Nonactin

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Nonactin
Nonactin.svg
Names
Other names
Ammonium ionophore
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.027.192 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
UNII
  • InChI=1S/C40H64O12/c1-21-17-29-9-13-34(49-29)26(6)38(42)46-23(3)19-31-11-15-36(51-31)28(8)40(44)48-24(4)20-32-12-16-35(52-32)27(7)39(43)47-22(2)18-30-10-14-33(50-30)25(5)37(41)45-21/h21-36H,9-20H2,1-8H3/t21-,22+,23+,24-,25-,26+,27+,28-,29-,30+,31+,32-,33-,34+,35+,36- X mark.svgN
    Key: RMIXHJPMNBXMBU-QIIXEHPYSA-N X mark.svgN
  • InChI=1/C40H64O12/c1-21-17-29-9-13-34(49-29)26(6)38(42)46-23(3)19-31-11-15-36(51-31)28(8)40(44)48-24(4)20-32-12-16-35(52-32)27(7)39(43)47-22(2)18-30-10-14-33(50-30)25(5)37(41)45-21/h21-36H,9-20H2,1-8H3/t21-,22+,23+,24-,25-,26+,27+,28-,29-,30+,31+,32-,33-,34+,35+,36-
    Key: RMIXHJPMNBXMBU-QIIXEHPYBK
  • C[C@@H]1C[C@H]2CC[C@H](O2)[C@@H](C(=O)O[C@H](C[C@@H]3CC[C@@H](O3)[C@H](C(=O)O[C@@H](C[C@H]4CC[C@H](O4)[C@@H](C(=O)O[C@H](C[C@@H]5CC[C@@H](O5)[C@H](C(=O)O1)C)C)C)C)C)C)C
Properties
C40H64O12
Molar mass 736.940 g·mol−1
Melting point 146 °C (295 °F; 419 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Nonactin is a member of a family of naturally occurring cyclic ionophores known as the macrotetrolide antibiotics. The other members of this homologous family are monactin, dinactin, trinactin and tetranactin which are all neutral ionophoric substances and higher homologs of nonactin. Collectively, this class is known as the nactins. Nonactin is soluble in methanol, dichloromethane, ethyl acetate and DMSO, but insoluble in water.

Contents

Sources

Nonactin is commercially available; as of 2006, these bacterial species produce nonactin: Streptomyces tsukubensis , Streptomyces griseus , Streptomyces chrysomallus and Streptomyces werraensis . Total syntheses have been reported. [1] [2]

Structure and properties

Nonactin was isolated by Corbaz et al. in 1955 from bacterial strains. [3] It is composed of four tetrahydrofuran rings and four esters linked by saturated aliphatic chain sections. Nonactin has a 48-member ring, built from 40 carbon and 12 (8 on the ring, 4 as ketones) oxygen atoms. Despite the 16 stereogenic centers, Nonactin is a meso compound, and therefore achiral. Liquid chromatography-mass spectrometry offers a modern approach to obtain more detailed process control data than the spectrophotometric and chromatographic measurements used in the past. [4]

Reactions

Nonactin is known for its ability to form complexes with alkali cations, most notably potassium and sodium. In general, nonactin (and other members of the nactin family) exhibits binding preferences for some ions over others. This ion selectivity is seen in other macrocyclic ligands, such as the cyclic ionophore valinomycin, which is also an antibiotic, and crown ethers. Although nonactin (and all nactins) exhibits an especially high cation selectivity for potassium ions over sodium ions or rubidium ions, it exhibits the highest selectivity for ammonium ions and thallium ions. Due to this property, nonactin is also called "ammonium ionophore". [5] [6]

During complexation, the nonactin backbone convolutes into a pattern resembling the seam of a tennis ball. In the potassium-nonactin complex, the potassium ion is entirely surrounded by four carbonyl oxygen atoms and the four oxygen atoms of the tetrahydrofuran ring. These eight oxygen atoms surrounding the ion are nearly equidistant from it and adopt a nearly cubic coordination sphere around the ion. In this complex, all polar carbonyl groups point inwards and nonpolar moieties point outwards, thus building up a hydrophobic exterior for the complex and making it soluble in lipid membranes. This is how nonactin is able to transport potassium ions across lipid membranes.

Biological effects

Nonactin has been reported to specifically inhibit the processing of cytoplasmic precursor proteins destined for the mitochondria. It is able to uncouple the oxidative phosphorylation of mitochondria of rat liver in a low concentration, and can also carry cations across biological and artificial membranes. [7] [8]

A nactins mixture, purposely enriched in tetranactin and poor in nonactin, known as polynactin(C), was used as a pesticide, but since 2004 is not used any more, presumably because its residuals appeared in food. [9]

Applications

Nactins have no known medical use. Ultrapure nonactin, practically free of other nactins, is used for ammonium-specific electrodes.

Related Research Articles

Ion channel Pore-forming membrane protein

Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ions across the cell membrane, controlling the flow of ions across secretory and epithelial cells, and regulating cell volume. Ion channels are present in the membranes of all cells. Ion channels are one of the two classes of ionophoric proteins, the other being ion transporters.

Transmembrane protein Protein spanning across a biological membrane

A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently undergo significant conformational changes to move a substance through the membrane. They are usually highly hydrophobic and aggregate and precipitate in water. They require detergents or nonpolar solvents for extraction, although some of them (beta-barrels) can be also extracted using denaturing agents.

An ion-selective electrode (ISE), also known as a specific ion electrode (SIE), is a transducer that converts the activity of a specific ion dissolved in a solution into an electrical potential. The voltage is theoretically dependent on the logarithm of the ionic activity, according to the Nernst equation. Ion-selective electrodes are used in analytical chemistry and biochemical/biophysical research, where measurements of ionic concentration in an aqueous solution are required.

Tetraethylammonium Ion

Tetraethylammonium (TEA), (NEt+
4
) or (Et4N+) is a quaternary ammonium cation consisting of four ethyl groups attached to a central nitrogen atom, and is positively charged. It is a counterion used in the research laboratory to prepare lipophilic salts of inorganic anions. It is used similarly to tetrabutylammonium, the difference being that its salts are less lipophilic and more easily crystallized.

Crown ether

Crown ethers are cyclic chemical compounds that consist of a ring containing several ether groups. The most common crown ethers are cyclic oligomers of ethylene oxide, the repeating unit being ethyleneoxy, i.e., –CH2CH2O–. Important members of this series are the tetramer (n = 4), the pentamer (n = 5), and the hexamer (n = 6). The term "crown" refers to the resemblance between the structure of a crown ether bound to a cation, and a crown sitting on a person's head. The first number in a crown ether's name refers to the number of atoms in the cycle, and the second number refers to the number of those atoms that are oxygen. Crown ethers are much broader than the oligomers of ethylene oxide; an important group are derived from catechol.

Gramicidin

Gramicidin, also called gramicidin D, is a mix of ionophoric antibiotics, gramicidin A, B and C, which make up about 80%, 5%, and 15% of the mix, respectively. Each has 2 isoforms, so the mix has 6 different types of gramicidin molecules. They can be extracted from Brevibacillus brevis soil bacteria. Gramicidins are linear peptides with 15 amino acids. This is in contrast to unrelated gramicidin S, which is a cyclic peptide.

Potassium selective electrodes are a type of ion selective electrode used in biochemical and biophysical research, where measurements of potassium concentration in an aqueous solution are required, usually on a real time basis.

Valinomycin Chemical compound

Valinomycin is a naturally occurring dodecadepsipeptide used in the transport of potassium and as an antibiotic. Valinomycin is obtained from the cells of several Streptomyces species, S. fulvissimus being a notable one.

Ionophore

An ionophore is a chemical species that reversibly binds ions. Many ionophores are lipid-soluble entities that transport ions across the cell membrane. Ionophores catalyze ion transport across hydrophobic membranes, such as liquid polymeric membranes or lipid bilayers found in the living cells or synthetic vesicles (liposomes). Structurally, an ionophore contains a hydrophilic center and a hydrophobic portion that interacts with the membrane.

Gramicidin S Chemical compound

Gramicidin S or Gramicidin Soviet is an antibiotic that is effective against some gram-positive and gram-negative bacteria as well as some fungi.

A23187

A23187 is a mobile ion-carrier that forms stable complexes with divalent cations. A23187 is also known as Calcimycin, Calcium Ionophore, Antibiotic A23187 and Calcium Ionophore A23187. It is produced at fermentation of Streptomyceschartreusensis.

Platensimycin Chemical compound

Platensimycin, a metabolite of Streptomyces platensis, is an antibiotic, which act by blocking enzymes.

Tyrocidine Chemical compound

Tyrocidine is a mixture of cyclic decapeptides produced by the bacteria Bacillus brevis found in soil. It can be composed of 4 different amino acid sequences, giving tyrocidine A–D. Tyrocidine is the major constituent of tyrothricin, which also contains gramicidin. Tyrocidine was the first commercially available antibiotic, but has been found to be toxic toward human blood and reproductive cells. The function of tyrocidine within its host B. brevis is thought to be regulation of sporulation.

Monensin Chemical compound

Monensin is a polyether antibiotic isolated from Streptomyces cinnamonensis. It is widely used in ruminant animal feeds.

Voltage-gated potassium channel Class of transport proteins

Voltage-gated potassium channels (VGKCs) are transmembrane channels specific for potassium and sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a crucial role in returning the depolarized cell to a resting state.

A protonophore, also known as a proton translocator, is an ionophore that moves protons across lipid bilayers or other type of membranes. This would otherwise not occur as protons cations (H+) have positive charge and hydrophilic properties, making them unable to cross without a channel or transporter in the form of a protonophore. Protonophores are generally aromatic compounds with a negative charge, that are both hydrophobic and capable of distributing the negative charge over a number of atoms by π-orbitals which delocalize a proton's charge when it attaches to the molecule. Both the neutral and the charged protonophore can diffuse across the lipid bilayer by passive diffusion and simultaneously facilitate proton transport. Protonophores uncouple oxidative phosphorylation via a decrease in the membrane potential of the inner membrane of mitochondria. They stimulate mitochondria respiration and heat production. Protonophores (uncouplers) are often used in biochemistry research to help explore the bioenergetics of chemiosmotic and other membrane transport processes. It has been reported that the protonophore has antibacterial activity by perturbing bacterial proton motive force.

Transmembrane channels, also called membrane channels, are pores within a lipid bilayer. The channels can be formed by protein complexes that run across the membrane or by peptides. They may cross the cell membrane, connecting the cytosol, or cytoplasm, to the extracellular matrix. Transmembrane channels are also found in the membranes of organelles including the nucleus, the endoplasmic reticulum, the Golgi apparatus, mitochondria, chloroplasts, and lysosomes.

Binding selectivity is defined with respect to the binding of ligands to a substrate forming a complex. Binding selectivity describes how a ligand may bind more preferentially to one receptor than another. A selectivity coefficient is the equilibrium constant for the reaction of displacement by one ligand of another ligand in a complex with the substrate. Binding selectivity is of major importance in biochemistry and in chemical separation processes.

Synthetic ion channels

Synthetic ion channels are de novo chemical compounds that insert into lipid bilayers, form pores, and allow ions to flow from one side to the other. They are man-made analogues of natural ion channels, and are thus also known as artificial ion channels. Compared to biological channels, they usually allow fluxes of similar magnitude but are

  1. minuscule in size,
  2. diverse in molecular architecture, and
  3. may rely on diverse supramolecular interactions to pre-form the active, conducting structures.

An uncoupler or uncoupling agent is a molecule that disrupts oxidative phosphorylation in prokaryotes and mitochondria or photophosphorylation in chloroplasts and cyanobacteria by dissociating the reactions of ATP synthesis from the electron transport chain. The result is that the cell or mitochondrion expends energy to generate a proton-motive force, but the proton-motive force is dissipated before the ATP synthase can recapture this energy and use it to make ATP. Uncouplers are capable of transporting protons through mitochondrial and lipid membranes.

References

  1. Ian Fleming & Sunil K. Ghosh (1994). "A total synthesis of nonactin". Journal of the Chemical Society, Chemical Communications (19): 2287. doi:10.1039/C39940002287.
  2. Ju Y.L.; Byeang H.K. (1996). "Total synthesis of nonactin". Tetrahedron. 52 (2): 571. doi:10.1016/0040-4020(95)00913-2.
  3. R. Corbaz; L. Ettlinger; E. Gäumann; W. Keller-Schierlein; F. Kradolfer; L. Neipp; V. Prelog; H. Zähner (1955). "Stoffwechselprodukte von Actinomyceten. 3. Mitteilung. Nonactin". Helvetica Chimica Acta . 38 (6): 1445–1448. doi:10.1002/hlca.19550380617.
  4. Jani P.; Emmert J.; Wohlgemuth R. (2008). "Process analysis of macrotetrolide biosynthesis during fermentation by means of direct infusion LC-MS". Biotechnol. J. 3 (2): 202–208. doi:10.1002/biot.200700174. PMID   18064609. S2CID   24106895.
  5. Nonactin product page from Fermentek
  6. Nonactin Bulletin
  7. [Krasne, S. S., G. G. Eisenman, and G. G. Szabo. "Freezing and Melting of Lipid Bilayers and the Mode of Action of Nonactin, Valinomycin, and Gramicidin." Freezing and Melting of Lipid Bilayers and the Mode of Action of Nonactin, Valinomycin, and Gramicidin. Sigma-Aldrich, n.d. Web.]
  8. [Total synthesis of nonactin. Ju Y.L.; Byeang H.K. ChemInform 52, 571, (1996)]
  9. Notification, the World Trade Organization's revocation of Polynactin agricultural usage, July 20, 2004.

Further reading