Valinomycin

LD50 = 2.5 mg/kg for mouse and 5 mg/kg for rabbit [1]

Valinomycin is a dodecadepsipeptide antibiotic, which is obtained from several Streptomyces strains. Valinomycin functions as a potassium-specific transporter and promotes the movement of K+ through lipid membranes. Excessive K+ efflux is an ionic mechanism underlying apoptosis.

In vitro: Valinomycin caused substantial CHO cells death within 12 h of treatment. Several apoptotic events were identified in valinomycin-treated CHO cells, including caspase-3 activation, phosphatidylserine (PS) membrane translocation, and mitochondrial membrane depolarization during the first few hours of treatment. K+ efflux was reduced by elevating extracellular K+ concentrations [2].

In vivo: Valinomycin is irritant in the case of eye and skin contact. Inhalation of valinomycin can cause breathing disturbances and even loss of conscious. Lethal doses (LD50) for mouse and rabbit is 2.5 mg/kg and 5 mg/kg respectively. Valinomycin also shows to provoke lots of chronic effects, including damage of the central and peripheral nervous system, eyes, lens and cornea [1].

Clinical trial: Because valinomycin’s toxicity to eukaryotic cells, it can not be used in human therapy [1].

References:
[1] Kroteń MA, Bartoszewicz M, Swiecicka I.  Cereulide and valinomycin, two important natural dodecadepsipeptides with ionophoretic activities. Pol J Microbiol. 2010;59(1):3-10.
[2] Abdalah R1, Wei L, Francis K, Yu SP.  Valinomycin-induced apoptosis in Chinese hamster ovary cells. Neurosci Lett. 2006 Sep 11;405(1-2):68-73. Epub 2006 Jul 20.

The structure of a valinomycin-hexaaquamagnesium trifluoromethanesulfonate compound.[Pubmed:27487337]

Acta Crystallogr C Struct Chem. 2016 Aug 1;72(Pt 8):627-33.

Valinomycin is a naturally occurring cyclic dodecadepsipeptide with the formula cyclo-[D-HiVA-->L-Val -->L-LA-->L-Val]3 (D-HiVA is D-alpha-hydroxyisovaleic acid, Val is valine and LA is lactic acid), which binds a K(+) ion with high selectively. In the past, several cation-binding modes have been revealed by X-ray crystallography. In the K(+), Rb(+) and Cs(+) complexes, the ester O atoms coordinate the cation with a trigonal antiprismatic geometry, while the six amide groups form intramolecular hydrogen bonds and the network that is formed has a bracelet-like conformation (Type 1 binding). Type 2 binding is seen with the Na(+) cation, in which the Valinomycin molecule retains the bracelet conformation but the cations are coordinated by only three ester carbonyl groups and are not centrally located. In addition, a picrate counter-ion and a water molecule is found at the center of the Valinomycin bracelet. Type 3 binding is observed with divalent Ba(2+), in which two cations are incorporated, bridged by two anions, and coordinated by amide carbonyl groups, and there are no intramolecular amide hydrogen bonds. In this paper, we present a new Type 4 cation-binding mode, observed in Valinomycin hexaaquamagnesium bis(trifluoromethanesulfonate) trihydrate, C54H90N6O18.[Mg(H2O)6](CF3SO3)2.3H2O, in which the Valinomycin molecule incorporates a whole hexaaquamagnesium ion, [Mg(H2O)6](2+), via hydrogen bonding between the amide carbonyl groups and the hydrate water H atoms. In this complex, Valinomycin retains the threefold symmetry observed in Type 1 binding, but the amide hydrogen-bond network is lost; the hexaaquamagnesium cation is hydrogen bonded by six amide carbonyl groups. (1)H NMR titration data is consistent with the 1:1 binding stoichiometry in acetonitrile solution. This new cation-binding mode of binding a whole hexaaquamagnesium ion by a cyclic polypeptide is likely to have important implications for the study of metal binding with biological models under physiological conditions.

Affinity Capillary Electrophoresis Applied to Investigation of Valinomycin Complexes with Ammonium and Alkali Metal Ions.[Pubmed:27473493]

Methods Mol Biol. 2016;1466:219-32.

This chapter deals with the application of affinity capillary electrophoresis (ACE) to investigation of noncovalent interactions (complexes) of Valinomycin, a macrocyclic dodecadepsipeptide antibiotic ionophore, with ammonium and alkali metal ions (lithium, sodium, potassium, rubidium, and cesium). The strength of these interactions was characterized by the apparent binding (stability, association) constants (K b) of the above Valinomycin complexes using the mobility shift assay mode of ACE. The study involved measurements of effective electrophoretic mobility of Valinomycin at variable concentrations of ammonium or alkali metal ions in the background electrolyte (BGE). The effective electrophoretic mobilities of Valinomycin measured at ambient temperature and variable ionic strength were first corrected to the reference temperature 25 degrees C and constant ionic strength (10 or 25 mM). Then, from the dependence of the corrected Valinomycin effective mobility on the ammonium or alkali metal ion concentration in the BGE, the apparent binding constants of the Valinomycin-ammonium or Valinomycin-alkali metal ion complexes were determined using a nonlinear regression analysis. Logarithmic form of the binding constants (log K b) were found to be in the range of 1.50-4.63, decreasing in the order Rb(+) > K(+) > Cs(+) > > Na(+) > NH4 (+) ~ Li(+).

Identification of Yeast Mutants Exhibiting Altered Sensitivity to Valinomycin and Nigericin Demonstrate Pleiotropic Effects of Ionophores on Cellular Processes.[Pubmed:27711131]

PLoS One. 2016 Oct 6;11(10):e0164175.

Ionophores such as Valinomycin and nigericin are potent tools for studying the impact of ion perturbance on cellular functions. To obtain a broader picture about molecular components involved in mediating the effects of these drugs on yeast cells under respiratory growth conditions, we performed a screening of the haploid deletion mutant library covering the Saccharomyces cerevisiae nonessential genes. We identified nearly 130 genes whose absence leads either to resistance or to hypersensitivity to Valinomycin and/or nigericin. The processes affected by their protein products range from mitochondrial functions through ribosome biogenesis and telomere maintenance to vacuolar biogenesis and stress response. Comparison of the results with independent screenings performed by our and other laboratories demonstrates that although mitochondria might represent the main target for both ionophores, cellular response to the drugs is very complex and involves an intricate network of proteins connecting mitochondria, vacuoles, and other membrane compartments.

Stimulation by pro-apoptotic valinomycin of cytosolic NADH/cytochrome c electron transport pathway-Effect of SH reagents.[Pubmed:27129925]

Int J Biochem Cell Biol. 2016 Jul;76:12-8.

Intrinsic and extrinsic apoptosis are both characterised by the presence of cytochrome c (cyto-c) in the cytosol. We present data on the extra-mitochondrial NADH oxidation catalysed by exogenous (cytosolic) cyto-c, as a possible answer to the paradox of apoptosis being an energy-dependent program but characterized by the impairment of the respiratory chain. The reduction of molecular oxygen induced by the cytosolic NADH/cyto-c pathway is coupled to the generation of an electrochemical proton gradient available for ATP synthesis. Original findings show that SH reagents inhibit the NADH/cyto-c system with a conformational change mechanism. The mitochondrial integrity-test of sulfite oxidase unequivocally demonstrates that this enzyme (120kDa) can be released outside but exogenous cyto-c (12.5kDa) does not permeate into mitochondria. Valinomycin at 2nM stimulates both the energy-dependent reversible mitochondrial swelling and the NADH/cyto-c oxidation pathway. The pro-apoptotic activity of Valinomycin, as well as to the dissipation of membrane potential, can be also ascribed to the increased activity of the NADH/cyto-c oxidation pathway useful as an additional source of energy for apoptosis. It can be speculated that the activation of the NADH/cyto-c system coupled to Valinomycin-induced mitochondrial osmotic swelling may represent a strategy to activate apoptosis in confined solid tumours.

Interaction of valinomycin and monovalent cations with the (Ca2+,Mg2+)-ATPase of skeletal muscle sarcoplasmic reticulum.[Pubmed:3158656]

J Biol Chem. 1985 Jun 25;260(12):7325-9.

The interactions of monovalent cations and of the K+-specific ionophore, Valinomycin, with the Ca2+-ATPase of skeletal muscle of sarcoplasmic reticulum have been studied in the absence of cation gradients by their effects on enzyme turnover and on the ATP plus Ca2+-dependent enhanced fluorescence of the ATP analogue, 2',3'-O-(2,4,6-trinitrocyclohexyldienylidine)-adenosine 5'-triphosphate (TNP-ATP) (Watanabe, T., and Inesi, G. (1982) J. Biol. Chem. 257, 11510-11516). Monovalent cations decreased turnover-dependent TNP-ATP fluorescence in the series K+ greater than Rb+ approximately equal to Cs+ greater than Na+ greater than Li+ (K0.5 = 49, 73, 75, 94, and 246 mM, respectively), consistent with the known specificity of the monovalent cation binding site that stimulates turnover and E-P hydrolysis. Valinomycin (200 nmol/mg), in the absence of monovalent cations, decreased ATPase activity by 30% and abolished the stimulatory effects of 150 mM KCl or NaCl on turnover. The ionophore alone enhanced TNP-ATP fluorescence by 20% and altered the specificity and affinity of the site that inhibited TNP-ATP fluorescence to Cs+ greater than Rb+ greater than K+ approximately equal to Na+ greater than Li+ (K0.5 = 79, 111, 134, 136, and 270 mM, respectively), which follows the Hofmeister series for effectiveness of monovalent lyotropic cations. TNP-ATP binding was not affected by either monovalent cations or Valinomycin. Inhibition of turnover-dependent TNP-ATP fluorescence appears to be a useful parameter for monitoring monovalent cation binding to the Ca2+-ATPase. It is concluded that the ionophore interacts directly with the Ca2+-ATPase, independent of its K+ conductance effects on the lipid bilayer, and modifies the affinity and specificity of the monovalent cation site, either by direct interaction or by the formation of a Valinomycin-monovalent cation-enzyme complex.

Valinomycin (NSC 122023) is a cyclic depsipeptide antibiotic first isolated from Streptomyces fulvissimus, act as a potassium selective ionophore. Valinomycin (NSC 122023) inhibits lymphocyte proliferation by its effects on the cell membrane, and induces apoptosis in CHO cells. Valinomycin induces activation of PINK1 leading to Parkin Ser65 phosphorylation.

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