of Hemicentrotus pulcherrimus. HpTb is expressed transiently from the hatched blastula stage through the mesenchyme blastula stage to the gastrula stage. By a combination of embryo microsurgery and antisense morpholino experiments, we show that HpTb is involved in the production of archenteron induction signals. However, HpTb is not involved in the production of signals responsible for the specification of secondary mesenchyme cells, the initial specification of primary mesenchyme cells, or the specification of endoderm. HpTb expression is controlled by nuclear localization of beta-catenin, suggesting that HpTb is in a downstream component of the Wnt signaling cascade. We also propose the possibility that HpTb is involved in the cascade responsible for the production of signals required for the spicule formation as well as signals from the vegetal hemisphere required for the differentiation of aboral ectoderm.

Amino Acid Sequence↗
PubMed2002

Arsenate reductases in prokaryotes and eukaryotes.

The ubiquity of arsenic in the environment has led to the evolution of enzymes for arsenic detoxification. An initial step in arsenic metabolism is the enzymatic reduction of arsenate [As(V)] to arsenite [As(III)]. At least three families of arsenate reductase enzymes have arisen, apparently by convergent evolution. The properties of two of these are described here. The first is the prokaryotic ArsC arsenate reductase of Escherichia coli. The second, Acr2p of Saccharomyces cerevisiae, is the only identified eukaryotic arsenate reductase. Although unrelated to each other, both enzymes receive their reducing equivalents from glutaredoxin and reduced glutathione. The structure of the bacterial ArsC has been solved at 1.65 A. As predicted from its biochemical properties, ArsC structures with covalent enzyme-arsenic intermediates that include either As(V) or As(III) were observed. The yeast Acr2p has an active site motif HC(X)(5)R that is conserved in protein phosphotyrosine phosphatases and rhodanases, suggesting that these three groups of enzymes may have evolved from an ancestral oxyanion-binding protein.

Arsenate Reductases↗
PubMed2003

Genetic variation in genes associated with arsenic metabolism: glutathione S-transferase omega 1-1 and purine nucleoside phosphorylase polymorphisms in European and indigenous Americans.

Individual variability in human arsenic metabolism has been reported frequently in the literature. This variability could be an underlying determinant of individual susceptibility to arsenic-induced disease in humans. Recent analysis revealing familial aggregation of arsenic metabolic profiles suggests that genetic factors could underlie interindividual variation in arsenic metabolism. We screened two genes responsible for arsenic metabolism, human purine nucleoside phosphorylase (hNP), which functions as an arsenate reductase converting arsenate to arsenite, and human glutathione S-transferase omega 1-1 (hGSTO1-1), which functions as a monomethylarsonic acid (MMA) reductase, converting MMA(V) to MMA(III), to develop a comprehensive catalog of commonly occurring genetic polymorphisms in these genes. This catalog was generated by DNA sequencing of 22 individuals of European ancestry (EA) and 24 individuals of indigenous American (IA) ancestry. In (Italic)hNP(/Italic), 48 polymorphic sites were observed, including 6 that occurred in exons, of which 1 was nonsynonymous (G51S). One intronic polymorphism occurred in a known enhancer region. In hGSTO1-1, 33 polymorphisms were observed. Six polymorphisms occurred in exons, of which 4 were nonsynonymous. In contrast to hNP, in which the IA group was more polymorphic than the EA group, in hGSTO1-1 the EA group was more polymorphic than the IA group, which had only 1 polymorphism with a frequency > 10%. Populations representing genetic admixture between the EA and IA groups, such as Mexican Hispanics, could vary in the extent of polymorphism in these genes based upon the extent of admixture. These data provide a framework in which to conduct genetic association studies of these two genes in relevant populations, thereby allowing hNP and hGSTO1-1 to be evaluated as potential susceptibility genes in human arsenicism.

Arsenic↗
PubMedDate not supplied

[Metachromatic leukodystrophy in adult patient initially diagnosed as multiple sclerosis].

The article presents a case of metachromatic leucodystrophy (MLD) of the adult onset type, in which atypical initial course could suggest multiple sclerosis. MLD is an inherited, metabolic, degenerative disease of the nervous system. It is caused by a deficiency of a lysosomal enzyme--arylsulphatase A, with the storage of cerebroside sulphate and demyelination affecting mainly the central and peripheral nervous system. In the reported case of a female aged 21 the clinical onset of the disease was at the age 20. The first neurological symptoms included a mild spastic paraparesis, ataxia of lower limbs, and imbalance. The neurological deterioration has been progressing since the onset. There was no family history of neurological or metabolic diseases, but the patient's parents were near relatives (first cousins). T-2 weighted MRI showed high intensity areas in the white matter, mainly periventricular. The clinical symptoms could suggest multiple sclerosis (of the primary progressive type). The patient was admitted to our Dept. in Oct. 2000, i.e. about a year since the onset. Her increasing spastic triparesis, cerebellar ataxia, neuropathy in lower limbs and cognitive deterioration were confirmed. Re-analysis of the patient's clinical picture and family history, her MRI scans and repeated neurophysiological examinations which demonstrated a damage of the central and peripheral nervous system, suggested metachromatic leucodystrophy. Therefore, it was decided to assay arylsulphatase A activity. The result confirmed the diagnosis of the late onset MLD. Additionally, molecular genetic examination was performed of a DNA sample obtained from the patient.

Adult↗
PubMed2004

Xanthine, xanthosine and its nucleotides: solution structures of neutral and ionic forms, and relevance to substrate properties in various enzyme systems and metabolic pathways.

The 6-oxopurine xanthine (Xan, neutral form 2,6-diketopurine) differs from the corresponding 6-oxopurines guanine (Gua) and hypoxanthine (Hyp) in that, at physiological pH, it consists of a approximately 1:1 equilibrium mixture of the neutral and monoanionic forms, the latter due to ionization of N(3)-H, in striking contrast to dissociation of the N(1)-H in both Gua and Hyp at higher pH. In xanthosine (Xao) and its nucleotides the xanthine ring is predominantly, or exclusively, a similar monoanion at physiological pH. The foregoing has, somewhat surprisingly, been widely overlooked in studies on the properties of these compounds in various enzyme systems and metabolic pathways, including, amongst others, xanthine oxidase, purine phosphoribosyltransferases, IMP dehydrogenases, purine nucleoside phosphorylases, nucleoside hydrolases, the enzymes involved in the biosynthesis of caffeine, the development of xanthine nucleotide-directed G proteins, the pharmacological properties of alkylxanthines. We here review the acid/base properties of xanthine, its nucleosides and nucleotides, their N-alkyl derivatives and other analogues, and their relevance to studies on the foregoing. Included also is a survey of the pH-dependent helical forms of polyxanthylic acid, poly(X), its ability to form helical complexes with a broad range of other synthetic homopolynucleotides, the base pairing properties of xanthine in synthetic oligonucleotides, and in damaged DNA, as well as enzymes involved in circumventing the existence of xanthine in natural DNA.

Animals↗
PubMed2000

Structure-function relationships in an anion-translocating ATPase.

The ArsAB ATPase is an efflux pump located in the inner membrane of Escherichia coli. This transport ATPase confers resistance to arsenite and antimonite by their extrusion from the cells. The pump is composed of two subunits, the catalytic ArsA subunit and the membrane subunit ArsB. The complex is similar in many ways to ATP-binding cassette ('ABC') transporters, which typically have two groups of six transmembrane-spanning helical segments and two nucleotide-binding domains (NBDs). The 45 kDa ArsB protein has 12 transmembrane-spanning segments. ArsB contains the substrate translocation pathway and is capable of functioning as an anion uniporter. The 63 kDa ArsA protein is a substrate-activated ATPase. It has two homologous halves, A1 and A2, which are clearly the result of an ancestral gene duplication and fusion. Each half has a consensus NBD. The mechanism of allosteric activation of the ArsA ATPase has been elucidated by a combination of molecular genetics and biochemical, structural and kinetic analyses. Conformational changes produced by binding of substrates, activator and/or products could be revealed by stopped-flow fluorescence measurements with single-tryptophan derivatives of ArsA. The results demonstrate that the rate-limiting step in the overall reaction is a slow isomerization between two conformations of the enzyme. Allosteric activation increases the rate of this isomerization such that product release becomes rate-limiting, thus accelerating catalysis. ABC transporters, which exhibit similar substrate activation of ATPase activity, can undergo similar conformational changes to overcome a rate-limiting step. Thus the ArsAB pump is a useful model for elucidating mechanistic aspects of the ABC superfamily of transport ATPases.

Adenosine Triphosphatases↗
PubMed1998

Genes for all metals--a bacterial view of the periodic table. The 1996 Thom Award Lecture.

Bacterial chromosomes have genes for transport proteins for inorganic nutrient cations and oxyanions, such as NH4+, K+, Mg2+, Co2+, Fe3+, Mn2+, Zn2+ and other trace cations, and PO4(3-), SO4(2-) and less abundant oxyanions. Together these account for perhaps a few hundred genes in many bacteria. Bacterial plasmids encode resistance systems for toxic metal and metalloid ions including Ag+, AsO2-, AsO4(3-), Cd2+, Co2+, CrO4(2-), Cu2+, Hg2+, Ni2+, Pb2+, TeO3(2-), Tl+ and Zn2+. Most resistance systems function by energy-dependent efflux of toxic ions. A few involve enzymatic (mostly redox) transformations. Some of the efflux resistance systems are ATPases and others are chemiosmotic ion/proton exchangers. The Cd(2+)-resistance cation pump of Gram-positive bacteria is membrane P-type ATPase, which has been labeled with 32P from [gamma-32P]ATP and drives ATP-dependent Cd2+ (and Zn2+) transport by membrane vesicles. The genes defective in the human hereditary diseases of copper metabolism, Menkes syndrome and Wilson's disease, encode P-type ATPases that are similar to bacterial cadmium ATPases. The arsenic resistance system transports arsenite [As(III)], alternatively with the ArsB polypeptide functioning as a chemiosmotic efflux transporter or with two polypeptides, ArsB and ArsA, functioning as an ATPase. The third protein of the arsenic resistance system is an enzyme that reduces intracellular arsenate [As(V)] to arsenite [As(III)], the substrate of the efflux system. In Gram-negative cells, a three polypeptide complex functions as a chemiosmotic cation/protein exchanger to efflux Cd2+, Zn2+ and Co2+. This pump consists of an inner membrane (CzcA), an outer membrane (CzcC) and a membrane-spanning (CzcB) protein that function together.

Adenosine Triphosphatases↗
PubMed1996

Bacterial resistances to toxic metal ions--a review.

Bacterial plasmids encode resistance systems for toxic metal ions, including Ag+, AsO2-, AsO4(3-), Cd2+, Co2+, CrO4(2-), Cu2+, Hg2+, Ni2+, Pb2+, Sb3+, TeO3(2-), Tl+ and Zn2+. The function of most resistance systems is based on the energy-dependent efflux of toxic ions. Some of the efflux systems are ATPases and others are chemiosmotic cation/proton antiporters. The Cd(2+)-resistance ATPase of Gram-positive bacteria (CadA) is membrane cation pump homologous with other bacterial, animal and plant P-type ATPases. CadA has been labeled with 32P from [alpha-32P] ATP and drives ATP-dependent Cd2+ (and Zn2+) uptake by inside-out membrane vesicles (equivalent to efflux from whole cells). Recently, isolated genes defective in the human hereditary diseases of copper metabolism, namely Menkes syndrome and Wilson's disease, encode P-type ATPases that are more similar to bacterial CadA than to other ATPases from eukaryotes. The arsenic resistance efflux system transports arsenite [As(III)], alternatively using either a double-polypeptide (ArsA and ArsB) ATPase or a single-polypeptide (ArsB) functioning as a chemiosmotic transporter. The third gene in the arsenic resistance system, arsC, encodes an enzyme that converts intracellular arsenate [As(V)] to arsenite [As(III)], the substrate of the efflux system. The triple-polypeptide Czc (Cd2+, Zn2+ and Co2+) chemiosmotic efflux pump consists of inner membrane (CzcA), outer membrane (CzcC) and membrane-spanning (CzcB) proteins that together transport cations from the cytoplasm across the periplasmic space to the outside of the cell.

Drug Resistance, Microbial↗
PubMed1996

Bacterial heavy metal resistance: new surprises.

Bacterial plasmids encode resistance systems for toxic metal ions including Ag+, AsO2-, AsO4(3-), Cd2+, CO2+, CrO4(2-), Cu2+, Hg2+, Ni2+, Pb2+, Sb3+, TeO3(2-), Tl+, and Zn2+. In addition to understanding of the molecular genetics and environmental roles of these resistances, studies during the last few years have provided surprises and new biochemical mechanisms. Chromosomal determinants of toxic metal resistances are known, and the distinction between plasmid resistances and those from chromosomal genes has blurred, because for some metals (notably mercury and arsenic), the plasmid and chromosomal determinants are basically the same. Other systems, such as copper transport ATPases and metallothionein cation-binding proteins, are only known from chromosomal genes. The largest group of metal resistance systems function by energy-dependent efflux of toxic ions. Some of the efflux systems are ATPases and others are chemiosmotic cation/proton antiporters. The CadA cadmium resistance ATPase of gram-positive bacteria and the CopB copper efflux system of Enterococcus hirae are homologous to P-type ATPases of animals and plants. The CadA ATPase protein has been labeled with 32P from gamma-32P-ATP and drives ATP-dependent Cd2+ uptake by inside-out membrane vesicles. Recently isolated genes defective in the human hereditary diseases of copper metabolism, Menkes syndrome and Wilson's disease, encode P-type ATPases that are more similar to the bacterial CadA and CopB ATPases than to eukaryote ATPases that pump different cations. The arsenic resistance efflux system transports arsenite, using alternatively either a two-component (ArsA and ArsB) ATPase or a single polypeptide (ArsB) functioning as a chemiosmotic transporter. The third gene in the arsenic resistance system, arsC, encodes an enzyme that converts intracellular arsenate [As (V)] to arsenite [As (III)], the substrate of the efflux system. The three-component Czc (Cd2+, Zn2+, and CO2+) chemiosmotic efflux pump of soil microbes consists of inner membrane (CzcA), outer membrane (CzcC), and membrane-spanning (CzcB) proteins that together transport cations from the cytoplasm across the periplasmic space to the outside of the cell. Finally, the first bacterial metallothionein (which by definition is a small protein that binds metal cations by means of numerous cysteine thiolates) has been characterized in cyanobacteria.

Arsenic↗
PubMed1998

Biochemical characterization of the human arsenite-stimulated ATPase (hASNA-I).

Arsenic is a potent toxin and carcinogen. In prokaryotes, arsenic detoxification is accomplished by chromosomal and plasmid-borne operon-encoded efflux systems. We have previously reported the cloning of hASNA-I, a human homologue of arsA encoding the ATPase component of the Escherichia coli arsenite transporter. Purified glutathione S-transferase (GST)-hASNA-I fusion protein was biochemically characterized, and its properties were compared with those of ArsA. The GST-hASNA-I exhibited a basal level of ATPase activity of 18.5 +/- 8 nmol/min/mg in the absence of arsenite. Arsenite produced a 1.6 +/- 0.1-fold stimulation of activity (p = 0. 0044), which was related to an increase in Vmax; antimonite did not stimulate activity. Two lines of evidence suggest that an oligomer is the most likely native form of hASNA-I. First, lysates of human embryo kidney 293 cells overproducing recombinant hASNA-I produced a single monomeric 37-kDa band on SDS-polyacrylamide gel electrophoresis (PAGE) and two distinct species when analyzed using nondenaturing PAGE. Second, chemical cross-linking of the 63-kDa GST-hASNA-I resulted in the formation of dimeric and tetrameric protein forms. The results indicate that hASNA-I is a distinct human arsenite-stimulated ATPase belonging to the same superfamily of ATPases represented by the E. coli ArsA protein.

Adenosine Triphosphatases↗
PubMed2000

Structure of the ArsA ATPase: the catalytic subunit of a heavy metal resistance pump.

Active extrusion is a common mechanism underlying detoxification of heavy metals, drugs and antibiotics in bacteria, protozoa and mammals. In Escherichia coli, the ArsAB pump provides resistance to arsenite and antimonite. This pump consists of a soluble ATPase (ArsA) and a membrane channel (ArsB). ArsA contains two nucleotide-binding sites (NBSs) and a binding site for arsenic or antimony. Binding of metalloids stimulates ATPase activity. The crystal structure of ArsA reveals that both NBSs and the metal-binding site are located at the interface between two homologous domains. A short stretch of residues connecting the metal-binding site to the NBSs provides a signal transduction pathway that conveys information on metal occupancy to the ATP hydrolysis sites. Based on these structural features, we propose that the metal-binding site is involved directly in the process of vectorial translocation of arsenite or antimonite across the membrane. The relative positions of the NBS and the inferred mechanism of allosteric activation of ArsA provide a useful model for the interaction of the catalytic domains in other transport ATPases.

Adenosine Triphosphatases↗
PubMed1997

Destabilization of the Ca2+-ATPase of sarcoplasmic reticulum by thiol-specific, heat shock inducers results in thermal denaturation at 37 degrees C.

A number of protein reactive compounds, including the thiol reagents diamide and arsenite, are known inducers of heat shock protein (HSP) synthesis and thermotolerance. These compounds are thought to damage cellular protein, which has been proposed to serve as the signal for induction. The specific mechanism of protein damage and its relation to thermal denaturation are unknown. The Ca2+-ATPase of sarcoplasmic reticulum, a membrane protein that contains 24 cys residues, was used to determine the effect of diamide, arsenite, N-ethylmaleimide (NEM), and the cys-specific probes Br-DMC and IAEDANS, which label one or two specific cys residues, respectively, on protein conformation and stability. The Ca2+-ATPase was chosen because diamide has been shown to affect the thermal properties of a class of membrane proteins of CHO cells (Freeman et al., 1995). The labeling of one or two thiols has no effect on activity or conformation, while more extensive reaction (but with less than approximately five to eight groups titrated) results in destabilization of the Ca2+-ATPase such that it denatures thermally at 37 degrees C. Higher levels of titration result in greater destabilization such that the protein is no longer stable at room temperature, with the production of a state similar to the thermally denatured state as assayed by activity, differential scanning calorimetry, ANS binding, and light scattering. The fractional denaturation induced by these thiol reagents, determined by the decrease in the heat absorbed during thermal denaturation, is directly proportional to inactivation of ATPase activity. Thus, inactivation of the Ca2+-ATPase by thiol reagents occurs because of denaturation not through oxidation of essential thiols. These results indicate that these thiol-specific heat shock inducers function by two mechanisms: (1) destabilization of proteins such that they thermally denature at 37 degrees C and (2) direct denaturation, apparently driven by thermal processes at room temperature, following more extensive reaction which results in extreme destabilization. We suggest that these are general mechanisms by which heat shock inducers damage proteins.

Animals↗
PubMed1993

Muscle contracture and twitch depression induced by arsenite in the mouse phrenic nerve-diaphragm.

The purpose of this investigation was to explore the possible mechanism of muscle contracture and twitch depression induced by arsenite in the mouse diaphragm. Arsenite-contracture was dependent on extracellular Ca2+; both EGTA and Ca(2+)-channel blockers (nifedipine and verapamil) inhibited arsenite-contracture. However, the activators caffeine and ryanodine and the inhibitor ruthenium red of the Ca2+ releasing channel of sarcoplasmic reticulum (SR) all exerted a profound inhibitory action on arsenite-contracture. Neither the Ca(2+)-release nor the Ca(2+)-ATPase activity of SR. were affected by 50 microM arsenite. These findings indicate a possibility that arsenite induced muscle contracture by enhancing Ca(2+)-entry which further induced Ca(2+)-release from SR. Moreover, the possible mechanism of twitch blockade induced by arsenite was studied by an electrophysiological technique. The frequency of miniature endplate potential (m.e.p.p.) was initially increased but eventually abolished by arsenite, while the amplitude of m.e.p.p. remained unaffected and that of endplate potential rapidly declined. It is considered that arsenite increased the spontaneous release of transmitter by enhancing Ca2+ entry into the nerve terminal and inhibited the evoked transmitter release possibly by acting at a certain site which governs transmitter release.

Animals↗
PubMed1996

Thapsigargin induces phosphorylation of the 27-kDa heat shock protein in human keratinocytes.

In the human keratinocyte line HaCaT, the nonphosphorylated 27-kDa heat shock protein (HSP27) isoform A (pI 6.5) is constitutively expressed. Application of thapsigargin, which inhibits Ca2+-ATPase in the endoplasmic reticulum, results in the rapid formation of the phosphorylated HSP27 isoform B (pI 6.0) and reduction of HSP27 A without affecting the synthesis of HSP27. The thapsigargin-dependent HSP27 isoform change is similar to that induced by 43 degrees C heat shock, but different from that induced by arsenite, where the biphosphorylated isoform HSP27 C (pI 5.7) is observed. The receptor agonist bradykinin, which increases intracellular Ca2+ (Ca(i)) level, shows no effect on the distribution of HSP27 isoforms. The responses of HSP27 isoforms to thapsigargin are independent of Ca(i) concentration in HaCaT cells. These observations suggest that the thapsigargin-induced change in HSP27 isoforms is dependent on the depletion of internal Ca2+ stores rather than on the increase in Ca(i) concentration. The thapsigargin-induced change in HSP27 isoforms is reduced by the tyrosine kinase inhibitor, genistein, but not the protein kinase C inhibitor, H-7. We propose that the modulation of HSP27 phosphorylation status by Ca(i) homeostasis may be mechanistically linked to control of keratinocyte growth and differentiation and responses of keratinocytes to extracellular stresses.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1999

Reversal of sodium arsenite inhibition of rat liver microsomal Ca2+ pumping ATPase by vitamin C.

Sodium arsenite (NaAsO2), at 10% of its median lethal dose, was administered to rats with and without vitamin C pretreatment. Liver microsomal fraction was isolated and the activity of Ca2+-ATPase was assayed. Sodium arsenite was found to inhibit the activity of the liver microsomal Ca2+-ATPase to 50% to that of control rats. The specific activity of the enzyme in rats administered sodium arsenite with vitamin C pretreatment was not significantly different from that of control rats.

Animals↗
PubMed1994

Inhibition of glucose transport in human erythrocytes by 2,3-dioxoindole (isatin).

10 mM isatin (2,3-dioxoindole) inhibited glucose influx into human erythrocytes by over 30%. The inhibition is of the competitive type, where the affinity constant (Kt) was increased from 5.71 (control) to 11.11 mM in the presence of isatin with no change in Vmax (130 nmol/min/ml packed cells). The observed inhibition of sugar transport by isatin was not mediated through membrane -SH groups accessible to iodoacetate, iodoacetamide, DTNB, DNP or sodium arsenite. Isatin inhibited sugar transport in the presence of 2 mM harmaline, an alkaloid inhibitor of Na+, K(+)-ATPase activity. The inhibition was non additive which suggests that these two compounds interact with the same or a similar site on the erythrocyte membrane.

Arsenites↗