chemistry Chemistry is the scientific study of the properties and behavior of matter. It is a natural science that covers the elements that make up matter to the compounds made of atoms, molecules and ions: their composition, structure, proper ...

, an ionophore () is a

chemical species A chemical species is a chemical substance or ensemble composed of chemically identical molecular entities that can explore the same set of molecular energy levels on a characteristic or delineated time scale. These energy levels determine the wa ...

that reversibly binds ions. Many ionophores are

lipid-soluble Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipoph ...

entities that transport ions across the

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

. Ionophores

catalyze Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...

ion transport across

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

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 are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many vir ...

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,, ''mikros'', "small") and ''organism'' from the el, ὀργανισμός, ''organismós'', "organism"). It is usually written as a single word but is sometimes hyphenated (''micro-organism''), especially in olde ...

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: Greece 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 ...

''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 Nigericin is an antibiotic derived from ''Streptomyces hygroscopicus''. Its isolation was described in the 1950s, and in 1968 the structure could be elucidated by X-ray crystallography. The structure and properties of nigericin are similar to the ...

. Many ionophores are produced naturally by a variety of

microbes A microorganism, or microbe,, ''mikros'', "small") and ''organism'' from the el, ὀργανισμός, ''organismós'', "organism"). It is usually written as a single word but is sometimes hyphenated (''micro-organism''), especially in olde ...

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

and

plants Plants are predominantly photosynthetic eukaryotes of the kingdom Plantae. Historically, the plant kingdom encompassed all living things that were not animals, and included algae and fungi; however, all current definitions of Plantae exclude ...

, 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 Charge or charged may refer to: Arts, entertainment, and media Films * '' Charge, Zero Emissions/Maximum Speed'', a 2011 documentary Music * ''Charge'' (David Ford album) * ''Charge'' (Machel Montano album) * ''Charge!!'', an album by The Aqu ...

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 the chemical element with the symbol K (from Neo-Latin '' kalium'') and atomic number19. Potassium is a silvery-white metal that is soft enough to be cut with a knife with little force. Potassium metal reacts rapidly with atmos ...

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 conven ...

. 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 residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

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 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 c ...

and

nystatin Nystatin, sold under the brandname Mycostatin among others, is an antifungal medication. It is used to treat '' Candida'' infections of the skin including diaper rash, thrush, esophageal candidiasis, and vaginal yeast infections. It may also be ...

. Ionophores that transport

hydrogen Hydrogen is the chemical element with the symbol H and atomic number 1. Hydrogen is the lightest element. At standard conditions hydrogen is a gas of diatomic molecules having the formula . It is colorless, odorless, tasteless, non-to ...

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 ether In organic chemistry, 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., . Impo ...

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 their ...

s, and

calixarene A calixarene is a macrocycle or cyclic oligomer based on a methylene-linked phenols. With hydrophobic cavities that can hold smaller molecules or ions, calixarenes belong to the class of cavitands known in host–guest chemistry. Nomenclature Cal ...

Pyrazole Pyrazole is an organic compound with the formula C3H3N2H. It is a heterocycle characterized by a 5-membered ring of three carbon atoms and two adjacent nitrogen atoms, which are in ortho-substitution. Pyrazole is a weak base, with p''K''b 11.5 ( ...

pyridine Pyridine is a basic 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, weakly alkaline, water-miscible liquid w ...

and bis-pyrazole derivatives have also been synthesized. These synthetic species are often

macrocyclic Macrocycles are often described as molecules and ions containing a ring of twelve or more atoms. Classical examples include the crown ethers, calixarenes, porphyrins, and cyclodextrins. Macrocycles describe a large, mature area of chemistry. ...

. Some synthetic agents are not macrocyclic, e.g. carbonyl cyanide-''p''-trifluoromethoxyphenylhydrazone. Even simple organic compounds, such as

phenol Phenol (also called carbolic acid) is an aromatic organic compound with the molecular formula . It is a white crystalline solid that is volatile. The molecule consists of a phenyl group () bonded to a hydroxy group (). Mildly acidic, it r ...

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 known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important ...

- and

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

-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 conven ...

through

biological membranes A biological membrane, biomembrane or cell membrane is a selectively permeable membrane that separates the interior of a cell from the external environment or creates intracellular compartments by serving as a boundary between one part of the c ...

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. That is, there is a difference in the energy required for electric charges ...

, 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

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 determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angles ...

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 In coordination chemistry, the first coordination sphere refers to the array of molecules and ions (the ligands) directly attached to the central metal atom. The second coordination sphere consists of molecules and ions that attached in various ...

surrounding the metal center. This affects the selectivity and affinity 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

most commonly via

passive transport Passive transport is a type of membrane transport that does not require energy to move substances across cell membranes. Instead of using cellular energy, like active transport, passive transport relies on the second law of thermodynamics to dri ...

, which is affected by

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

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

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 pancrustacean hexapod invertebrates of the class Insecta. They are the largest group within the arthropod phylum. Insects have a chitinous exoskeleton, a three-part body ( head, thorax and abdomen), three pa ...

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 on or inside another organism, the host, causing it some harm, and is adapted structurally to this way of life. The entomologist E. O. Wilson ha ...

. Some ionophores have been introduced into medicinal products for dermatological and

veterinary Veterinary medicine is the branch of medicine that deals with the prevention, management, diagnosis, and treatment of disease, disorder, and injury in animals. Along with this, it deals with animal rearing, husbandry, breeding, research on nutri ...

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 Chloroquine is a medication primarily used to prevent and treat malaria in areas where malaria remains sensitive to its effects. Certain types of malaria, resistant strains, and complicated cases typically require different or additional medi ...

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 joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are inv ...

and

lupus erythematosus 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, blo ...

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

shampoo Shampoo () is a hair care product, typically in the form of a viscous liquid, that is used for cleaning hair. Less commonly, shampoo is available in solid bar format. Shampoo is used by applying it to wet hair, massaging the product into the ...

s for

seborrheic dermatitis Seborrhoeic dermatitis, sometimes inaccurately referred to as seborrhoea, is a long-term skin disorder. Symptoms include red, scaly, greasy, itchy, and inflamed skin. Areas of the skin rich in oil-producing glands are often affected including the ...

. It also serves as an

anti-fouling agent Fouling is the accumulation of unwanted material on solid surfaces. The fouling materials can consist of either living organisms (biofouling) or a non-living substance (inorganic or organic). Fouling is usually distinguished from other surf ...

in paints to cover and protect surfaces against

mildew Mildew is a form of fungus. It is distinguished from its closely related counterpart, mould, largely by its colour: moulds appear in shades of black, blue, red, and green, whereas mildew is white. It appears as a thin, superficial growth consi ...

and

algae Algae (; singular alga ) is an informal term for a large and diverse group of photosynthetic eukaryotic organisms. It is a polyphyletic grouping that includes species from multiple distinct clades. Included organisms range from unicellular micr ...

Clioquinol Clioquinol (iodochlorhydroxyquin) is an antifungal drug and antiprotozoal drug. It is neurotoxic in large doses. It is a member of a family of drugs called hydroxyquinolines which inhibit certain enzymes related to DNA replication. The drugs h ...

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 that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As ...

Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an uns ...

and

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms beco ...

. Gramicidin is used in throat lozenges and has been used to treat infected wounds.

Epigallocatechin gallate Epigallocatechin gallate (EGCG), also known as epigallocatechin-3-gallate, is the ester of epigallocatechin and gallic acid, and is a type of catechin. EGCG – the most abundant catechin in tea – is a polyphenol under basic research for i ...

is used in many

dietary supplements A dietary supplement is a manufactured product intended to supplement one'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 in order ...

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 Taste, flavor or enhance taste, appearance, or other sensory qualities. Some additives have been used for centuries as part of an effort to preserve food, for example vinegar (pickling), sal ...

and in

Hinokitiol Hinokitiol (β-thujaplicin) is a natural monoterpenoid found in the wood of trees in the family Cupressaceae. It is a tropolone derivative and one of the thujaplicins. Hinokitiol is used in oral and skin care products, and is a food additive us ...

(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 ...

extending agent in food packaging, and

wood preservative Wood easily degrades without sufficient preservation. Apart from structural wood preservation measures, there are a number of different chemical preservatives and processes (also known as "timber treatment", "lumber treatment" or "pressure treat ...

timber Lumber is wood that has been processed into dimensional lumber, including beams and planks or boards, a stage in the process of wood production. Lumber is mainly used for construction framing, as well as finishing (floors, wall panels, w ...

treatment.

Polyene antimycotic Polyene antimycotics, sometimes referred to as polyene antibiotics, are a class of antimicrobial polyene compounds that target fungi. These polyene antimycotics are typically obtained from some species of ''Streptomyces'' bacteria. Previously, ...

s, 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 cryptococcosis ...

, are a subgroup of macrolides 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 sterol 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 ergosterol, t ...

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 Monensin is a polyether antibiotic isolated from '' Streptomyces cinnamonensis''. It is widely used in ruminant animal feeds. The structure of monensin was first described by Agtarap et al. in 1967, and was the first polyether antibiotic to have ...

, lasalocid, salinomycin, narasin,

maduramicin Maduramicin (maduramycin) is an antiprotozoal agent used in veterinary medicine to prevent coccidiosis Coccidiosis is a parasitic disease of the intestinal tract of animals caused by coccidian protozoa. The disease spreads from one animal to a ...

, 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 i ...

poultry Poultry () are domesticated birds kept by humans for their eggs, their meat or their feathers. These birds are most typically members of the superorder Galloanserae (fowl), especially the order Galliformes (which includes chickens, qu ...

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

ruminants Ruminants (suborder Ruminantia) are hoofed herbivorous grazing or browsing mammals that are able to acquire nutrients from plant-based food by fermenting it in a specialized stomach prior to digestion, principally through microbial actions. The ...

, such as

cattle Cattle (''Bos taurus'') are large, domesticated, cloven-hooved, herbivores. They are a prominent modern member of the subfamily Bovinae and the most widespread species of the genus '' Bos''. Adult females are referred to as cows and adult ...

, 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 nonenveloped, linear, positive-sense single-stranded RNA viruses, as well as its genus ''Enterovirus'', which also includes poliovirus and echovir ...

, 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 co ...

, HCV, HSV, HCoV-229E, HIV,

mengovirus Mengovirus, also known as Columbia SK virus, mouse Elberfield virus, and Encephalomyocarditisvirus (EMCV), belongs to the genus ''Cardiovirus'' which is a member of the ''Picornaviridae''. Its genome is a single stranded positive-sense RNA molecu ...

MERS-CoV ''Middle East respiratory syndrome–related coronavirus'' (''MERS-CoV''), or EMC/2012 ( HCoV-EMC/2012), is the virus that causes Middle East respiratory syndrome (MERS). It is a species of coronavirus which infects humans, bats, and camels. Th ...

, rhinovirus,

SARS-CoV-1 Severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1; or Severe acute respiratory syndrome coronavirus, SARS-CoV) is a strain of coronavirus that causes severe acute respiratory syndrome (SARS), the respiratory illness responsible for t ...

Zika virus ''Zika virus'' (ZIKV; pronounced or ) is a member of the virus family (biology), family ''Flaviviridae''. It is mosquito-borne disease, spread by daytime-active ''Aedes'' mosquitoes, such as ''Aedes aegypti, A. aegypti'' and ''Aedes albopict ...

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