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PubMed2000

Role of metals in the reaction catalyzed by protein farnesyltransferase.

Protein farnesyltransferase catalyzes the posttranslational farnesylation of several proteins involved in signal transduction, including Ras, and is a target enzyme for antitumor therapies. Efficient product formation catalyzed by protein farnesyltransferase requires an enzyme-bound zinc cation and high concentrations of magnesium ions. In this work, we have measured the pH dependence of the chemical step of product formation, determined under single-turnover conditions, and have demonstrated that the prenylation rate constant is enhanced by two deprotonations. Substitution of the active site zinc by cadmium demonstrated that one of the ionizations reflects deprotonation of the metal-coordinated thiol of the peptide "CaaX" motif, pK(a1) = 6.0. These data provide additional evidence for the direct involvement of a metal-coordinated sulfur nucleophile in catalysis. The second ionization was assigned to a hydroxyl on the pyrophosphate moiety of farnesyl pyrophosphate, pK(a2) = 7.4. Deprotonation of this group is important for binding of magnesium. This second ionization is not observed for catalysis in the absence of magnesium or when the substrate is farnesyl monophosphate. These data indicate that the maximal rate constant for prenylation requires formation of a zinc-coordinated thiolate nucleophile and enhancement of the electrophilic character at C1 of the farnesyl chain by magnesium ion coordination of the pyrophosphate leaving group.

Alkyl and Aryl Transferases↗

PubMed2005

H-bonding interactions and control of thiolate nucleophilicity and specificity in model complexes of zinc metalloproteins.

It is shown in model complexes designed to mimic the binding site of zinc-thiolate proteins that a single hydrogen bond between an amide N-H and a Zn-coordinated thiolate reduces its reactivity toward electrophiles by up to 2 orders of magnitude. In addition, we show that a single N-H...S hydrogen bond is sufficient to achieve near 100% regiospecificity of reaction between a strong, and hence inherently indiscriminate, alkylating agent like trimethyloxonium tetraflouroborate and a single sulfur in a dithiolate construct. The importance of these results in understanding how systems such as the zinc fingers of the GATA family and the E. coli DNA repair protein Ada, which share the same pseudotetrahedral structure and tetracysteinyl ligation around the zinc, can fulfill such widely divergent (structural vs reactive) roles and how specificity of reaction in such multi-thiolate containing systems can be achieved is discussed.

Binding Sites↗

PubMed2004

Influence of zinc deficiency on cell-membrane fluidity in Jurkat, 3T3 and IMR-32 cells.

We investigated whether zinc deficiency can affect plasma membrane rheology. Three cell lines, human leukaemia T-cells (Jurkat), rat fibroblasts (3T3) and human neuroblastoma cells (IMR-32), were cultured for 48 h in control medium, in zinc-deficient medium (1.5 microM zinc; 1.5 Zn), or in the zinc-deficient medium supplemented with 15 microM zinc (15 Zn). The number of viable cells was lower in the 1.5 Zn group than in the control and 15 Zn groups. The frequency of apoptosis was higher in the 1.5 Zn group than in the control and 15 Zn groups. Membrane fluidity was evaluated using the 6-(9-anthroyloxy)stearic acid and 16-(9-anthroyloxy)palmitic acid probes. Membrane fluidity was higher in 1.5 Zn cells than in the control cells; no differences were observed between control cells and 15 Zn cells. The effect of zinc deficiency on membrane fluidity at the water/lipid interface was associated with a higher phosphatidylserine externalization. The higher membrane fluidity in the hydrophobic region of the bilayer was correlated with a lower content of arachidonic acid. We suggest that the increased fluidity of the membrane secondary to zinc deficiency is in part due to a decrease in arachidonic acid content and the apoptosis-related changes in phosphatidylserine distribution.

3T3 Cells↗

PubMed1999

Effect of zinc on carp (Cyprinus carpio L.) erythrocytes.

The effect of zinc exposure on some properties of the carp erythrocyte membrane was studied in vitro. Red blood cells plasma membranes were separated from other cellular membranes using a combination of differential and density gradient centrifugation. The purity of obtained plasma membrane preparations was determined by measuring the activity of the marker enzymes. Electrophoretic patterns of the main erythrocyte membrane proteins excluded their degradation during the isolation and purification procedure. Carp erythrocyte membranes, obtained from cells previously incubated with increasing ZnSO4 concentrations, were used to elucidate the effect of zinc ions on their physical and biochemical properties. Using fluorescent probes: 12-AS and TMA-DPH, we found that zinc ions reduced the fluidity of the lipid bilayer, both in the middle and near the aqueous interface. Moreover, it was observed that zinc had no significant influence neither on the Na,K-ATPase activity nor on the thiol groups content in the erythrocyte membrane. We also detected that incubation of erythrocytes with zinc lead to the marked decrease of hemolytic resistance of the cells. Our studies demonstrate that zinc at higher concentrations may be toxic to carp erythrocytes causing changes in the membrane fluidity and hemolytic resistance.

Acid Phosphatase↗

PubMed2002

EPR and optical absorption studies of VO(II)-doped zinc Tris thiourea sulfate.

Electron paramagnetic resonance (EPR) of vanadyl ion as an impurity in polycrystalline zinc tris thiourea sulfate (ZTS), a prominent nonlinear optical host, has been studied at X-band frequencies at room temperature. Spin-Hamiltonian parameters and molecular orbital coefficients have been calculated. The optical absorption spectra have also been studied to deduce the crystal field parameters.

Electron Spin Resonance Spectroscopy↗

PubMed2005

Enantioselective addition of vinylzinc reagents to aldehydes catalyzed by modular ligands derived from amino acids.

[reaction: see text] A series of N-acylethylenediamine-based ligands were synthesized from Boc-protected amino acids. The ligands were screened for the ability to catalyze the asymmetric addition of vinylzinc reagents to aldehydes. Three sites of diversity on the ligands were optimized for this reaction using a positional scanning approach. The optimized ligand 3d was found to catalyze the formation of 15 different (E)-allylic alcohols with enantioselectivities that ranged from 52 to 91% ee and yields that ranged from 40 to 90%. This ligand was especially effective for the reaction of aromatic aldehydes with vinylzinc reagents derived from bulky terminal alkynes. Ligand 3d catalyzed the addition of (E)-(3,3-dimethylbut-1-enyl)(ethyl)zinc to 2-naphthaldehyde to give (R,E)-4,4-dimethyl-1-(naphthalene-1-yl)pent-2-en-1-ol in 89% ee. The ee of this product could be increased to 97% through a single recrystallization.

Aldehydes↗

PubMed1996

The role of zinc in selective neuronal death after transient global cerebral ischemia.

Zinc is present in presynaptic nerve terminals throughout the mammalian central nervous system and likely serves as an endogenous signaling substance. However, excessive exposure to extracellular zinc can damage central neurons. After transient forebrain ischemia in rats, chelatable zinc accumulated specifically in degenerating neurons in the hippocampal hilus and CA1, as well as in the cerebral cortex, thalamus, striatum, and amygdala. This accumulation preceded neurodegeneration, which could be prevented by the intraventricular injection of a zinc chelating agent. The toxic influx of zinc may be a key mechanism underlying selective neuronal death after transient global ischemic insults.

Aminoquinolines↗

PubMed1978

Induction by alpha-mercapto-beta-arylacrylic acids of low-molecular-weight zinc-binding protein in rat liver.

Intraperitoneal injections of alpha-mercapto-beta-(2-furyl)acrylic acid (MFA) induced incorporation of zinc into a low-molecular-weight metalloprotein fraction in rat-liver cytosol. Cytosol of control rats contained little or none of this material. alpha-Mercapto-beta-(2-thienyl)acrylic acid induced less incorporation of zinc in this fraction than did MFA. Twenty-two hours after administration of 65ZnSO4 (50 mumol/kg) and MFA (200 mumol/kg), serum concentrations of both total and radioisotopic zinc were markedly elevated, compared to serum concentrations in rats administered only 65ZnSO4. Further, in livers of MFA-treated rats, radioisotopic zinc concentration was significantly greater in all cytosol zinc-containing proteins resolved by gel chromatography, but total zinc was elevated only in the metallothionein fraction and not in proteins of higher molecular weight. This appears to be the first example of induction of a metallothionein-like protein by a procedure not involving food restriction or administration of metal salts.

Acrylates↗

PubMed2005

ADAM33 enzyme properties and substrate specificity.

ADAM33 is an asthma susceptibility gene recently identified through a genetic study of asthmatic families [van Eerdewegh, et al. (2002) Nature 418, 426-430]. To understand the function of the gene product, the recombinant metalloproteinase domain of human ADAM33 was purified and tested for its substrate cleavage specificity using peptides derived from beta-amyloid precursor protein (APP). A single Ala substitution at the P2 position of a 10-residue APP peptide, YEVHHQKLVF, yielded a 20-fold more efficient substrate. Terminal truncation studies identified a minimal nine-residue core (P5-P4') important for ADAM33 recognition and cleavage. Full positional scanning of the 10-mer peptide using the 19 naturally occurring l-amino acids (excluding Cys) revealed a substrate specificity profile. A strong preference for Val or Ile at P3, Ala at P2, and Gln at P1' was observed. The substrate binding model based on the X-ray structure of the ADAM33-inhibitor complex supported the observed substrate specificity profile. On the basis of this, an improved substrate was designed and a fluorescence resonance energy transfer (FRET) assay was developed using a fluorogenic derivative of this substrate. Kinetic studies confirmed that the best substrate, FRET-P2 [K(Dabcyl)YRVAFQKLAE(Edans)K], was approximately 100-fold more efficient than the wild-type APP peptide substrate, with a k(cat)/K(m) value of (3.6 +/- 0.1) x 10(4) s(-)(1) M(-)(1). Using this substrate and the FRET assay, ADAM33 enzyme activity and thermal stability were characterized. ADAM33 dependence on buffer conditions, detergents, and temperature was examined, and optimal conditions were defined. Accurate K(i) values for tissue inhibitors of metalloproteinase and small molecule compounds were obtained.

ADAM Proteins↗

PubMed1985

A novel proteolytic activity in serum processes rat prohaptoglobin.

The heterotetrameric plasma glycoprotein rat haptoglobin previously was shown to be synthesized by hepatocytes in a precursor form, prohaptoglobin, which contains one alpha-subunit region and one beta-subunit region. Two of these molecules, each with a molecular weight of 45,000, are joined by a disulfide bond and subsequently the subunit regions of each polypeptide are separated by site-specific proteolysis, yielding the tetrameric native protein. Although some of this processing occurs intracellularly, a substantial proportion of the prohaptoglobin is secreted [J. M. Hanley, T. H. Haugen, and E. C. Heath (1983) J. Biol. Chem. 258, 7858-7869]. However, a proteolytic activity was found in rat plasma and serum which also is capable of site-specific cleavage of prohaptoglobin. Further investigation of this novel activity has demonstrated that it cleaves prohaptoglobin accurately, in the same site-specific manner as the intracellular protease, and that it most likely is not a serine protease or a metalloenzyme but can be inhibited by sulfhydryl-reactive compounds. Furthermore, it appears to be synthesized and secreted by hepatocytes, and thus may be identical to the intracellular processing protease.

Alkaloids↗

PubMed2006

Surfactant-assistant and facile synthesis of hollow ZnS nanospheres.

Small and monodisperse ZnS hollow nanospheres with outer diameter ranging from 60 to 70 nm and wall thickness of 15-20 nm were fabricated in a large scale by a simple surfactant polyethylene glycol (PEG) assisted method. The diameter and the wall thickness of the hollow nanospheres could be controlled by manipulating the amount of PEG and the aging time, respectively. Moreover, the wall of these hollow nanospheres is very compact. The product was characterized by X-ray power diffraction (XRD), transmission electron microscopy (TEM), UV-vis spectrum and fluorescence spectroscopy. The photocatalytic activity of as-prepared ZnS hollow nanospheres was also evaluated by using methyl orange (MO) as a model organic compound and the result revealed that their photocatalytic activity is a little lower than that of Degussa P25 TiO(2) but better than that of ZnS nanocrystals prepared by literature method. Furthermore, a rational mechanism to the formation and evolution of the products is proposed.

Nanotubes↗

PubMed1986

Magnesium deficiency inhibits biosynthesis of blood glutathione and tumor growth in the rat.

Previously we found that blood glutathione (GSH) levels increase in response to tumor growth in the rat and that this increase is not prevented with zinc deficiency. We also found that zinc deficiency which inhibited tumor growth did not prevent this increase in blood GSH. Therefore, the objectives of this study were to determine the effects of another nutritional modification, namely magnesium deficiency, on blood GSH status and on tumor growth. Magnesium was selected because it is an obligatory cofactor in GSH synthesis and in all biosynthetic reactions involving ATP. To this end, magnesium- and zinc-deficient rats with and without tumors were compared to pair-fed control rats with and without tumors. After 32 days of depletion, the rats were killed, and blood samples were analyzed for nonprotein sulfhydryls (SH) and specifically for GSH. The key finding was that in magnesium-deficient rats with or without tumors, blood GSH levels were low and SH levels were normal indicating a decrease in GSH biosynthesis. In contrast, zinc deficiency affected SH and GSH in parallel. Thus, these two deficiencies must act by different mechanisms. The zinc data verified our earlier results obtained with a different tumor type and rat strain, for blood GSH levels increased in tumor-bearing rats fed control diets, and zinc deficiency did not prevent this increase. Depletion of magnesium or zinc was equally effective in inhibiting tumor growth. These results provide in vivo evidence of a magnesium requirement for GSH biosynthesis in rat erythrocytes. Further, the results suggest that magnesium deficiency may inhibit tumor growth by limiting GSH synthesis from SH precursors.

Animals↗

PubMed2004

Zinc-porphyrin Solvation in folded and unfolded states of Zn-cytochrome c.

After a brief review of the use of photochemical triggers and heme metal substitution to probe the folding dynamics of cytochrome c, we present new results on the photophysics and photochemistry of folded and unfolded states of the zinc-substituted protein (Zn-cyt c). Our measurements of Zn-cyt c triplet state decay kinetics reveal a systematic isotope effect on lifetimes: the decay in the folded protein (tau(H)2(O) approximately 10 ms) is only modestly affected by isotopically substituted buffers (k(H)2(O)/k(D)2(O) = 1.2), whereas a reduced triplet lifetime (approximately 1.3 ms) and greater isotope effect (1.4) were found for the chemically denatured, fully unfolded protein. The shortest lifetime (0.1-0.4 ms) and greatest isotope effect (1.5) were found for a fully exposed model compound, zinc-substituted N-acetyl-microperoxidase-8 (ZnAcMP8), implying that the unfolded protein provides some protection to the Zn-porphyrin group even under fully denaturing conditions. Further evidence for partial structure in unfolded Zn-cyt c comes from bimolecular quenching experiments using Ru(NH(3))(6)(3+) as an external Zn-porphyrin triplet state quencher. In the presence of quencher, partially unfolded protein at midpoint guanidinium chloride (GdmCl) and urea concentrations exhibits biphasic triplet decay kinetics, a fast component corresponding to an extended, solvent-exposed state (6.6 x 10(8) M(-1) s(-1) in GdmCl, 6.3 x 10(8) M(-1) s(-1) in urea) and a slow component attributable to a compact, relatively solvent-inaccessible, state (5.9 x 10(7) M(-1) s(-1) in GdmCl, 8.6 x 10(6) M(-1) s(-1) in urea). The variation in Zn-porphyrin solvation for the compact states in the two denaturants reveals that the cofactor in the partially unfolded protein is better protected in urea solutions.

Animals↗

PubMed2003

Apoptosis in the normal and inflamed airway epithelium: role of zinc in epithelial protection and procaspase-3 regulation.

The epithelium lining the airways is a physical barrier as well as a regulator of physiological and pathological events in the respiratory system. Damage to the epithelium by oxidants released from inflammatory cells is a critical factor in the pathogenesis of airway inflammatory diseases such as bronchial asthma. In these diseases, excessive apoptosis may be a likely mechanism responsible for damage to, and sloughing, of airway epithelial cells. Factors that increase the airway epithelium's resilience to apoptosis are likely to lessen the severity of this disease. One such factor is the dietary metal zinc. A special role for labile intracellular pools of zinc as anti-apoptotic agents in the regulation of the caspases, has emerged over the past two decades. This review focuses on caspase-inhibitory functions of zinc in airway epithelial cells, apparent abnormalities of zinc homeostasis in asthmatics and studies from the authors' laboratory which showed that zinc was strategically localized in the apical cytoplasm of airway epithelium to control caspase-3 activated apoptosis. These findings are discussed in the context of recent data from a murine model of allergic asthma, showing that loss of airway epithelial zinc was accompanied by changes in levels of both procaspase-3 and active caspase-3 and that nutritional zinc deprivation further increased airway epithelial apoptosis. We hypothesize that zinc has a protective role for the airway epithelium against oxyradicals and other noxious agents, with important implications for asthma and other inflammatory diseases where the epithelial barrier is vulnerable and compromised.

Animals↗

PubMed2004

Inducible superoxide dismutase 1 aggregation in transgenic amyotrophic lateral sclerosis mouse fibroblasts.

High molecular weight detergent-insoluble complexes of superoxide dismutase 1 (SOD1) enzyme are a biochemical abnormality associated with mutant SOD1-linked familial amyotrophic lateral sclerosis (FALS). In the present study, SOD1 protein from spinal cords of transgenic FALS mice was fractionated according to solubility in saline, zwitterionic, non-ionic or anionic detergents. Both endogenous mouse SOD1 and mutant human SOD1 were least soluble in SDS, followed by NP-40 and CHAPS, with an eight-fold greater detergent resistance of mutant protein overall. Importantly, high molecular weight mutant SOD1 complexes were isolated with SDS-extraction only. To reproduce SOD1 aggregate pathology in vitro, primary fibroblasts were isolated and cultured from neonatal transgenic FALS mice. Fibroblasts expressed abundant mutant SOD1 without spontaneous aggregation over time with passage. Proteasomal inhibition of cultures using lactacystin induced dose-dependent aggregation and increased the SDS-insoluble fraction of mutant SOD1, but not endogenous SOD1. In contrast, paraquat-mediated superoxide stress in fibroblasts promoted aggregation of endogenous SOD1, but not mutant SOD1. Treatment of cultures with peroxynitrite or the copper chelator diethyldithiocarbamate (DDC) alone did not modulate aggregation. However, DDC inhibited lactacystin-induced mutant SOD1 aggregation in transgenic fibroblasts, while exogenous copper slightly augmented aggregation. These data suggest that SOD1 aggregates may derive from proteasomal or oxidation-mediated oligomerisation pathways from mutant and endogenous subunits respectively. Furthermore, these pathways may be affected by copper availability. We propose that non-neural cultures such as these transgenic fibroblasts with inducible SOD1 aggregation may be useful for rapid screening of compounds with anti-aggregation potential in FALS.

Acetylcysteine↗

PubMed2005

Keap1, the sensor for electrophiles and oxidants that regulates the phase 2 response, is a zinc metalloprotein.

Induction of the phase 2 response, a major cellular reaction to oxidative/electrophile stress depends on a protein triad: actin-tethered Keap1 that binds to Nrf2. Inducers react with Keap1 releasing Nrf2 for nuclear translocation and activation of the antioxidant response element (ARE), which regulates phase 2 genes. The primary sensors for inducers are certain uniquely reactive cysteine thiols of Keap1. Recombinant murine Keap1 contains 0.9 zinc atoms per monomer as determined by inductively coupled plasma-optical emission spectrometry: its zinc content depends on the metal composition of the overexpression medium. Simultaneous direct measurement of bound zinc using a pyridazoresorcinol chelator and protein thiol groups using 4,4'-dipyridyl disulfide has established that (i) zinc is bound to reactive cysteine thiols of Keap1 and is displaced stoichiometrically by inducers, (ii) with these cysteines mutated to alanine, the affinity for zinc is reduced by nearly 2 orders of magnitude, and (iii) the association constant of Keap1 for zinc is 1.02 (+/-0.19) x 10(11) M(-)(1), consistent with a Zn(2+) metalloprotein. Co(2+) substitution for Zn(2+) yields an optical spectrum consistent with tetrahedral metal coordination. Coincident binding of inducers and release of zinc alters the conformation of Keap1, as shown by a profound decline of its tryptophan fluorescence and depression of fluorescence of a hydrophobicity probe. Thus, regulation of the phase 2 response involves chemical modification of critical cysteine residues of Keap1, whose reactivity is modulated by zinc binding. Keap1 is a zinc-thiol protein endowed with a delicate switch controlled by both metal-binding and thiol reactivity.

Acute-Phase Reaction↗

PubMed1996

Mechanism of Fe(III)-Zn(II) purple acid phosphatase based on crystal structures.

Purple acid phosphatase is a widely distributed non-specific phosphomonoesterase. X-ray structures of the dimeric 111-kDa Fe(III)-Zn(II) kidney bean purple acid phosphatase (kbPAP) complexed with phosphate, the product of the reaction, and with tungstate, a strong inhibitor of the phosphatase activity, were determined at 2.7 and 3.0 angstroms resolution, respectively. Furthermore the resolution of the unligated enzyme, recently solved at 2.9 angstroms could be extended to 2.65 angstroms with completely new data. The binding of both oxoanions is not accompanied by larger conformational changes in the enzyme structure. Small movements with a maximal coordinate shift of 1 angstroms are only observed for the active site residues His295 and His296. In the inhibitor complex as well as in the product complex, the oxoanion binds in a bidentate bridging mode to the two metal ions, replacing two of the presumed solvent ligands present in the unligated enzyme form. As also proposed for the unligated structure a bridging hydroxide ion completes the coordination spheres of both metal ions to octahedral arrangements. All three structures reported herein support a mechanism of phosphate ester hydrolysis involving interaction of the substrate with Zn(II) followed by a nucleophilic attack on the phosphorus by an Fe(III)-coordinated hydroxide ion. The negative charge evolving at the pentacoordinated transition state is probably stabilized by interactions with the divalent zinc and the imidazole groups of His202, His295, and His296, the latter protonating the leaving alcohol group.

Acid Phosphatase↗

PubMed1976

Bovine lens leucine aminopeptidase. A study of possible roles for the thiol groups in holo- and apoenzyme.

The apoenzyme of leucine aminopeptidase has to be prepared either under inert conditions or in the presence of 2-thioethanol. Due to the removal of essential zinc ions, buried -SH groups are exposed. These -SH groups show a higher reactivity than the six -SH groups accessible in the native zinc enzyme. During the incubation of the zinc enzyme with guanidine hydrochloride, up to 36 -SH groups are titratble in dependence on the concentration of guanidine hydrochloride. The -SH groups can be distinguished by their reactivity towards Ellman's reagent and can be differentiated into four classes with respect to their function.

Animals↗