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PubMed1978

Complex formation between the uncoupler carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) and valinomycin in the presence of potassium.

Spectroscopic evidence is presented which indicates that the uncoupler carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) and the peptide antibiotic valinomycin form a complex in the presence of potassium. Complex formation has been observed both in aqueous and nonaqueous media. Several techniques have been used to indicate the existence of a complex in aqueous solution. In the presence of valinomycin and K+, the absorption spectrum of FCCP is significantly perturbed, and there is also a large induced circular dichroism signal. In addition, the previously characterized complex which forms between valinomycin, K+, and the fluorescent probe 8-anilino-1-naphthalene-sulfonate (ANS) in aqueous solution is apparently disrupted by the addition of FCCP. The result is an effective quenching of the fluorescence due to the bound probe as it is displaced from the valinomycin.K+ by the uncoupler. In a nonpolar solvent, the absorption spectrum of FCCP is also perturbed by valinomycin in the presence of K+, again indicating the formation of a complex. These data point to the importance of considering the role of valinomycin.K+.uncoupler complex in interpreting physiological or ion transport data in which these substances have been used together.

Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone↗
PubMed1977

[Effect of the ionophore antibiotic valinomycin on the lymphocyte blast-transformation reaction induced by phytohemagglutinin].

The effect of valinomycin on blast-transformation of human lymphocytes has been studied. The lymphocyte response was assayed by incorporation of radioactive precursor into DNA. DNA synthesis by PHA-stimulated lymphocytes was inhibited by valinomycin at concentration of 10(-8) M. The effect of high concentrations of valinomycin on the cells appeared to be irreversible. Excess of potassium in the medium was not effective in preventing the inhibitory action of valinomycin. An extensive washing of cells did not result in any release of the bound drug in the 10(-8) M concentration. The results are consistent with a hypothesis that lymphocyte stimulation is critically dependent on the level of intracellular K+.

DNA↗
PubMed1996

Conformational study of valinomycin: a molecular dynamics approach.

Valinomycin is a highly flexible cyclic dodecadepsipeptide that transports ions across membranes. Such a flexibility in the conformation is required for its biological function since it has to encounter a variety of environments and liganding state. Exploration of conformational space of this molecule is therefore important and is one of the objectives of the present study that has been carried out by means of high temperature Molecular Dynamics. Further, the stability of the known bracelet-like structure of the uncomplexed valinomycin and the inherent flexibility around this structure has been investigated. The uncomplexed form of valinomycin has been simulated at 75-100 K for 1 ns in order to elucidate the average conformational properties. An alanine-analog of valinomycin has been simulated under identical conditions in order to evaluate the effect of sidechain on the conformational properties, The studies confirm the effect of sidechain on conformational equilibrium.

Journal Article↗
PubMed1975

The action of valinomycin in uncoupling corn mitochondria.

Valinomycin in the presence of potassium is a potent uncoupler of corn (Zea mays L.) mitochondria, eliminating respiratory control. Valinomycin produces higher steady state potassium phosphate swelling which can be reversed to give active shrinkage if mersalyl is added to block the Pi(-)/OH(-) antiporter. Respiration declines concurrently. Uncouplers accelerate the shrinkage and restore the respiration. The same results can be obtained with sodium phosphate if gramicidin D is substituted as ionophore.It is concluded that valinomycin uncoupling is the result of cyclic salt transport, with influx pumping of potassium phosphate via the Pi(-)/OH(-) antiporter and efflux pumping via a K(+)/H(+) antiporter. The result is a higher level of steady state swelling, rapid turnover of the proton gradient, and uncoupled respiration rates. The level of steady state swelling can be manipulated by varying the valinomycin or K(+) concentrations, with high concentrations favoring activation of the efflux pump.A mosaic membrane model with high resistance for proton and monovalent cation penetration to the cation(+)/H(+) antiporter is used to explain the results.

Journal Article↗
PubMed1967

Gramicidin, valinomycin, and cation permeability of Streptococcus faecalis.

Gramicidin and valinomycin in concentrations of 10(-7) and 10(-6)m, respectively, inhibited the growth of Streptococcus faecalis. Inhibition of growth was associated with loss of Rb(+) and K(+) from the cells, and could be reversed by addition of excess K(+). Cells treated with these antibiotics exhibited greatly increased permeability to certain cations; no effect was observed on the penetration of other small molecules. Unlike normal cells, cells treated with gramicidin rapidly lost internal Rb(+) by passive exchange with external cations, including H(+), all monovalent alkali metals, NH(4) (+), Mg(++), and tris(hydroxymethyl)aminomethane. Exchange was rapid even at 0 C and was independent of energy metabolism. The effect of valinomycin was more selective. Cellular Rb(+) was rapidly displaced by external H(+), K(+), Rb(+), and Cs(+); other cations were less effective. The exchange was independent of metabolism but strongly affected by temperature. Under certain conditions, polyvalent cations inhibited exchange between (86)Rb and Rb(+) induced by valinomycin. The antibiotic apparently neither stimulates nor inhibits the energy-dependent K(+) pump of S. faecalis, but exerts its effect on the passive permeability of the membrane to cations. The increased permeability to specific cations induced by gramicidin and valinomycin is a sufficient explanation for the inhibition of growth, glycolysis, and other processes.

Anti-Bacterial Agents↗
PubMed1991

Molecular conformation of a D,L stereoisomeric analogue of valinomycin, cyclo[-(L-Val-L-Hyi-L-Val-D-Hyi)2-(D-Val-L-Hyi-L-Val-D-Hyi)-].

The crystal structure of a synthetic analogue of valinomycin, cyclo[-(L-Val-L-Hyi-L-Val-D-Hyi)2-(D-Val-L-Hyi-L-Val-D -Hyi)-] ([L-Val1, L-Val5]meso-valinomycin), C60H102N6O18, has been determined. Crystals grown from petroleum ether are orthorhombic, space group P2(1)2(1)2(1), with cell parameters a = 16.41(1), b = 18.76(1), c = 25.86(1) A, and Z = 4. The atomic coordinates for nonhydrogen atoms, except those of terminal carbons on one side chain, were refined in the anisotropic thermal motion approximation. The coordinate parameters of the H atoms were incorporated into the structure factor calculations at geometrically expected positions. Values of the standard and weighted R factors after refinement are 0.074 and 0.083, respectively. The crystal structure of the molecule is asymmetric and adopts a conformation with four 4----1 type and one 6----1 type intramolecular hydrogen bonds between amide nitrogens and carbonyl oxygens. Valinomycin binds potassium more than 100 times strongly than the D,L stereoisomeric analogue, as a result of a different spatial orientation of potentially interacting carbonyl groups.

Amino Acid Sequence↗
PubMed1991

Valinomycin and its interaction with ions in organic solvents, detergents, and lipids studied by Fourier transform IR spectroscopy.

The structure of valinomycin in a range of organic solvents of varying polarity and in detergent and lipid dispersions has been studied by Fourier transform ir spectroscopy. In solvents of low polarity such as chloroform, ir spectra of valinomycin are fully consistent with the bracelet structure proposed on the basis of nmr spectroscopy, showing a single narrow amide I component attributable to the presence of beta-turns and a single band arising from nonhydrogen-bonded ester C = O groups. K+ complexation results in a downward shift in the amide I band frequency, indicating an increase in the strength of the amide hydrogen bonds, along with a shift to lower frequencies of the ester C = O absorption due to a reduction in electron density in these bonds upon complexation. Identical results were obtained with NH4+, a finding not previously reported. In solvents of both medium (CHCl3/DMSO 3:1) and high (pure DMSO) polarity, we find evidence of significant disruption of the internal hydrogen-bonding network of the peptide and the appearance of a band suggesting the presence of free amide C = O groups. In such solvents, complexation with K+ and NH4+ was not observed. The structure of valinomycin in detergent micelles resembles that in nonpolar organic solvents. However, changes were found in the amide I and ester carbonyl maxima as 2H2O penetrated the micelle which suggest significant interaction between the solvent and peptide. Complexation with K+ was reduced in cationic detergent micelles as a result of a decrease in the effective K+ concentration due to charge repulsion at the micelle surface.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed2006

Deciphering the biosynthetic codes for the potent anti-SARS-CoV cyclodepsipeptide valinomycin in Streptomyces tsusimaensis ATCC 15141.

Valinomycin was recently reported to be the most potent agent against severe acute respiratory-syndrome coronavirus (SARS-CoV) in infected Vero E6 cells. Aimed at generating analogues by metabolic engineering, the valinomycin biosynthetic gene cluster has been cloned from Streptomyces tsusimaensis ATCC 15141. Targeted disruption of a nonribosomal peptide synthetase (NRPS) gene abolishes valinomycin production, which confirms its predicted nonribosomal-peptide origin. Sequence analysis of the NRPS system reveals four distinctive modules, two of which contain unusual domain organizations that are presumably involved in the generation of biosynthetic precursors D-alpha-hydroxyisovaleric acid and L-lactic acid. The respective adenylation domains in these two modules contain novel substrate-specificity-conferring codes that might specify for a class of hydroxyl acids for the biosynthesis of the depsipeptide natural products.

Animals↗
PubMed1975

Interaction between membrane properties and proteins synthesis in reticulocytes - a two step inhibition of protein synthesis by valinomycin.

In this work we consider the differential effect of Valinomycin used at different concentrations both on the protein synthesis of reticulocytes and on 42K exchange. We demonstrate that there is a two step action of this antibiotic. At 10(-6)M and below the drug has no effect on the 42K exchange, but it stops, however reversibly, protein synthesis. At 10(-5)M the drug has a very sharp action on the 42K exchange and stops protein synthesis in an irreversible way. Ribosomal population checked by two ways, sucrose gradient and direct counting on E.M. sections shows that at low concentrations of Valinomycin (10(-8)M to 10(-6)M) there is no breakdown of the polysomes which can be detected by either one of these methods. On the contrary, after short incubation with 10(-5)M of Valinomycin the breakdown of ribosomes is very clear, as evidenced by sucrose gradient analysis. By direct ribosomes clusters counting on E.M. sections this breakdown is seen only after long incubation.

Animals↗
PubMed1980

Characterization of [3H]-valinomycin binding to red blood cell membrane.

Valinomycin was tritiated by exchange and its biological activity found to be similar to that of non-labeled drug. [3H]-valinomycin binds to red blood cell membranes following a biphasic pattern. High concentrations of the drug lead to an irreversible binding while low concentrations lead to a completely reversible binding. Maximum binding was obtained at acidic pH (pH 4.2) and physiological temperature (37 degrees C). We demonstrate that valinomycin binds strongly to the lipidic phase of the membrane. When binding to erythrocytes and reticulocytes was compared, it was found that the mature red blood cells had less binding capacity than the reticulocytes.

Animals↗
PubMed1985

Opposing interactions of ionophores (valinomycin and monensin) on calcium ion uptake in rat retinal preparations.

Valinomycin is a potent inhibitor of taurine-stimulated ATP-dependent calcium ion uptake in rat retinal membrane preparations but had no effect on ATP-dependent calcium ion uptake in the absence of taurine and no effect on ATP-independent calcium ion uptake. The presence of potassium ions in the buffer systems were required for valinomycin to be inhibitory. On the contrary, monensin stimulated calcium ion uptake in the ATP-dependent system but had no effect on ATP-independent calcium ion uptake. The crude retinal homogenate was also fractionated into various subcellular components. The fraction which contained photoreceptor cell synaptosomes (P1) had a higher specific activity for taurine-stimulated ATP-dependent calcium ion uptake than the crude homogenate or either the fractions which contained synaptosomes derived from the plexiform layer (P2) or rod outer segments (ROS). No differences in calcium ion uptake were observed in the various subcellular fractions compared to the homogenate when assayed for ATP-dependent calcium ion uptake. Valinomycin inhibited both ATP-dependent and taurine-stimulated ATP-dependent calcium ion uptake in the P1, P2, and ROS fractions while monensin stimulated the ATP-dependent calcium ion uptake in the subcellular fractions.

Adenosine Triphosphatases↗
PubMed1978

Some effects of trinitrocresolate and valinomycin on Na and K transport across thin lipid bilayer membranes: a steady-state analysis with simultaneous tracer and electrical measurements.

This paper describes the effect of trinitrocresolate anions (TNC-) on the electrical conductance (Gm), and tracer-measured unidirectional Na and K fluxes (MNa and MK) across bilayers formed from sheep red cell lipids dissolved in decane. In the absence of TNC-, typical low conductances were observed, while the cation fluxes were too low to measure by our techniques (less than 10(-12) moles cm-2 sec-1). In the presence of TNC- (10(-2) M), Gm increased and TNC- was the main charge carrier in the system. The cationic fluxes were also much increased, but the membranes showed no significant selectivity between K and Na. Furthermore, the Na and K fluxes were at least two orders of magnitude larger than the ionic fluxes calculated from Gm. Thus, almost all of the K and Na transport across the membrane in the presence of TNC- is electrically silent and is probably carried out as KTNC and NaTNC ion pairs. In the presence of valinomycin (10(-6) M) and no TNC-, both the ion fluxes and Gm were 10(3) times larger in KCl than in NaCl, thus exhibiting the characteristic high selectivity of valinomycin for K over Na. In the presence of both valinomycin (10(-6) M) and TNC- (10(-2) M), this selectivity disappeared in that both Gm and MNa in the NaCl system were similar to the respective values in the KCl system. Even under these conditions, most of the Na is still transported by a process which does not carry charge. Both Gm and Mx increased alike and monotonically with increasing temperature over the range 7 to 30 degrees C. In the absence of TNC- the enthalpies of activation were invariably higher in KCl than in NaCl. Addition of TNC- produced equal enthalpies of activation for both Na and K containing systems suggesting a common, temperature-dependent, rate-determining step in charge transfer and the electrically silent cation fluxes.

Biological Transport↗
PubMed2005

Impedance analysis of phosphatidylcholine membranes modified with valinomycin.

The effect of the ion carrier valinomycin on the electrochemical features of the phosphatidylcholine membrane was investigated by electrochemical impedance spectroscopy. Phosphatidylcholine and valinomycin were chosen for the study because they fulfil essential functions in lively organisms. The experimental impedance values obtained in the presence of different amounts of carrier, studied with several potassium ion concentrations, were used for the research ability of valinomycin to form a 1:1 potassium ion complex on the lipid bilayer/electrolyte solution interface. Based on derived mathematical equations, the heterogeneous equilibrium constant (K (h)), association rate constant of the complex (k (R)) and dissociation rate constant of the complex (k (D)) were calculated. The result of the investigation is the proposal of a new method for the determination of the parameters used to describe the chemical reaction at the interface between a carrier molecule from the membrane and a monovalent ion from the aqueous phase.

Electric Capacitance↗
PubMed1992

Calorimetry of tetraether lipids from Thermoplasma acidophilum: incorporation of alamethicin, melittin, valinomycin, and nonactin.

The development and application of model membrane systems on the basis of tetraether lipids from Thermoplasma acidophilum has been proposed. In this respect incorporation of membrane proteins and ionophores is indispensable and is demonstrated in the case of alamethicin, melittin, nonactin, and valinomycin by calorimetry. Dipalmitoylphosphatidylcholine (DPPC) and dihexadecylmaltosylglycerol (DHMG) were chosen for comparison. Melittin and alamethicin prove to broaden the lipid phase transition and to reduce the melting temperature Tm and enthalpy change (delta H) of the main phospholipid from T. acidophilum (MPL) and DPPC. The decrease in Tm, however, is more pronounced in DPPC than in MPL. Valinomycin shows only a marginal effect on the temperature and width of the transition; delta H is reduced in MPL and remains constant in DPPC and DHMG. With nonactin the phase transition of DPPC is quenched, and delta H and the half-height width are increased. DHMG is affected to a lesser extent and MPL only marginally. The four ionophores exhibit different modulation of the phase transition behavior of the various lipids as expected from their varying molecular structures. Thus, the integral membrane protein alamethicin, the peripheral protein melittin, valinomycin, and nonactin interact primarily with lipid head groups and are readily incorporated into the tetraether lipid structures.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1978

Control of respiration in proteoliposomes containing cytochrome aa3. I. Stimulation by valinomycin and uncoupler.

1. Both valinomycin and p-trifluoromethoxy carbonyl cyanide phenylhydrazone (FCCP) are required for full release of respiration by cytochrome c oxidase-containing proteoliposomes (prepared by sonicating beef heart cytochrome aa3 in salt solution with 4 parts phosphatidylcholine, 4 parts phosphatidylethanolamine and 2 parts cardiolipin) in the presence of external ascorbate and cytochrome c. In the absence of valinomycin the response to FCCP is rather sluggish, as reported by Wrigglesworth et al. (1976) (Abstracts, 10th Int. Congr. Biochem., No. 06-6-230). 2. The Km for cytochrome c in 67 mM, pH 7.4, phosphate buffer with ascorbate as substrate, was 9 micrometer in both absence and presence of valinomycin and FCCP. Energization thus acts non-competitively towards cytochrome c oxidation. 3. The apparent Km for oxygen is greater in the energized than in the deenergized state; double reciprocal plots of respiration rate versus oxygen concentration are concave downward in the absence of uncouplers, as found with intact mitochondria. Energization thus acts "competitively" towards oxygen. 4. Despite the lack of a functional ATPase system, all the kinetic features of energization found in intact mitochondria can be mimicked in the reconstituted liposomes. This supports the chemiosmotic idea that electrical and perhaps H+ gradients modify the oxidase activity in reconstituted vesicles.

Ascorbic Acid↗
PubMed1982

Differential effects of 2,4-dinitrophenol and valinomycin (+ K+) on uncoupler-stimulated ATPase of human tumor mitochondria.

The uncoupler-stimulated mitochondrial ATPase of four human tumors, mouse kidney, brain and fetal liver exhibited a characteristic behavior when preincubated with the H+-conducting uncouplers, dinitrophenol, CCCP, S-13 and gramicidin. The ATPase activity was considerably lower with preincubation than without. Preincubation with valinomycin (+ K+), on the other hand, did not result in a significant decrease of the ATPase activity. These results may be contrasted with those obtained with liver or heart mitochondria, the ATPase activity of which did not suffer any loss when preincubated with dinitrophenol. The effect of preincubation with dinitrophenol on the tumor mitochondria could not be accounted for by dinitrophenol-induced Mg2+ efflux, since the differential effects of dinitrophenol and valinomycin (+ K+) remained even when ATPase activity was determined in presence of Mg2+. Small amounts of ATP and ADP in the preincubation mixture containing dinitrophenol protected against the decay of the ATPase activity, implicating the exchangeable adenine nucleotides in the tumor mitochondria. In a model system where liver mitochondria were depleted of their adenine nucleotides, a lower ATPase activity was indeed obtained. However, direct determination of the concentrations of adenine nucleotides in dinitrophenol- and valinomycin-treated tumor mitochondria revealed only slight differences.

2,4-Dinitrophenol↗
PubMed1975

Effect of valinomycin on ion transport in bacterial cells and on bacterial growth.

The antimicrobial action of valinomycin relative to the K+ and Na+ contents of the medium has been investigated in several species of bacteria, particularly in Streptococcus faecalis, which effects energy-linked transport exclusively via degradation of glycolytic ATP, Micrococcus lysodeikticus, effecting active ion transport by respiration and Staphylococcus aureus, the energy-dependent ion transport of which is due to both glycolytic ATP degradation and respiration. It was demonstrated that valinomycin does not act on K+ transport in the glycolysing cells in the same manner as it does on respiring cells under similar conditions. Addition of valinomycin to respiring cells leads to an increase in K+ influx against the concentrational gradient in both growing and resting cells. In contrast to this, antibiotic-treated glycolysing cells experience passive K+ outflow down the concentrational gradient. It was thus concluded that the electrical potential cannot be the driving force for the energy-linked K+ transport in glycolysing cells.

Adenosine Triphosphate↗
PubMed1976

Facilitated transport of di- and trinitrophenolate ions across lipid membranes by valinomycin and nonactin.

The conductance of black lipid membranes in the presence of 2,4,6-trinitrophenol (or 2,4-dinitrophenol) is considerably enhanced, if the cation carriers valinomycin, enniatin B or nonactin are added. The effect is, however, largely independent of the cation concentration and is identical for the cations Li+, Na+ and Ba2+. This finding, as well as the sign and magnitude of the diffusion potential in the presence of a gradient of picrate are consistent with the assumption that the transport of picrate anions is facilitated by the above-mentioned macrocyclic compounds, but that cations are not directly involved. A model is suggested which, based on the generation of mobile defect structures by the incorporation of large molecules, allows one to explain facilitated transport without the assumption of stable chemical bonds between a carrier and its transported substrate. If K+ is present in the aqueous phase, the conductance is largely determined by the permeation of the cation complexes of valinomycin and nonactin. The conductance is, however, increases by adsorption of picrate anions to the membrane surface. The negative surface potential generated by the adsorption layer seems to be responsible for the saturation of the conductance at high picrate concentrations in the absence of valinomycin and nonactin.

Anti-Bacterial Agents↗