chemistry Chemistry is the scientific study of the properties and behavior of matter. It is a physical science within the natural sciences that studies the chemical elements that make up matter and chemical compound, compounds made of atoms, molecules a ...

, an ionophore () is a

chemical species Chemical species are a specific form of chemical substance or chemically identical molecular entities that have the same molecular energy level at a specified timescale. These entities are classified through bonding types and relative abundance of ...

that reversibly binds ions. Many ionophores are lipid-soluble entities that transport ions across the

cell membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...

. Ionophores catalyze ion transport across

hydrophobic In chemistry, hydrophobicity is the chemical property of a molecule (called a hydrophobe) that is seemingly repelled from a mass of water. In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, thu ...

membranes, such as liquid polymeric membranes (carrier-based ion selective electrodes) or

lipid bilayer The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes form a continuous barrier around all cell (biology), cells. The cell membranes of almost all organisms and many viruses a ...

s 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. Some ionophores are synthesized by

microorganisms A microorganism, or microbe, is an organism of microscopic size, which may exist in its single-celled form or as a colony of cells. The possible existence of unseen microbial life was suspected from antiquity, with an early attestation in ...

to import ions into their cells. Synthetic ion carriers have also been prepared. Ionophores selective for cations and anions have found many applications in analysis. These compounds have also shown to have various biological effects and a synergistic effect when combined with the ion they bind.

Classification

Biological activities of metal ion-binding compounds can be changed in response to the increment of the metal concentration, and based on the latter compounds can be classified as "metal ionophores", " metal chelators" or "metal shuttles". If the biological effect is augmented by increasing the metal concentration, it is classified as a "metal ionophore". If the biological effect is decreased or reversed by increasing the metal concentration, it is classified as a "metal chelator". If the biological effect is not affected by increasing the metal concentration, and the compound-metal complex enters the cell, it is classified as a "metal shuttle". The term ionophore (from

Greek Greek may refer to: Anything of, from, or related to Greece, a country in Southern Europe: *Greeks, an ethnic group *Greek language, a branch of the Indo-European language family **Proto-Greek language, the assumed last common ancestor of all kno ...

''ion carrier'' or ''ion bearer'') was proposed by Berton Pressman in 1967 when he and his colleagues were investigating the antibiotic mechanisms of valinomycin and nigericin. Many ionophores are produced naturally by a variety of

microbes A microorganism, or microbe, is an organism of microscopic size, which may exist in its single-celled form or as a colony of cells. The possible existence of unseen microbial life was suspected from antiquity, with an early attestation in ...

fungi A fungus (: fungi , , , or ; or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and mold (fungus), molds, as well as the more familiar mushrooms. These organisms are classified as one ...

and

plants Plants are the eukaryotes that form the kingdom Plantae; they are predominantly photosynthetic. This means that they obtain their energy from sunlight, using chloroplasts derived from endosymbiosis with cyanobacteria to produce sugars f ...

, and act as a defense against competing or pathogenic species. Multiple synthetic membrane-spanning ionophores have also been synthesized. The two broad classifications of ionophores synthesized by microorganisms are: *Carrier ionophores that bind to a particular ion and shield its charge from the surrounding environment. This makes it easier for the ion to pass through the

interior of the lipid membrane. However, these ionophores become unable to transport ions under very low temperatures. An example of a carrier ionophore is valinomycin, a molecule that transports a single

potassium Potassium is a chemical element; it has Symbol (chemistry), symbol K (from Neo-Latin ) and atomic number19. It is a silvery white metal that is soft enough to easily cut with a knife. Potassium metal reacts rapidly with atmospheric oxygen to ...

cation An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...

. Carrier ionophores may be proteins or other molecules. *Channel formers that introduce a

hydrophilic A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press. In contrast, hydrophobes are n ...

pore into the membrane, allowing ions to pass through without coming into contact with the membrane's

interior. Channel forming ionophores are usually large

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

s. This type of ionophores can maintain their ability to transfer ions at low temperatures, unlike carrier ionophores. Examples of channel-forming ionophores are gramicidin A and

nystatin Nystatin, sold under the brand name Mycostatin among others, is an antifungal medication. It is used to treat ''Candida (fungus), Candida'' infections of the skin including diaper rash, Candidiasis, thrush, esophageal candidiasis, and vaginal ...

. Ionophores that transport

hydrogen Hydrogen is a chemical element; it has chemical symbol, symbol H and atomic number 1. It is the lightest and abundance of the chemical elements, most abundant chemical element in the universe, constituting about 75% of all baryon, normal matter ...

ions (H⁺, i.e. protons) across the cell membrane are called protonophores. Iron ionophores and chelating agents are collectively called siderophores.

Synthetic ionophores

Many synthetic ionophores are based on crown ethers,

cryptand In chemistry, cryptands are a family of synthetic, bicyclic and polycyclic, multidentate ligands for a variety of cations. The Nobel Prize for Chemistry in 1987 was given to Donald J. Cram, Jean-Marie Lehn, and Charles J. Pedersen for ...

s, and calixarenes.

Pyrazole Pyrazole is an organic compound with the chemical formula, formula . It is a heterocycle characterized as an azole with a 5-membered ring of three carbon atoms and two adjacent nitrogen atoms, which are in Arene substitution pattern, ortho-substi ...

pyridine Pyridine is a basic (chemistry), basic heterocyclic compound, heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom . It is a highly flammable, weak ...

and bis-pyrazole derivatives have also been synthesized. These synthetic species are often macrocyclic. Some synthetic agents are not macrocyclic, e.g. carbonyl cyanide-''p''-trifluoromethoxyphenylhydrazone. Even simple organic compounds, such as

phenol Phenol (also known as carbolic acid, phenolic acid, or benzenol) is an aromatic organic compound with the molecular formula . It is a white crystalline solid that is volatile and can catch fire. The molecule consists of a phenyl group () ...

s, exhibit ionophoric properties. The majority of synthetic receptors used in the carrier-based anion-selective electrodes employ transition elements or metalloids as anion carriers, although simple organic

urea Urea, also called carbamide (because it is a diamide of carbonic acid), is an organic compound with chemical formula . This amide has two Amine, amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest am ...

- and

thiourea Thiourea () is an organosulfur compound with the formula and the structure . It is structurally similar to urea (), with the oxygen atom replaced by sulfur atom (as implied by the '' thio-'' prefix). The properties of urea and thiourea differ s ...

-based receptors are known.

Mechanism of action

Ionophores are chemical compounds that reversibly bind and transport

ions An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...

through biological membranes in the absence of a protein pore. This can disrupt the

membrane potential Membrane potential (also transmembrane potential or membrane voltage) is the difference in electric potential between the interior and the exterior of a biological cell. It equals the interior potential minus the exterior potential. This is th ...

, and thus these substances could exhibit cytotoxic properties. Ionophores modify the permeability of biological membranes toward certain ions to which they show affinity and selectivity. Many ionophores are lipid-soluble and transport ions across hydrophobic membranes, such as lipid bilayers found in the living cells or synthetic vesicles ( liposomes), or liquid polymeric membranes (carrier-based ion selective electrodes). Structurally, an ionophore contains a hydrophilic center and a hydrophobic portion that interacts with the membrane. Ions are bound to the hydrophilic center and form an ionophore-ion complex. The structure of the ionophore-ion complex has been verified by

X-ray crystallography X-ray crystallography is the experimental science of determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to Diffraction, diffract in specific directions. By measuring th ...

Chemistry

Several chemical factors affect the ionophore activity. The activity of an ionophore-metal complex depends on its geometric configuration and the coordinating sites and atoms which create coordination environment surrounding the metal center. This affects the selectivity and

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

towards a certain ion. Ionophores can be selective to a particular ion but may not be exclusive to it. Ionophores facilitate the transport of ions across biological membranes most commonly via passive transport, which is affected by

lipophilicity Lipophilicity (from Greek λίπος "fat" and φίλος "friendly") is the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such compounds are called lipophilic (translated ...

of the ionophore molecule. The increase in lipophilicity of the ionophore-metal complex enhances its permeability through lipophilic membranes. The hydrophobicity and hydrophilicity of the complex also determines whether it will slow down or ease the transport of metal ions into cell compartments. The reduction potential of a metal complex influences its thermodynamic stability and affects its reactivity. The ability of an ionophore to transfer ions is also affected by the temperature.

Biological properties

Ionophores are widely used in cell physiology experiments and biotechnology as these compounds can effectively perturb gradients of ions across biological membranes and thus they can modulate or enhance the role of key ions in the cell. Many ionophores have shown antibacterial and antifungal activities. Some of them also act against

insect Insects (from Latin ') are Hexapoda, hexapod invertebrates of the class (biology), class Insecta. They are the largest group within the arthropod phylum. Insects have a chitinous exoskeleton, a three-part body (Insect morphology#Head, head, ...

pests PESTS was an anonymous American activist group formed in 1986 to critique racism, tokenism, and exclusion in the art world. PESTS produced newsletters, posters, and other print material highlighting examples of discrimination in gallery represent ...

and

parasites Parasitism is a close relationship between species, where one organism, the parasite, lives (at least some of the time) on or inside another organism, the host, causing it some harm, and is adapted structurally to this way of life. The en ...

. Some ionophores have been introduced into medicinal products for dermatological and veterinary use. A large amount of research has been directed toward investigating novel antiviral, anti-inflammatory, anti-tumor, antioxidant and neuroprotective properties of different ionophores. Chloroquine is an antimalarial and antiamebic drug. It is also used in the management of

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...

and

lupus erythematosus is a collection of autoimmune diseases in which the human immune system becomes hyperactive and attacks healthy tissues. Symptoms of these diseases can affect many different body systems, including joints, skin, kidneys, blood cells, heart, ...

. Pyrithione is used as an anti-dandruff agent in medicated shampoos for

seborrheic dermatitis Seborrhoeic dermatitis (also spelled seborrheic dermatitis in American English) is a long-term skin disorder. Symptoms include flaky, scaly, greasy, and occasionally itchy and inflamed skin. Areas of the skin rich in sebum, oil-producing gland ...

. It also serves as an anti-fouling agent in paints to cover and protect surfaces against mildew and

algae Algae ( , ; : alga ) is an informal term for any organisms of a large and diverse group of photosynthesis, photosynthetic organisms that are not plants, and includes species from multiple distinct clades. Such organisms range from unicellular ...

. Clioquinol and PBT2 are 8-hydroxyquinoline derivatives. Clioquinol has antiprotozoal and topical antifungal properties, however its use as an antiprotozoal agent has widely restricted because of neurotoxic concerns. Clioquinol and PBT2 are currently being studied for neurodegenerative diseases, such as

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is an incurable neurodegenerative disease that is mostly Genetic disorder#Autosomal dominant, inherited. It typically presents as a triad of progressive psychiatric, cognitive, and ...

and

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

. Gramicidin is used in

throat lozenges A throat lozenge (also known as a cough drop, sore throat sweet, troche, cachou, pastille or cough sweet) is a small, typically medicated tablet intended to be dissolved slowly in the mouth to temporarily stop coughs, lubricate, and soothe irri ...

and has been used to treat infected wounds. Epigallocatechin gallate is used in many

dietary supplements A dietary supplement is a manufactured product intended to supplement a person's diet by taking a pill, capsule, tablet, powder, or liquid. A supplement can provide nutrients either extracted from food sources, or that are synthetic ...

and has shown slight cholesterol-lowering effects.

Quercetin Quercetin is a plant flavonol from the flavonoid group of polyphenols. It is found in many fruits, vegetables, leaves, seeds, and grains; capers, red onions, and kale are common foods containing appreciable amounts of it. It has a bitter flavor ...

has a bitter flavor and is used as a

food additive Food additives are substances added to food to preserve flavor or enhance taste, appearance, or other sensory qualities. Some additives, such as vinegar ( pickling), salt ( salting), smoke ( smoking) and sugar ( crystallization), have been used f ...

and in

. Hinokitiol (ß- thujaplicin) is used in commercial products for skin, hair and oral care, insect repellents and deodorants. It is also used as a food additive,

shelf-life Shelf life is the length of time that a commodity may be stored without becoming unfit for use, consumption, or sale. In other words, it might refer to whether a commodity should no longer be on a pantry shelf (unfit for use), or no longer on a s ...

extending agent in food packaging, and

wood preservative Wood preservation refers to any method or process, or even technique, used to protect the wood and extend its service life. Most wood species are susceptible to both biological (''biotic'') and non-biological (''abiotic'') factors that cause d ...

timber Lumber is wood that has been processed into uniform and useful sizes (dimensional lumber), including beams and planks or boards. Lumber is mainly used for construction framing, as well as finishing (floors, wall panels, window frames). ...

treatment. Polyene antimycotics, such as

, natamycin and

amphotericin B Amphotericin B is an antifungal medication used for serious fungal infections and leishmaniasis. The fungal infections it is used to treat include mucormycosis, aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, and cryptococ ...

, are a subgroup of

macrolides Macrolides are a class of mostly natural products with a large macrocycle, macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. Macrolides belong to the polyketide class of natural prod ...

and are widely used antifungal and antileishmanial medications. These drugs act as ionophores by binding to

ergosterol Ergosterol (ergosta-5,7,22-trien-3β-ol) is a mycosterol found in cell membranes of fungi and protozoa, serving many of the same functions that cholesterol serves in animal cells. Because many fungi and protozoa cannot survive without ergostero ...

in the fungal cell membrane and making it leaky and permeable for K⁺ and Na⁺ ions, as a result contributing to fungal cell death. Carboxylic ionophores, i.e. monensin, lasalocid, salinomycin, narasin, maduramicin, semduramycin and laidlomycin, are marketed globally and widely used as anticoccidial feed additives to prevent and treat

coccidiosis Coccidiosis is a parasitic disease of the intestinal tract of animals caused by coccidian protozoa. The disease spreads from one animal to another by contact with infected feces or ingestion of infected tissue. Diarrhea, which may become bloody ...

poultry Poultry () are domesticated birds kept by humans for the purpose of harvesting animal products such as meat, Eggs as food, eggs or feathers. The practice of animal husbandry, raising poultry is known as poultry farming. These birds are most typ ...

. Some of these compounds have also been used as growth and production promoters in certain

ruminants Ruminants are herbivorous grazing or browsing artiodactyls belonging to the suborder Ruminantia that are able to acquire nutrients from plant-based food by Enteric fermentation, fermenting it in a specialized stomach prior to digestion, principa ...

, such as

cattle Cattle (''Bos taurus'') are large, domesticated, bovid ungulates widely kept as livestock. They are prominent modern members of the subfamily Bovinae and the most widespread species of the genus '' Bos''. Mature female cattle are calle ...

, and chickens, however this use has been mainly restricted because of safety issues. Zinc ionophores have been shown to inhibit replication of various viruses ''in vitro'', including

coxsackievirus Coxsackieviruses are a few related enteroviruses that belong to the ''Picornaviridae'' family of viral envelope, nonenveloped, linear, positive-sense single-stranded RNA viruses, as well as its genus ''Enterovirus'', which also includes poliovi ...

, equine arteritis virus,

coronavirus Coronaviruses are a group of related RNA viruses that cause diseases in mammals and birds. In humans and birds, they cause respiratory tract infections that can range from mild to lethal. Mild illnesses in humans include some cases of the comm ...

, HCV, HSV, HCoV-229E, HIV, mengovirus, MERS-CoV,

rhinovirus The rhinovirus (from the "nose", , romanized: "of the nose", and the ) is a Positive-sense single stranded RNA virus, positive-sense, single-stranded RNA virus belonging to the genus ''Enterovirus'' in the family ''Picornaviridae''. Rhinoviru ...

, SARS-CoV-1,

Zika virus Zika virus (ZIKV; pronounced or ) is a member of the virus family ''Flaviviridae''. It is spread by daytime-active ''Aedes'' mosquitoes, such as '' A. aegypti'' and '' A. albopictus''. Its name comes from the Ziika Forest of Uganda, where ...

References

External links

Fluka ionophores for ion-selective electrodes''Structures and Properties of Naturally Occurring Polyether Antibiotics'', J. Rutkowski, B. Brzezinski; open access review article ''Polyether ionophores—promising bioactive molecules for cancer therapy'', A. Huczyński; open access review article
{Dead link, date=January 2020 , bot=InternetArchiveBot , fix-attempted=yes Ionophores Membrane biology Charge carriers Ions