In
chemistry, an ionophore (from
Greek ion and -phore 'ion carrier') is a
chemical species that reversibly binds
ions.[1] 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 (carrier-based ion selective electrodes) or
lipid bilayers found in the living cells or synthetic vesicles (
liposomes).[1] Structurally, an ionophore contains a hydrophilic center and a hydrophobic portion that interacts with the membrane.
Some ionophores are synthesized by
microorganisms 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.[2] These compounds have also shown to have various biological effects and a synergistic effect when combined with the ion they bind.[3]
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".[3] 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
Greekion 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.[4]
Many ionophores are produced naturally by a variety of
microbes,
fungi and
plants, and act as a defense against competing or pathogenic species. Multiple synthetic membrane-spanning ionophores have also been synthesized.[5]
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
hydrophobic interior of the lipid membrane.[6] However, these ionophores become unable to transport ions under very low temperatures.[7] An example of a carrier ionophore is
valinomycin, a molecule that transports a single
potassiumcation. Carrier ionophores may be proteins or other molecules.
Channel formers that introduce a
hydrophilic pore into the membrane, allowing ions to pass through without coming into contact with the membrane's
hydrophobic interior.[8] Channel forming ionophores are usually large
proteins. This type of ionophores can maintain their ability to transfer ions at low temperatures, unlike carrier ionophores.[7] Examples of channel-forming ionophores are
gramicidin A and
nystatin.
Ionophores that transport
hydrogen 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,
cryptands, and
calixarenes.
Pyrazole-
pyridine and bis-pyrazole derivatives have also been synthesized.[9] These synthetic species are often
macrocyclic.[10] Some synthetic agents are not macrocyclic, e.g.
carbonyl cyanide-p-trifluoromethoxyphenylhydrazone. Even simple organic compounds, such as
phenols, 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- and
thiourea-based receptors are known.[11]
Mechanism of action
Ionophores are chemical compounds that reversibly bind and transport
ions through
biological membranes in the absence of a protein pore. This can disrupt the
membrane potential, and thus these substances could exhibit cytotoxic properties.[1] 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).[1] 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.[12]
Chemistry
Several chemical factors affect the ionophore activity.[13] 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 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 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.[14] Many ionophores have shown antibacterial and antifungal activities.[15] Some of them also act against
insects,
pests and
parasites. Some ionophores have been introduced into medicinal products for
dermatological and
veterinary use.[16][17] A large amount of research has been directed toward investigating novel antiviral, anti-inflammatory, anti-tumor, antioxidant and neuroprotective properties of different ionophores.[15][18][3]
Polyene antimycotics, such as
nystatin,
natamycin and
amphotericin B, are a subgroup of
macrolides and are widely used antifungal and antileishmanial medications. These drugs act as ionophores by binding to
ergosterol in the fungal cell membrane and making it leaky and permeable for
K+ and
Na+ ions, as a result contributing to fungal cell death.[32]
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