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PubMed1991

Thermodynamics of actin polymerization; influence of the tightly bound divalent cation and nucleotide.

Previous work by this laboratory has shown that the tightly bound divalent cation of actin affects the enthalpy of the polymerization reaction for ATP-actin (Selden et al. (1986) J. Muscle Res. Cell Motil. 7, 215-224). In the present study, we have measured the temperature dependence of polymerization for actin containing ATP or ADP as the bound nucleotide and Mg2+ or Ca2+ (Mg-actin or Ca-actin) as the tightly bound divalent cation. In contrast to the marked effect of the tightly bound divalent cation on enthalpy and entropy changes for the polymerization of ATP-actin, ADP-actin polymerization is affected very little by the tightly bound divalent cation. The Arrhenius and van't Hoff plots for polymerization of Ca-ATP-, Mg-ADP- and Ca-ADP-actin were found to be non-linear. The free energy data for actin polymerization have been analyzed as a second order function of absolute temperature (Osborne et al. (1976) Biochemistry 15, 317-320). The values of the enthalpy change and activation enthalpy change for Ca-ATP-, Mg-ADP- and Ca-ADP-actin polymerization were found to be temperature-dependent, in contrast to those for Mg-ATP-actin, which were nearly constant over the temperature range studied. These results suggest that (1) polymerization of actin which does not contain both Mg2+ and ATP may be a multi-step reaction including a rate-limiting step and (2) Mg-ATP-actin has a unique conformation which enhances its ability to polymerize.

Actins↗
PubMed1986

Tubulin polymerization with ATP is mediated through the exchangeable GTP site.

Glycerol-induced tubulin polymerization supported by non-guanine nucleotides was examined. The electrophoretically homogeneous tubulin was devoid of nucleoside diphosphate kinase activity and 95% saturated with exchangeable GDP and nonexchangeable GTP. All purine ribonucleoside 5'-triphosphates were active but no polymerization occurred with CTP or UTP. All polymerization reactions, as a function of nucleotide concentration, were similar: above a minimum (threshold) concentration, as the amount of nucleotide increased the reaction became progressively more rapid and extensive with a progressively shorter nucleation period. Threshold concentrations of ATP, XTP, ITP and GTP were 0.6 mM, 0.3 mM, 30 microM and 7 microM, respectively. Most ribose- and polyphosphate-modified ATP analogs also supported polymerization at high concentrations, but the activity of these analogs relative to ATP was very similar to the activity of cognate GTP analogs relative to GTP. Polymerization with ATP was associated with an ATPase reaction. ATP hydrolysis was potently inhibited by GDP and GTP and altered by antimitotic drugs in parallel with the effects of these agents on GTP hydrolysis. Substantial amounts of [8-14C]GDP bound in the exchangeable site of tubulin were displaced during polymerization with GTP or ATP, but much higher concentrations of ATP were required for equivalent displacement of the tubulin-bound GDP. Polymerization with GTP or ATP was inhibited in a qualitatively similar manner by GDP, with increasing concentrations of GDP causing a progressive prolongation of the nucleation period and reduction in reaction rate and extent. However, complete inhibition of polymerization required that GDP:GTP much greater than 1, but that GDP:ATP much less than 1. Inhibition appeared to be primarily competitive, since with higher triphosphate concentrations higher GDP concentrations were required for comparable inhibition. We conclude that ATP effects on tubulin polymerization are mediated through a feeble interaction at the exchangeable GTP site.

Adenosine Triphosphate↗
PubMed2006

Polymerization efficacy of simplified adhesive systems studied by NMR and MRI techniques.

OBJECTIVE: To ascertain the efficacy of polymerization of self-etching dental adhesives in different solvent evaporation conditions. MATERIAL AND METHODS: Four self-etching adhesive systems were studied. Two of them are classified as mild two-step self-etching adhesives (Clearfil SE Bond, Protect Bond) and the other two are strong one-step systems (Xeno III, ADP-Prompt-L-Pop). The influence of temperature and duration of the air-drying period on photo-polymerization was followed by: gravimetry, (1)H solid-state NMR spectroscopy and stray-field MRI. The evolution of proton magnetization with irradiation time was recorded and correlated with volumetric polymerization shrinkage and extent of reaction; evaporation and hardening effects were identified. RESULTS: Main variables determining water-solvent evaporation of the tested adhesives are: (1) water/HEMA relative concentration, (2) presence of photoinitiator compounds in the primer (SEB) and (3) presence of ethanol (XENO). SEB shows the highest extent of photo-polymerization of the tested adhesives. The lowest volumetric contraction was obtained for APLP and XENO and the attempt to remove the solvents did not increase the extent of polymerization significantly. CONCLUSIONS: Temperature increase following photo-polymerization reaction is dominant towards the effect of the drying step for solvent evaporation in self-etching systems. Attempts to remove the solvents did not increase the extent of polymerization, so other problems are impairing the polymerization of one-step adhesives. CLINICAL SIGNIFICANCE: The use of tested one-step adhesives is discouraged as the attained low extent of polymerization may lead to low bond strength, high susceptibility to degradation and also will favor a continuing etching effect on the underlying dentin.

Dental Bonding↗
PubMed2005

Influence of polymerization mode on flexural properties of esthetic resin luting agents.

STATEMENT OF PROBLEM: Dual-polymerized esthetic resin luting agents have become popular. However, it is not clear whether the autopolymerized versions of such products have adequate strength to meet clinical requirements. PURPOSE: The aim of this study was to investigate the effect of different polymerization modes on the flexural properties of esthetic resin luting agents. MATERIAL AND METHODS: Ten esthetic resin luting agents were studied. Materials with 3 polymerization modes (dual, auto, and light) were Appeal, Calibra, Illusion, Lute-It, and Variolink-II; those with 2 polymerization modes (dual and auto) were Bistite-II-DC, Cement-It-C&B, Clearfil-DC-Cement, Linkmax, and Nexus2-Dual-Syringe. Five flexural strength specimens (2 x 2 x 25 mm) were made for every available polymerization mode for each material. The specimens were stored in distilled water for 24 hours at 37 degrees C. The specimens were then tested for flexural strength (MPa) and flexural modulus (GPa) using the 3-point bending method on a universal material testing machine at a cross-head speed of 0.5 mm/min. Data were analyzed by Kruskal-Wallis and Mann-Whitney tests (alpha=.05). RESULTS: Flexural strength values were the highest for dual-polymerized Nexus2-Dual-Syringe (155 MPa), whereas the values were lowest for autopolymerized Bistite-II-DC (56 MPa) and light-polymerized Appeal (63 MPa). Flexural moduli values ranged from 4.3 to 10.0 GPa. The polymerization mode and luting agent influenced flexural strength and modulus significantly (P<.05). CONCLUSION: Dual-polymerized resin luting agents had higher or equal flexural strength compared to the autopolymerized mode. All the groups tested passed the flexural strength requirement of the ISO 4049 specification.

Dental Stress Analysis↗
PubMed2006

Influence of dentin bonding agents and polymerization modes on the bond strength between translucent fiber posts and three dentin regions within a post space.

STATEMENT OF PROBLEM: Debonding is the most frequent failure encountered with translucent fiber posts and usually occurs along the post space dentin-adhesive interface. PURPOSE: The purpose of this study was to evaluate the effect of different dentin bonding agents and polymerization modes on the bond strength between translucent fiber posts and root dentin in different regions of the post space. MATERIAL AND METHODS: Forty maxillary canines with similar root lengths were selected, sectioned at the cemento-enamel junction, and the roots were endodontically treated. Following post space preparation, the roots were divided into 4 groups of 10 specimens each, and the post spaces were treated with 1 of 4 different dentin bonding agents: light-polymerized, single-bottle bonding agent Excite (Group EX); dual-polymerized, single-bottle bonding agent Excite DSC (Group EX-DSC); self-etching primer Clearfil Liner Bond 2V with a light-polymerized bonding agent, Bond A (Group CL-LC); or self-etching primer Clearfil Liner Bond 2V with a dual-polymerized bonding agent, Bond A+B (Group CL-DC). Translucent fiber posts (D.T. Light-Post), 2.2 mm in diameter, were luted (Panavia F) in each specimen after respective dentin bonding procedures. The roots were cut into 3-mm-thick sections, perpendicular to the long-axis in cervical, middle, and apical post space dentin. Push-out tests were performed with a universal testing machine at a crosshead speed of 0.5 mm/min, and bond strength values (MPa) were calculated by dividing the force at which bond failure occurred by the bonded area of the post. The data were analyzed with 1- and 2-way analysis of variance and Tukey multiple comparison tests (alpha=.05). Dentin adhesive bonding mechanisms in different regions of the post spaces were evaluated with a scanning electron microscope. RESULTS: The highest mean bond strength values were obtained for Group CL-LC (18.3 +/- 4.1 MPa). The dual-polymerized bonding agent resulted in significantly lower bond strength (P<.001) in combination with self-etching primer (Group CL-DC) (13.2 +/- 2.5 MPa). The light-polymerized and dual-polymerized single-bottle bonding agents provided similar bond strengths (12.7 +/- 5.0 for EX; 13.5 +/- 5.3 for EX-DSC). The regional bond strength values of single-bottle bonding agents were reduced significantly in apical post space dentin (P<.001). Self-etching primers did not demonstrate regional differences in post space dentin bonding and dense resin tags were apparent. CONCLUSION: Data suggests that the self-etching primer system used in this study was unaffected by the morphological variations in the post space dentin compared to the single-bottle bonding agents. Dual polymerization did not improve the bond strength values of the bonding agents tested.

Analysis of Variance↗
PubMed2000

Surface active properties of polyoxyethylene macromonomers and their role in radical polymerization in disperse systems.

Conventional dispersion polymerization and copolymerization of low-molecular weight (conventional) unsaturated monomers allows preparation of monodisperse and micronsize polymer particles. A similar behavior can be found in the surfactant-free dispersion polymerization of non-traditional vinyl monomers, unsaturated macromonomers. The latter systems allow preparation of random, comb-like, star-like and graft copolymers as well. An interesting alternative arises with the use of amphiphilic reactive macromonomers that contain a polymerizable group and aggregate into an organized structure -- a micelle. Under such conditions the high rate of polymerization and ultrafine (microparticles) polymer dispersions are generated. Thus, the surface-active macromonomers promote the formation of micelles and polymer growth within the main reaction loci -- polymer particles. Furthermore, the surface-active compounds can be formed during the copolymerization of hydrophilic macromonomer and hydrophobic low-molecular weight comonomer. The reactive surface-active oligomeric radicals are incorporated into the polymer matrix or the particle surface layer, which prevents them from subsequent migration. Besides, the covalently bound surface-active groups at the particle surface strongly increase the colloidal stability of final polymer dispersion. This article presents a review of the current literature in the field of the surfactant-free dispersion polymerization of the polyoxyethylene unsaturated macromonomers. Besides a short introduction into some kinetic aspects of radical polymerization of traditional monomers in homogeneous and disperse systems, we mainly focus on the organized aggregation of amphiphilic polyoxyethylene macromonomers, the characterization of amphiphilic graft copolymers and their aggregation properties, and radical copolymerization of polyoxyethylene macromonomers. We discuss the birth and growth of chains, the transfer of reaction loci from the continuous phase to polymer particles, the diffusion-controlled termination, association of amphiphilic reaction by-products, the particle growth by agglomeration, the particle nucleation, the deactivation of polymer chain growth and the colloidal stability. Effects of initiator type and concentration, the surface activity of macromonomer, the macromonomer type and concentration, temperature, additives and the type of continuous phase on the kinetics of polymerization, and colloidal parameters of the reaction system are also evaluated. Variation of the polymer coil density, the polymer-polymer interaction, and polymer-solvent interaction with the molecular weight, diluent and method (light scattering, the size exclusion, etc.) are discussed. Polymerization of macromonomers provides regularly branched polymers with varied branching density. Since both the degree of polymerization and the length of branches may be varied, polymeric materials with specific properties can be prepared.

Chemical Phenomena↗
PubMed1984

Lateral diffusion and phase separation in two-dimensional solutions of polymerized butadiene lipid in dimyristoylphosphatidylcholine bilayers. A photobleaching and freeze fracture study.

Mixed vesicles of dimyristoylphosphatidylcholine (DMPC) and a polymerizable lipid containing one diene group per chain are studied by freeze fracture electron microscopy and by the photobleaching (fluorescence recovery after photobleaching) technique. Large thin-walled vesicles of some micron in diameter become more stable after photochemical polymerization. Before polymerization bilayers of the diene lipid exhibit a liquid crystal-to-gel transition at Tg = 31 degrees C. Upon polymerization the transition remains but shifts to a slightly higher temperature (Tg* = 34 degrees C). The transitions in both cases are accompanied by a freezing in of the lateral mobilities. The mixed vesicle exhibits lateral phase separation after polymerization. Before polymerization the two lipids appear miscible at all compositions in the fluid state and at DMPC concentrations at or below 50 mol % in the solid state. After polymerization a two-dimensional solution of the polymer in DMPC is obtained at T greater than Tg*, while lateral phase segregation into DMPC-rich domains and patches of the polymer is observed at T less than Tg*. The domain structure appears identical irrespective of whether polymerization is performed at T greater than Tg or at T less than Tg. A typical value of the diameter of the polymerized lipid domains (approximately 400 A) indicates a rather small aggregation number (N less than 100 monomers). The lateral diffusion coefficient in butadiene-lipid bilayers only decreases from D1 = 3.10(-7) cm2/s to D1 = 8.10(-8) cm2/s (that is by a factor of 4) upon polymerization. This is consistent with the freeze fracture finding of a small aggregation number. We point out the similarities of the mixed vesicles with plasma membranes coupled to the cytoskeleton.

Butadienes↗
PubMed1999

Modulating insulin-release profile from pH/thermosensitive polymeric beads through polymer molecular weight.

Stimuli-sensitive statistical terpolymers of N-isopropylacrylamide (NIPAAm) (temperature-sensitive), butyl methacrylate (BMA) and acrylic acid (AA) (pH-sensitive) of various molecular weight (MW) with NIPAAm/BMA/AA feed mol ratio of 85/5/10 were used to modulate release of insulin, a model protein drug, from pH/thermosensitive polymeric beads. Protein drug loading from an aqueous medium into the beads was achieved by preparing a 7 or 10% (w/v) polymer solution with 0.2% (w/v) insulin at low pH and below the lower critical solution temperature (LCST) of the polymer (pH 2.0 and 4 degrees C), and then dropping the solution into an oil bath above the LCST of the solution (35 degrees C). This loading procedure maintained protein stability while achieving high loading efficiency, between 90 and 95% in the beads. Insulin-release studies from beads prepared from terpolymers of the same composition but increasing MW were performed at pH 2.0 and 7.4, at 37 degrees C. It was observed that there was negligible loss of insulin at pH 2.0 from the beads, indicating no burst effect. At pH 7.4, insulin release was seen from all the beads and the release rate was a function of the MW of the polymer. The low MW polymeric beads eroded, dissolved and released most of the insulin within 2 h at pH 7.4 and 37 degrees C, the intermediate MW polymeric beads swelled slightly, dissolved and released most of the insulin within 4 h, whereas the high MW polymeric beads swelled slowly and gradually released the loaded insulin over a period of 8 h. Thus, the release of protein from the low MW polymeric beads is controlled by the rate of dissolution of the polymer, whereas the release from the high MW polymeric beads is controlled by swelling of the beads and drug diffusion. Studies using fluorescein-labeled insulin revealed that insulin was uniformly distributed in the beads regardless of polymer MW. The loaded and released insulin were fully bioactive. Based on the described results, the low MW polymeric beads may be used for immediate delivery of protein drugs in the duodenum, the intermediate MW polymeric beads may be used for lower small intestine targeting, while the high MW polymeric beads may be used to target protein drugs predominantly to the colon.

Administration, Oral↗
PubMed1997

Impaired actin polymerization and depolymerization in neutrophils from patients with thermal injury.

Acquired neutrophil dysfunction is considered an important cause of increased susceptibility to infection in patients with burns. In the early postinjury phase, large amounts of circulating chemo-attractants, cytokines and endotoxins induce strong systemic activation of neutrophils which may impair their motile functions. Actin is the most prevalent component of the microfilament lattice that generates force for the neutrophil motile responses, and in the present study we examined the dynamics of actin polymerization and depolymerization in neutrophils from 11 patients with large burns. At admission, the amount of polymerized actin in unstimulated neutrophils was 39.9 per cent higher than that of parallel controls. In addition, there was a positive correlation between the amount of polymerized actin and the total body surface area (TBSA) burn. The time course of patient neutrophil actin polymerization in response to FMLP, C5a, (Ser-IL-8)72, (Ala-IL-8)77 and crosslinking of surface Fc gamma RII was similar to that of controls, and the maximal amount of neutrophil F-actin was demonstrated after 30 s stimulation. At the peak of actin polymerization, however, patient neutrophils contained 27.3, 24.0, 24.7 and 25.6 per cent more polymerized actin than control cells stimulated with FMLP, (Ser-IL,-8)77, (Ala-8)77 and Fc gamma RII crosslinking, respectively. However, the relative increase of neutrophil F-actin following stimulation was significantly lower in patients than in controls. Moreover, the rate of patient neutrophil actin depolymerization was 39.0, 23.5, 63.3 and 51.7 per cent lower than that of controls after stimulation with FMLP, C5a (Ser-IL-8)72 and Fc gamma RII crosslinking, respectively. At discharge, the dynamics of neutrophil actin polymerization and depolymerization were similar to that of controls. The results demonstrate that in neutrophils during the early postburn phase, there are increased basal levels of polymerized actin, a lower responsiveness to stimulation and a reduced rate of actin depolymerization. As periodic polymerization and depolymerization of actin is essential for all neutrophil motile responses, it is probable that the alterations observed may contribute significantly to the overall neutrophil dysfunction following thermal injury.

Actins↗
PubMed2000

Decreased lateral aggregation of a variant recombinant fibrinogen provides insight into the polymerization mechanism.

We analyzed the polymerization of BbetaA68T fibrinogen, the recombinant counterpart of fibrinogen Naples, a variant known to have decreased thrombin binding. When polymerized with equal thrombin concentrations, BbetaA68T fibrinogen had a longer lag time and lower rate of lateral aggregation, V(max), than normal recombinant fibrinogen, but a similar final turbidity. At thrombin concentrations that equalized the rates of fibrinopeptide A release, BbetaA68T fibrinogen polymerized with a lag time and V(max) similar to normal, but reached a significantly lower final turbidity. Similar results were produced when BbetaA68T was polymerized with Ancrod, which cleaves fibrinopeptide A at the same rate from either fibrinogen, and when BbetaA68T desA monomers were polymerized. The polymerization of desAB fibrin monomers, which circumvents fibrinopeptide release, was the same for both fibrinogens. We confirmed that turbidity was indicative of fiber thickness by scanning electron microscopy of fibrin clots. Here, we present the first experimental evidence of fibrin polymerization with a normal period of protofibril formation and rate of lateral aggregation, but with a significantly decreased extent of lateral aggregation. We conclude that the decreased lateral aggregation seen in BbetaA68T fibrinogen is due to an altered step in the enzymatic phase of its polymerization process. We propose that during normal polymerization a subtle conformational change in the E domain occurs, between the release of FpA and FpB, and that this change modulates the mechanism of lateral aggregation. Without this change, the lateral aggregation of BbetaA68T fibrinogen is impaired such that variant clots have thinner fibers than normal clots.

Alanine↗
PubMed1993

Characterization of the reversible taxol-induced polymerization of plant tubulin into microtubules.

Taxol has been reported to induce the polymerization of plant tubulin into microtubules, albeit weakly when compared to that of mammalian tubulin [Morejohn, L.C., & Fosket, D.E. (1984) J. Cell Biol. 99, 141-147], suggesting that taxol, a product of plant secondary metabolism, may interact poorly with plant microtubules. To test this idea in detail, we have investigated critical parameters affecting taxol-dependent microtubule polymerization and stability using tubulins from model cell lines of maize [Zea mays cv. Black Mexican Sweet (BMS)] and tobacco [Nicotiana tabacum cv. Bright Yellow 2 (BY-2)]. When plant tubulin dimer is isolated by using a modified version of the original method [Morejohn, L.C., & Fosket, D.E. (1982) Nature 297, 426-428], most of the tubulin polymerizes at 25 degrees C, with critical dimer concentrations (Cc) of 0.06 mg/mL for BMS tubulin and 0.13 mg/mL for BY-2 tubulin. When taxol-induced assembly is initiated with a 0-25 degrees C temperature jump, 42% of polymer is polymorphic, presumably due to aberrant nucleation events. Taxol-induced assembly at 2 degrees C minimizes the formation of polymorphic structures and is much more rapid than that of purified bovine brain tubulin, indicating a functional difference in the polymerization domains of these diverse tubulins. Temperature ramping during taxol-induced polymerization affords > or = 95% assembly of plant tubulin into polymer consisting of 86% microtubules, which may be completely depolymerized by a combined treatment with low temperature and Ca2+. We report for the first time that plant tubulin may be subjected to numerous cycles of efficient taxol-induced polymerization and cold/Ca(2+)-induced depolymerization with little loss of polymerization competence. Gel filtration chromatography at low temperature may be used to separate taxol from soluble plant tubulin dimer, which retains its characteristic polymerization and herbicide-binding properties. Our results demonstrate that despite its origin from plants, taxol is a potent drug for the reversible polymerization of plant microtubules.

Calcium↗
PubMed1981

Mechanism of action of phalloidin on the polymerization of muscle actin.

Under conditions where muscle actin only partially polymerizes, or where it does not polymerize at all, a significant enhancement of polymerization was observed if equimolar phalloidin was also present. The increased extent of polymerization in the the presence of phalloidin can be explained by the reduced critical actin concentration of partially polymerized populations at equilibrium. Under such conditions, the rate of polymerization, as judged by the length of time to reach half the viscosity plateau, was found to be essentially independent of the phalloidin concentration. Moreover, the initial rate of polymerization of actin was also found to be independent of phalloidin concentration. However, phalloidin apparently causes a reduction in the magnitude of the reverse rates in the polymerization reaction, as was demonstrated by the lack of depolymerization of phalloidin-treated actin polymers. This effect of phalloidin is also supported by the identification of actin nuclei and short polymers in populations of G-actin incubated with phalloidin in the absence of added KCl. Our conclusion, then, is that phalloidin influences the polymerization of actin by stabilizing nuclei and polymers as they are formed.

Actins↗
PubMed1982

On the mechanism of de novo polymerization by form I polynucleotide phosphorylase of Micrococcus luteus.

The diastereomers of adenosine 5'-O-(1-thiodiphosphate) (ADP alpha S) have been tested as substrates for the polymerization reaction of primer-independent polynucleotide phosphorylase from Micrococcus luteus. The preferred substrate is ADP alpha S(Sp), which has a similar Km and a greatly reduced Vmax when compared to the natural substrate ADP. The other diastereomer, ADP alpha S(Rp), is preferentially cleaved by a polyphosphate kinase activity (present with the phosphorylase) that may be responsible for the removal of the 5'-beta-phosphate during de novo polymerization, leading to the observed 5'-phospho-poly(A). Inhibitor studies suggest that the kinase and de novo polymerization sites are not coincident. During de novo polymerization of the diastereomeric mixture, ADP alpha S(Rp) is selectively used to form 5' termini, whereas ADP alpha S(Sp) serves to support the chain elongation. Thus there are two stereochemically distinct subsites for initiating polymerization. ADP beta S functions as a substrate for polynucleotide phosphorylase with kinetic properties similar to those of ADP, indicating that removal of the beta-phosphate (a thiophosphate) is not a kinetically important step and probably occurs after polymerization is complete. The average chain length of the polymeric product is considerably smaller for ADP alpha S vs. ADP beta S or ADP, suggesting that the degree of processivity of the polymerization is determined by competition between the rate of polymerization and the rate of dissociation of the growing chain.

Adenosine Diphosphate↗
PubMed2003

Tau polymerization: role of the amino terminus.

The abnormal polymerization of the tau molecule into insoluble filaments is a seminal event in the neurodegenerative process underlying Alzheimer's disease. Previous experimentation has shown that the microtubule-binding repeat region of the molecule is vital for its ability to polymerize in vitro into filaments similar to those found in Alzheimer's disease. However, it is becoming clear that regions outside the microtubule-binding repeat, such as exons 2 and 3 and the carboxy-terminal tail, can greatly influence its polymerization. Since it has been previously postulated that the amino terminus of tau could be involved in generating pathological conformations in the disease state, its role in the polymerization process was investigated. This report demonstrates that the removal of the amino terminus greatly inhibits the polymerization of the tau molecule, reducing both the rate and extent of polymerization. These results support the hypothesis that the ability of tau to form specific conformations involving the amino terminus is an early event in the formation of tau polymers in the disease state. Furthermore, the mutation of arginine 5 to leucine ((R)5(L)), mimicking an amino-terminal tau mutation found in a single case of FTDP-17, enhances the polymerization of the tau molecule. Therefore, the amino terminus of the tau molecule, while largely overlooked in studies of its polymerization, is a significant contributor to the polymerization process.

Alzheimer Disease↗
PubMed1999

A novel endogenous antimalarial: Fe(II)-protoporphyrin IX alpha (heme) inhibits hematin polymerization to beta-hematin (malaria pigment) and kills malaria parasites.

The polymerization of hemoglobin-derived ferric-protoporphyrin IX [Fe(III)PPIX] to inert hemozoin (malaria pigment) is a crucial and unique process for intraerythrocytic plasmodia to prevent heme toxicity and thus a good target for new antimalarials. Quinoline drugs, i.e., chloroquine, and non-iron porphyrins have been shown to block polymerization by forming electronic pi-pi interactions with heme monomers. Here, we report the identification of ferrous-protoporphyrin IX [Fe(II)PPIX] as a novel endogenous anti-malarial. Fe(II)PPIX molecules, released from the proteolysis of hemoglobin, are first oxidized and then polymerized to hemozoin. We obtained Fe(II)PPIX on preparative scale by electrochemical reduction of Fe(III)PPIX, and the reaction was monitored by cyclic voltammetry. Polymerization assays at acidic pH were conducted with the resulting Fe(II)PPIX using a spectrophotometric microassay of heme polymerization adapted to anaerobic conditions and the products characterized by infrared spectroscopy. Fe(II)PPIX (a) did not polymerize and (b) produced a dose-dependent inhibition of Fe(III)PPIX polymerization (IC(50) = 0.4 molar equiv). Moreover, Fe(II)PPIX produced by chemical reduction with thiol-containing compounds gave similar results: a dose-dependent inhibition of heme polymerization was observed using either L-cysteine, N-acetylcysteine, or DL-homocysteine, but not with L-cystine. Cyclic voltammetry confirmed that the inhibition of heme polymerization was due to the Fe(II)PPIX molecules generated by the thiol-mediated reduction of Fe(III)PPIX. These results point to Fe(II)PPIX as a potential endogenous antimalarial and to Fe(III)PPIX reduction as a potential new pharmacological target.

Animals↗
PubMed2001

Polymerization of lactide with zinc and magnesium beta-diiminate complexes: stereocontrol and mechanism.

A series of zinc(II) and magnesium(II) alkoxides based upon a beta-diiminate ligand framework has been prepared. [(BDI-1)ZnO(i)Pr](2) [(BDI-1) = 2-((2,6-diisopropylphenyl)amido)-4-((2,6-diisopropylphenyl)imino)-2-pentene] exhibited the highest activity and stereoselectivity of the zinc complexes studied for the polymerization of rac- and meso-lactide to poly(lactic acid) (PLA). [(BDI-1)ZnO(i)()Pr](2) polymerized (S,S)-lactide to isotactic PLA without epimerization of the monomer, rac-lactide to heterotactic PLA (P(r) = 0.94 at 0 degrees C), and meso-lactide to syndiotactic PLA (P(r) = 0.76 at 0 degrees C). The polymerizations are living, as evidenced by the narrow polydispersities of the isolated polymers in addition to the linear nature of number average molecular weight versus conversion plots and monomer-to-catalyst ratios. The substituents on the beta-diiminate ligand exert a significant influence upon the course of the polymerizations, affecting both the degree of stereoselectivity and the rate of polymerization. Kinetic studies with [(BDI-1)ZnO(i)Pr](2) indicate that the polymerizations are first order with respect to monomer (rac-lactide) and 1.56 order in catalyst. Polymerization experiments with [(BDI-1)MgO(i)Pr](2) revealed that this complex is extremely fast for the polymerization of rac-lactide, polymerizing 500 equiv in 96% yield in less than 5 min at 20 degrees C.

Biocompatible Materials↗
PubMed1995

ADP-induced platelet aggregation and actin polymerization. Involvement of GpIIb/IIIa and the effect of Mg2+.

We have investigated the effects of Mg2+ (added to platelet rich plasma [PRP] as 10mM MgCl2 or MgSO4) on the platelet aggregation and actin polymerization that occurs in response to adenosine diphosphate (ADP). The PRP was prepared from blood containing hirudin as anticoagulant. Mg2+ added before 1 microM ADP completely inhibited aggregation and markedly inhibited actin polymerization. Mg2+ (10mM) added before 10 microM ADP converted irreversible aggregation into a reversible response; similarly, apparently irreversible actin polymerization was converted to a reversible response in which polymerization was followed by some actin depolymerization. Mg2+ added after inducing platelet aggregation with 10 microM ADP produced parallel disaggregation of platelets and actin depolymerization. Actin polymerization occurs immediately on adding ADP to PRP (in association with shape change) and further polymerization occurs in association with platelet aggregation. When aggregation (and the actin polymerization associated with this) was prevented by adding M148, a monoclonal antibody directed at the GpIIb/IIIa complex, or simply by avoiding stirring the sample, Mg2+ had no effect on actin polymerization/depolymerization. Thus Mg2+ only affected the changes in actin that were associated with the aggregation response. This was in contrast to iloprost (which acts at the PGI2 receptor to stimulate adenylate cyclase) which induced rapid actin depolymerization when added after ADP stimulation of platelets under circumstances where platelet aggregation was avoided. These results show that Mg2+ affects actin polymerization as well as platelet aggregation, and that it affects the actin polymerization associated with aggregation but not that associated with shape change (in contrast to iloprost which inhibits both).(ABSTRACT TRUNCATED AT 250 WORDS)

Actins↗
PubMed1995

Polymerization of recombinant Hb S-Kempsey (deoxy-R state) and Hb S-Kansas (oxy-T state).

In order to investigate the role of the R (relaxed) to T (tense) structural transition in facilitating polymerization of deoxy-Hb S, we have engineered and expressed two Hb S variants which destabilize either T state (Hb S-Kempsey, alpha 2 beta 2 Val-6,Asn-99) or R state structures (Hb S-Kansas, alpha 2 beta 2 Val-6, Thr-102). Polymerization of deoxy-Hb S-Kempsey, which shows high oxygen affinity and increased dimer dissociation, required about 2- and 6-fold higher hemoglobin concentrations than deoxy-Hb S for polymerization in low and high phosphate concentrations, and its kinetic pattern of polymerization was biphasic. In contrast, oxy- or CO Hb S-Kansas, which shows low oxygen affinity and increased dimer dissociation, polymerized at a slightly higher critical concentration than that required for polymerization of deoxy-Hb S in both low and high phosphate buffers. Polymerization of oxy- and CO Hb S-Kansas was linear and showed no delay time, which is similar to oversaturated oxy- or CO Hb S. These results suggest that nuclei formation, which occurs during the delay time prior to deoxy-Hb S polymerization, does not occur in T state oxy-Hb S-Kansas, even though the critical concentration for polymerization of T state oxy-Hb S-Kansas is similar to that of T state deoxy-Hb S.

Carboxyhemoglobin↗