Structure of a new [11]cytochalasin, cytochalasin H or kodo-cytochalasin-1.
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Crystallography↗
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The binding sites of cytochalasin D. II. Their relationship to hexose transport and to cytochalasin B.
Cytochalasin B (CB) was able to compete with tritiated cytochalasin D (3H-CD) for binding sites in HEp-2 cells. The pattern of inhibition suggested that CB associates with a low affinity class of CD binding sites. Glucose and maltose did not inhibit binding of 3H-CD to isolated HEp-2 plasma membrane. Inhibition of hexose transport by CD was negligible, but CD did not block the potent inhibition of this transport by CB. These results indicate that CD does not bind to the high affinity CB receptor reportedly associated with the hexose transport system, and that this receptor cannot mediate the morphological effects of CD. Both CD and CB induced contraction-zeoisis in HEp-2 cells; CB was less potent than CD, and their effects appeared to be additive. It was concluded that the high affinity binding sites for CD and CB are different, but that these congeners share a low affinity site. Both high and low affinity sites for CD appear to mediate its morphological effects; only the low affinity class appears to be involved for CB. Possible identification of the common low affinity binding site as actomyosin (detailed in Tannenbaum et al., '77) is further discussed.
Binding Sites↗
[Cytochalasin B (phomin): degradation reactions and cyclization of B-cytochalasinic acid to 21,22-dihydro-isocytochalasin A (author's transl)].
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Cyclization↗
Cytochalasins A and B from strains of Phoma exigua var. exigua and formation of cytochalasin B in potato gangrene.
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Ascomycota↗
Cytochalasin inhibits the rate of elongation of actin filament fragments.
Submicromolar concentrations of cytochalasin inhibit the rate of assembly of highly purified dictyostelium discoideum actin, using a cytochalasin concentration range in which the final extent of assembly is minimally affected. Cytochalasin D is a more effective inhibitor than cytochalasin B, which is in keeping with the effects that have been reported on cell motility and with binding to a class of high-affinity binding sites from human erythrocyte membranes (Lin and Lin. 1978. J. Biol. CHem. 253:1415; Lin and Lin. 1979. Proc. Natl. Acad. Sci. U.S.A. 76:2345); 5x10(-7) M cytochalasin B lowers it to 70 percent of the control value, whereas 10(-7) M cytochalasin B lowers the rate to 25 percent. Fragments of F-actin were used to increase the rate of assembly fivefold by providing more filament ends on to which monomers could add. Under these conditions, cytochalasin has an even more dramatic effect on the assembly rate; the concentrations of cytochalasin B and cytochalasin D required for half-maximal inhibition are 2x10(-7) M and 10(-8) M, respectively. The assembly rate is most sensitive to cytochalasin when actin assembly is carried out in the absence of ATP (with 3 mM ADP present to stabilize the actin). In this case, the concentrations of cytochalasin B and cytochalasin D required for half-maximal inhibition are 4x10(-8) M and 1x10(-9) M, respectively. A scatchard plot has been obtained using [(3)H]cytochalasin B binding to F-actin in the absence of ATP. The K(d) from this plot (approximately 4x10(-8) M) agrees well with the concentration of cytochalasin B required for half-maximal inhibition of the rate of assembly under these conditions. The number of cytochalasin binding sites is roughly one per F-actin filament, suggesting that cytochalasin has a specific action on actin filament ends.
Actins↗
The use of cytochalasins in studies on the molecular biology of virus--host cell interactions.
In conclusion, one can say that the cytochalasins--in their brief history of application in virology--have proven to be valuable tools in studies on the molecular biology of virus--host cell interactions. On the other hand, viral systems can be useful in defining the primary sites of action of cytochalasins in certain cells. In interpreting the effects of cytochalasins on virus replication, however, one must take into consideration that the cytochalasins exert a wide variety of alterations in cellular functions. Infections by viruses interfere primarily with the synthesis of host DNA, RNA, and proteins. The experiments reviewed here were carried out with different viruses, different cell lines, and--more important--under very different experimental conditions. Nevertheless, a number of informative observations emerge which provide insight into specific aspects of the interaction of viruses with their host cells, and help us to understand the mode of action of cytochalasins on specific cellular functions: Cytochalasins may decrease or increase the competence of cells for infection by viruses. For the DNA viruses, vaccinia virus and adenovirus, cytochalasin treatment of host cells resulted in a reduced virus yield; whereas for the RNA viruses, poliovirus, parainfluenza virus, and VSV, cytochalasin treatment results in an increased virus yield. The precise mechanism by which cytochalasins exert these effects remain unclear. It is proposed that the cytochalasin-mediated enhancement of cell infectibility for poliovirus--the only system for which this effect has been studied in more detail--is primarily due to a reduction of polypeptide chain initiation. This reduction dramatically amplifies the inherent translational advantage of virus mRNAs over host cell mRNAs, resulting in a relative stimulation of viral mRNA translation. The cytochalasin-mediated sensitization of cells for infection by isolated poliovirus RNA is explainable by a comparable effect on protein synthesis. In this case, cytochalasin may act in part by substituting for the function of a viral protein(s). When cytochalasin B is added to cells which have previously been infected by intact HSV, formation of infectious virus particles is severely inhibited...
Cell Line↗
Effect of cytochalasin B and D on groups of insulin receptors and on insulin action in rat adipocytes. Possible evidence for a structural relationship of the insulin receptor to the glucose transport system.
The possible physiological importance of the groups of insulin receptors on rat adipocytes and the relationship of these groups to insulin action were investigated. The effect of cytochalasin B and D on biological actions of insulin was measured and compared with the effect of these agents on the ultrastructural distribution of groups of insulin receptors. Cytochalasin B had no effect on epinephrine-stimulated lipolysis, insulin inhibition of epinephrine-stimulated lipolysis, or insulin stimulation of protein synthesis. Cytochalasin B, over a concentration range of 50 nM to 5 muM, progressively inhibited the basal glucose transport system, as measured by glucose oxidation, 2-deoxyglucose transport, and 3-O-methylglucose transport. Insulin was capable of fully stimulating remaining basal transport at submaximal concentrations of cytochalasin B. Insulin pretreatment of adipocytes partially protected the glucose transport system from inhibition by cytochalasin B. Cytochalasin B markedly altered the distribution pattern of insulin receptors, which caused an increase in the number of single receptor molecules by decreasing the number of larger groups. A significant correlation (r = 0.964; P < 0.001) was found between the percent increase in single receptors and the percent decrease in glucose transport. Ferritin-insulin pretreatment of adipocytes prevented disruption of the groups of insulin receptors by cytochalasin B. Cytochalasin D had no effect on the biological actions of insulin or on the groups of insulin receptors. These data suggest that the ability of insulin to affect adipocyte metabolism is independent of the hormone occupying adjacent, grouped receptor sites. The marked contrast in effects of cytochalasin B and D on groups of insulin receptors and glucose transport suggests that the microfilament system is not involved in insulin action or in holding the groups of insulin receptors together, as both agents are known disrupters of microfilaments and inhibitors of actin gelation. The correlation between the effects of cytochalasin B on insulin receptor distribution and glucose transport leads to the speculation that the glycoprotein molecules containing the insulin receptor are functionally linked with the glucose transport system.
Adipose Tissue↗
Modulation of macrophage C3b receptor function by cytochalasin-sensitive structures.
A quantitative rosette assay was employed in order to determine if through pharmacologic probes we could gain an insight into the nature of the interaction between C3b-coated particles and the macrophage C3b receptor. Rabbit alveolar macrophage monolayers were challenged with chromium-labeled, complement-coated (via cold agglutinin) human erythrocytes (HEC3b) and the per cent of bound counts determined in the distilled water lysate. With this assay system in which ingestion is negligible, the cytochalasins (A greater than E greater than D greater than B) produced the most marked inhibition of rosette formation compared to control treated monolayers. No agent examined produced consistent augmentation. Cytochalasin A at 10(-5), 10(-6), and 10(-7) M inhibited rosette formation by 77+/- 2, 44 +/- 4 and 15 +/- 7 (S.E.), per cent, respectively. Cytochalasin E was also markedly inhibitory, Cytochalasins B and D produced approximately 30% inhibition at 10(-5) M. The cytochalasin effect was not secondary to an interaction between these agents and complement-sensitized erythrocytes, although cytochalasin E was also able to reduce erythrocyte-bouund C3b reactivity. Cytochalasin A and E modulation of the macrophage C3b reactivity occurred within a few minutes and was only slightly reversible. Cytochalasins A and E could also disrupt performed rosettes but the effect was not as pronounced as when these agents were present before and/or during the actual adherence phenomenon. Vinblastine and colchicine (10(-5) and 10(-6) M) also produced significant inhibition of rosette formation, although the magnitude of the effect was less than that for cytochalasins A and E. Further characterization of the vinblastine and colchicine effect demonstrated that the inhibition was rapid, irreversible over a 60-min incubation, and not explained by an alteration in macrophage attachment or in HEC3b reactivity. Agents producing insignificant inhibition of rosette formation included the following: dibutyryl cAMP and cAMP agonists (PGE1, theophylline), 8-bromo cGMP and cGMP agonists (carbachol, asorbic acid), dimethylsulfoxide, heparin, ethanol, dextran sulfate, DEAE-dextran, and poly-L-lysine. The data suggest that cytochalasin, vinblastine and colchicine sensitive membrane structures, most likely microfilaments and microtubules, are important in the interaction of C3b-coated particles with the macrophage C3b receptor.
Agglutinins↗
Cytochalasin B-induced superoxide production in polycation-treated neutrophils.
Cytochalasin B alone induces little superoxide production in intact rabbit peritoneal neutrophils. The cytochalasin causes a strong production of superoxide in cells treated with membrane-permeabilizing polycations. Several polycations were able to express the activating effect of cytochalasin B. Especially the poly-L-arginine with a molecular weight of 24,000 proved to be effective. The effectiveness of some polycations is limited because they inactivate the superoxide-generating oxidase system of the neutrophil. Cytochalasin B-induced superoxide production starts at poly-L-arginine concentrations that cause a change of membrane permeability. At the concentrations of cytochalasin B used in our experiments, the binding of [3H]cytochalasin B is not enhanced in poly-L-arginine-treated cells as compared with control cells. Activation of superoxide production by cytochalasin B in polycation-treated neutrophils occurs both in the presence or absence of extracellular Ca2+. When the cells are pretreated with agents that known to interfere with intracellular Ca2+, the subsequent activation is strongly inhibited, suggesting a role for intracellular Ca2+ in cytochalasin B-induced activation. It is suggested that cytochalasin B alone is not able to activate all the steps that eventually result in complete activation of the superoxide-generating oxidase and that membrane perturbation by polycation provides activation of the remaining steps.
Amino Acid Sequence↗
Action of cytochalasin A, a sulfhydryl-reactive agent, on sugar metabolism and membrane-bound adenosine triphosphatase of yeast.
Cytochalasin A at 10-20 mug/ml inhibits growth and sugar uptake by Saccharomyces strain 1016. The effects of cytochalasin A in intact cells were completely prevented when 1 mM cysteine or dithiothreitol was added along with cytochalasin A, but were not eliminated by thiols added after inhibition had occurred. Purified yeast hexokinase, glucose-6-P dehydrogenase, phosphofructokinase and aldolase were not sensitive to cytochalasin A (20 mug/ml). Glyceraldehyde-3-P dehydrogenase was strongly inhibited by cytochalasin A (5 mug/ml); activity was promptly restored by thiols. Anaerobic glycolysis was inhibited by cytochalasin A or by iodoacetate; unlike iodoacetate, cytochalasin A did not cause accumulation of sugar phosphates. In contrast, cytochalasin A, but not iodoacetate, inhibited isolated membrane-bound ATPases. Cytochalasin A is a sulfhydryl-reactive agent and has membrane-related effects (adenosine triphosphatase) which may well be the basis of its interference with energy-dependent uptake of solutes.
Adenosine Triphosphatases↗
Characterization of (3H)cytochalasin B binding to the fat cell plasma membrane.
Transport of D-[3H]deoxyglucose and D-[3H]glucose by purified fat cell plasma membranes was markedly inhibited by cytochalasin B,dipyridamole, or phlorizin. The rate of L-[3H]glucose uptake was significantly slower and was unaffected by cytochalasin B. Both the rates of association of [3H]cytochalasin B with the fat cell plasma membrane and its dissociation from the membrane was significantly enhanced by the presence of Ca2+ or Mg2+. Scatchard plot analysis of [3H]cytochalasin B binding to fat cell membranes indicated the presence of high affinity and low affinity sites which exhibited apparent dissociation constants of about 6 X 10(-7) M and 5 X 10(-6) M, respectively. The concentration of cytochalasin B which half-maximally inhibited D-glucose transport was about 5 X 10(-7) M, indicating the high affinity sites are involved in transport inhibition. D-Glucose at concentrations as high as 100 mM had no effect on the binding of [3H]cytochalasin B to these high affinity sites, while the transport inhibitors phlorizin, phloretin, and dipyridamole markedly inhibited this binding. The protein reagents N-ethylmaleimide, 2-hydroxy-5-nitrobenzylbromide, 1-fluoro-2,4-dinitrobenzene, dithiothreitol, and trypsin also reduced binding. Extracted fat cell plasma membrane lipids dispersed by sonication did not bind [3H]cytochalasin B nor take up glucose by a cytochalasin B-sensitive pathway. The results indicate that cytochalasin B inhibits hexose transport in fat cells secondary to its interaction with membrane protein sites distinct from those which bind D-glucose.
2-Hydroxy-5-nitrobenzyl Bromide↗
Response of adrenal tumor cells to adrenocorticotropin: site of inhibition by cytochalasin B.
The ability of cytochalasin B to inhibit the steroidogenic response of mouse adrenal tumor cells (Y-1) to adrenocorticotropin (ACTH) was examined with two aims: to consider the specificity of the inhibitor and to determine at what point(s) in the steroidogenic pathway it acts. Cytochalasin B did not inhibit protein synthesis or transport of [3H]-cholesterol into the cells nor did it alter total cell concentration of ATP. Together with previous evidence, this suggests that the effects of cytochalasin observed are relatively specific in these cells. Cytochalasin inhibits the increase in conversion of [3H]cholesterol to 20alpha-[3H]dihydroprogesterone (20alpha-hydroxypregn-4-en-3-one: a major product of the steroid pathway in Y-1 cells) produced by ACTH but does not inhibit conversion of cholesterol to pregnenolone by mitochondrial and purified enzyme preparations from Y-1 cells and bovine adrenal, respectively. Cytochalasin does not inhibit the conversion of pregnenolone to 20alpha-dihydroprogesterone but was shown to inhibit increased transport of [3H]cholesterol to mitochondria resulting from the action of ACTH. These findings indicate that cytochalasin acts after cholesterol has entered the cells and before it is subjected to side-chain cleavage in mitochondria. In view of the known action of cytochalasin on microfilaments, it is proposed that these organelles are necessary for the transport of cholesterol to the mitochondrial cleavage enzyme and that at least one effect of ACTH (and cyclic AMP) is exerted upon this transport process. The specificity of the effects of cytochalasin is considered in relation to this conclusion.
20-alpha-Dihydroprogesterone↗
Effects of cytochalasin B on the aggregation, electrophoretic mobility and surface morphology of chick neural retina cells.
Over a concentration range of o-5-10 mug/cm-3, cytochalasin B caused a biphasic change in the electrophoretic mobility of disaggregated neural retina cells. An initial rise in anodal mobility at low concentrations of the drug was transformed into a reduction in the mobility below that of the control at a concentration of 10 mug/cm-3. The effect of cytochalasin B was found to be reversible by washing treated cells in cytochalasin B-free media. This was investigated at a concentration of cytochalasin at which the greatest difference existed between the mobilities of the control and experimental cell suspensions. Reaggregation of cell dispersions failed to show any significant difference in the rate of aggregation between cytochalasin B-treated cells and the control. Scanning electron microscopy of cells fixed while in suspension also showed little significant change in the surface morphology upon application of cytochalasin B. In high concentrations of the drug cells appeared somewhat smoother in outline, but no correlation was found between changes in surface morphology and the variations in cell electrophoretic mobility. It is concluded that the observed changes in electrophoretic mobility may be attributed to a binding of cytochalasin B to the cell membrane. This lends support to the hypothesis that the primary site of action of cytochalasin B may be the plasma membrane.
Animals↗
Cytochalasin B binding proteins in human erythrocyte membranes. Modulation of glucose sensitivity by site interaction and partial solubilization of binding activities.
We have previously described three different cytochalasin B binding sites in human erythrocyte membranes, a D-glucose-sensitive site (Site I), a cytochalasin E-sensitive site (Site II), and a site (Site III) insensitive to both D-glucose and cytochalasin E. Ligand bindings to each of these sites were considered to be independent (Jung, C., and Rampal, A. (1977) J. Biol. Chem. 252, 5456-5463). However, we have obtained subsequently the following evidence which indicated that an interaction occurs between Sites II and III, and this modulates sensitivity of Site III to the sugar. The displacement of cytochalasin E greatly exceeds the sum of their independent displacements. This ghosts extracted with EDTA or 2,3-dimethylmaleic anhydride at low ionic strength lack Site II activity but retain Site I and III activities, and both of these activities are displaceable by D-glucose alone. This indicated that the removal of Site II from the membrane confers glucose sensitivity to Site III. These observations are consistent with a model that Sites II and III in the membrane exist in a close association through which unliganded Site II maintains the glucose insensitivity of Site III, and once site II is liganded or removed by extraction this association is disrupted and Site III becomes glucose-sensitive. The ghosts extracted with Triton X-100 retain a cytochalasin B binding activity similar to that of site II (Kd = 1.8 X 10(-7) M, cytochalasin E-sensitive, glucose-insensitive), whereas a binding activity similar to that of Site I (Kd = 4 X 10(-7) M, cytochalasin E-insensitive, glucose-sensitive) is recovered in the Triton extract. A cytochalasin B binding activity similar to that of Site II is solubilized by EDTA at low ionic strength.
Cytochalasin B↗
Reversible inhibition of the norepinephrine induction of lactate dehydrogenase by cytochalasin B in rat glial C6 cells.
The cyclic AMP mediated induction of lactate dehydrogenase (LDH: E.C. 1.1.1.27) activity by norepinephrine in the rat glial cell line C6 is inhibited by cytochalasin B. Doses of 5, 15, and 25 microgram/ml of cytochalasin B inhibited the induction equally. Twenty-five microgram/ml of cytochalasin B inhibited the induction reversibly, and had no effect on basal enzyme level. No effect of cytochalasin B on general protein synthesis was found, nor did it increase the rate of decline of enzyme activity in deinduced cells. It therefore appears to block LDH induction by selectivity inhibiting its synthesis. Cytochalasin B had no effect on the transient (intracellular and extracelllular) rise in cyclic AMP generated in response to norepinephrine treatment. Cytochalasin B was effective when added during the transcription dependent phase (first 3 hours) but not during the translation dependent phase (after 3 hours) of LDH induction. The suggestion is discussed that cytochalasin B inhibits one of the early events of the inductive process.
Animals↗
The oral apparatus of Tetrahymena pyriformis, strain WH-6. III. The binding of 3H-cytochalasin B by the isolated oral apparatus.
The binding of tritium-labelled cytochalasin B by the isolated oral apparatus of Tetrahymena pyriformis, strain WH-6, syngen 1, was investigated. Equilibrium binding studies revealed approximately 1.4 x 10(5) cytochalasin B binding sites per oral apparatus. A Scatchard plot indicates a single class of binding affinities with an association constant of 10(5) liters/mole. Rapid release of oral apparatus-bound cytochalasin B occurred when oral apparatuses were washed and resuspended in 1 mM TRIS without cytochalasin B. Because cytochalasin B binding to oral apparatus microtubular protein was not detected, microtubules are probably not the cytochalasin B binding site. The probable nature of the cytochalasin B binding site within the oral apparatus is discussed.
Animals↗
Specific interaction of cytochalasins with muscle and platelet actin filaments in vitro.
The cytochalasins (CE, CD, CB and H2CB) inhibit numerous cellular processes which require the interaction of actin with other structural and contractile proteins. In this report we describe the effects of the cytochalasins on the viscosity and morphology of muscle and platelet actin. The cytochalasins decreased the viscosity of F-actin solutions. The effect of H2CB, CB and CD ON F-actin viscosity was maximal at concentrations of 20-50 micro M and did not increase with time. In contrast, CE caused a progressive decrease in the viscosity of F-actin solutions which was dependent upon the concentration of CE and the duration of incubation of the CE-actin mixture. After two hours of incubation of drug-actin mixtures, the relative effectiveness of the cytochalasins in reducing the viscosity of F-actin was CE greater than CD greater than CB=H2CB. The effects of CD and CE were paralleled by morphologic changes in negatively stained actin filaments. The effects of the cytochalasins on the viscosity and morphology of muscle and platelet actin were the same whether the drugs were added before or after the polymerization of the protein. These studies show that the interaction of the cytochalasins with actin is highly specific. Because the relative potencies of these drugs for affecting motile processes and the relative affinities of the drugs for binding sites within a variety of cells are CE greater than CD greater than CB=H2CB, the effects of cytochalasins on actin described here may contribute to some of the biological effects of the drugs on motile processes.
Actins↗
Effect of cytochalasin B on formation and properties of muscle F-actin.
Cytochalasin B stimulated polymerization and decreased the concentration of G-actin remaining in equilibrium with F-actin filaments. Polymerization in the presence of cytochalasin B gave rise to a smaller increase of viscosity but to the same increase in light scattering, compared to polymerization in the absence of cytochalasin B. Cytochalasin B reduced the viscosity of F-actin and caused the appearance of ATP hydrolysis by F-actin. The cytochalasin B-induced ATPase activity was inhibited by concentrations of KCl higher than 50 mM. The cytochalasin B-induced ATPase activity was enhanced by ethyleneglycol bis(alpha-aminoethyl ether)-N,N'-tetraacetic acid and reduced by MgCl2 at concentrations higher than 0.75 mM. The findings suggest that the stability of actin filaments is reduced by cytochalasin B.
Actins↗