An uncoupler or uncoupling agent is a molecule that disrupts

oxidative phosphorylation Oxidative phosphorylation(UK , US : or electron transport-linked phosphorylation or terminal oxidation, is the metabolic pathway in which Cell (biology), cells use enzymes to Redox, oxidize nutrients, thereby releasing chemical energy in order ...

prokaryotes A prokaryote (; less commonly spelled procaryote) is a single-celled organism whose cell lacks a nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Ancient Greek (), meaning 'before', and (), meaning 'nut' ...

and

mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...

photophosphorylation In the process of photosynthesis, the phosphorylation of ADP to form ATP using the energy of sunlight is called photophosphorylation. Cyclic photophosphorylation occurs in both aerobic and anaerobic conditions, driven by the main primary source of ...

chloroplasts A chloroplast () is a type of membrane-bound organelle, organelle known as a plastid that conducts photosynthesis mostly in plant cell, plant and algae, algal cells. Chloroplasts have a high concentration of chlorophyll pigments which captur ...

and

cyanobacteria Cyanobacteria ( ) are a group of autotrophic gram-negative bacteria that can obtain biological energy via oxygenic photosynthesis. The name "cyanobacteria" () refers to their bluish green (cyan) color, which forms the basis of cyanobacteri ...

by dissociating the reactions of ATP synthesis from the

electron transport chain An electron transport chain (ETC) is a series of protein complexes and other molecules which transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...

. The result is that the cell or mitochondrion expends energy to generate a

proton-motive force Chemiosmosis is the movement of ions across a semipermeable membrane bound structure, down their electrochemical gradient. An important example is the formation of adenosine triphosphate (ATP) by the movement of hydrogen ions (H+) across a membra ...

, but the proton-motive force is dissipated before the

ATP synthase ATP synthase is an enzyme that catalyzes the formation of the energy storage molecule adenosine triphosphate (ATP) using adenosine diphosphate (ADP) and inorganic phosphate (Pi). ATP synthase is a molecular machine. The overall reaction catalyzed ...

can recapture this energy and use it to make ATP. Because the intracellular supply of protons is replenished, uncouplers actually stimulate cellular metabolism and oxygen consumption (despite their inhibitory effects on oxidative phosphorylation) and increase the energy cost of generating ATP. Uncouplers are capable of transporting protons through mitochondrial and lipid membranes.

Description

Classical uncouplers have five properties: # the complete release of respiratory control # the substitution of all coupled processes (

ATP synthesis ATP synthase is an enzyme that catalyzes the formation of the energy storage molecule adenosine triphosphate (ATP) using adenosine diphosphate (ADP) and inorganic phosphate (Pi). ATP synthase is a molecular machine. The overall reaction catalyzed ...

, transhydrogenation, reverse electron flow,

active transport In cellular biology, active transport is the movement of molecules or ions across a cell membrane from a region of lower concentration to a region of higher concentration—against the concentration gradient. Active transport requires cellula ...

of cations, etc.) by a cyclic proton transport mediated by the uncoupler # the elimination of all protonic and cationic gradients generated across the mitochondrial or prokaryotic membrane # no discrimination in these actions between one coupling site and another # no discrimination between coupled processes driven by electron transfer and coupled processes driven by ATP hydrolysis Pseudo-uncouplers show one or more of these properties, but not all, and thus must be combined with one or more other pseudo-uncouplers to achieve full uncoupling.

Classical uncouplers

The following compounds are known to be classical uncouplers: * 2,4-dinitrophenol (DNP) * 2,5-di

nitrophenol Nitrophenols are compounds of the formula HOC6H5−x(NO2)x. The conjugate bases are called nitrophenolates. Nitrophenols are more acidic than phenol itself. Mono-nitrophenols with the formula HOC6H4NO2. Three isomeric nitrophenols exist: ...

* 1799 (α,α′-bis(hexafluoracetonyl)acetone) *

BAM15 BAM15 is a novel mitochondrial protonophore uncoupler capable of protecting mammals from acute renal ischemic-reperfusion injury and cold-induced kidney tubule damage. It is being studied for the treatment of obesity sepsis Sepsis is a poten ...

, ''N''⁵,''N''⁶-bis(2-fluorophenyl)-

,2,5 The comma is a punctuation mark that appears in several variants in different languages. Some typefaces render it as a small line, slightly curved or straight, but inclined from the vertical; others give it the appearance of a miniature fille ...

xadiazolo ,4-''b''yrazine-5,6-diamine * 2-''tert''-butyl-4,6-dinitrophenol (Dinoterb) * 6-''sec''-butyl-2,4-dinitrophenol (Dinoseb) * C₄R1 (a short-chain alkyl derivative of

rhodamine Rhodamine is a family of related dyes, a subset of the triarylmethane dyes. They are derivatives of xanthene. Important members of the rhodamine family are rhodamine 6G, Rhodamin WT, Texas Red (Sulforhodamin 101), rhodamine 123, and rhod ...

19) * Carbonyl cyanide

phenylhydrazone Hydrazones are a class of organic compounds with the structure . They are related to ketones and aldehydes by the replacement of the oxygen =O with the = functional group. They are formed usually by the action of hydrazine on ketones or aldehydes. ...

(CCP) * Carbonyl cyanide ''m''-chlorophenyl hydrazone (CCCP) * Carbonyl cyanide-''p''-trifluoromethoxyphenyl hydrazone (FCCP) * CDE () (produced by Verbesina) *

Chlorfenapyr Chlorfenapyr is an insecticide, and specifically a pro-insecticide (meaning it is metabolized into an active insecticide after entering the host). It is derived from a class of microbially produced compounds known as halogenated pyrroles. Histor ...

(after N-dealkylation by P450, an insecticide in

IRAC IRAC ( ) is an acronym that generally stands for: Issue, Rule, Application, and Conclusion. It functions as a methodology for legal analysis. The IRAC format is mostly used in hypothetical questions in law school and bar exams. Sections of an IR ...

group 13) * CZ5 *

Desaspidin Desaspidin is an anthelmintic. Desapidin may occur in natural form within some plants such as Coastal woodfern, ''Dryopteris arguta''. Since the 1950s the inhibition effects of desapidins upon phosphorylation in chloroplast A chloroplast ...

Dicoumarol Dicoumarol ( INN) or dicumarol ( USAN) is a naturally occurring anticoagulant drug that depletes stores of vitamin K (similar to warfarin, a drug that dicoumarol inspired). It is also used in biochemical experiments as an inhibitor of reductase ...

* Dinitro-''ortho''-cresol (DNOC) *

Ellipticine Ellipticine is a tetracyclic alkaloid first extracted from the tree species ''Ochrosia elliptica'' and ''Rauvolfia sandwicensis'' which inhibits the enzyme topoisomerase II via intercalation (biochemistry), intercalative binding to DNA. ...

* Endosidin 9 (ES9) * Flufenamic acid *

Niclosamide Niclosamide, sold under the brand name Niclocide among others, is an anthelmintic medication used to treat tapeworm infestations, including diphyllobothriasis, hymenolepiasis, and taeniasis. It is not effective against other worms such as ...

ethanolamine (NEN) * Ppc-1 (a

secondary metabolite Secondary metabolites, also called ''specialised metabolites'', ''secondary products'', or ''natural products'', are organic compounds produced by any lifeform, e.g. bacteria, archaea, fungi, animals, or plants, which are not directly involved ...

produced by '' Polysphondylium pseudocandidum'') *

Pentachlorophenol Pentachlorophenol (PCP) is an organochlorine compound used as a pesticide and a disinfectant. First produced in the 1930s, it is marketed under many trade names. It can be found as pure PCP, or as the sodium salt of PCP, the latter of which disso ...

(PCP) * Perfluorotriethylcarbinol * S-13 (5-chloro-3-''t''-butyl-2′-chloro-4′-nitro

salicylanilide Salicylanilide is a chemical compound which is the amide of salicylic acid and aniline. It is classified as both a salicylamide and an anilide. Derivatives of salicylanilide have a variety of pharmacological uses. Chlorinated derivatives inclu ...

) * TTFB (4,5,6,7-tetrachloro-2-trifluoromethyl

benzimidazole Benzimidazole is a heterocyclic aromatic organic compound. This bicyclic compound may be viewed as fused rings of the aromatic compounds benzene and imidazole. It is a white solid that appears in form of tabular crystals. Preparation Benzimi ...

) * Malonoben (tyrphostin A9, SF-6847, AG17) * (+)-

usnic acid Usnic acid is a naturally occurring dibenzofuran derivative found in several lichen species with the formula C18H16O7. It was first isolated by German scientist W. Knop in 1844 and first synthesized between 1933 and 1937 by Frank H. Curd and Al ...

XCT-790 XCT-790 is a potent and selective inverse agonist ligand of the estrogen-related receptor alpha (ERRα). Independent of its inhibition of ERRα, XCT-790 is a potent mitochondrial electron transport chain uncoupler. Mitochondrial electron transpo ...

* mitoFluo (10- -(3-hydroxy-6-oxo-xanthen-9-yl)benzoylxydecyl-triphenyl-phosphonium bromide) *

Triclosan Triclosan (sometimes abbreviated as TCS) is an antibacterial and antifungal agent present in some consumer products, including toothpaste, soaps, detergents, toys, and surgical cleaning treatments. It is similar in its uses and mechanism of act ...

(Trichloro-2'-hydroxydiphenyl ether) * Pyrrolomycin C (produced by Genus Streptomyces) *

Salicylic acid Salicylic acid is an organic compound with the formula HOC6H4COOH. A colorless (or white), bitter-tasting solid, it is a precursor to and a active metabolite, metabolite of acetylsalicylic acid (aspirin). It is a plant hormone, and has been lis ...

(if taken in extreme excess)

Pseudo-uncouplers

The following compounds are known to be pseudo-uncouplers: *

Azide In chemistry, azide (, ) is a linear, polyatomic anion with the formula and structure . It is the conjugate base of hydrazoic acid . Organic azides are organic compounds with the formula , containing the azide functional group. The dominant ...

Biguanide Biguanide () is the organic compound with the formula HN(C(NH)NH2)2. It is a colorless solid that dissolves in water to give a highly basic solution. These solutions slowly hydrolyse to ammonia and urea. Synthesis Biguanide can be obtained fro ...

s *

Bupivacaine Bupivacaine, marketed under the brand name Marcaine among others, is a medication used to decrease sensation in a specific small area. In nerve blocks, it is injected around a nerve that supplies the area, or into the spinal canal's epidural ...

* Calcimycin (

A23187 A23187 is a mobile ion-carrier that forms stable complexes with divalent cations (ions with a charge of +2). A23187 is also known as Calcimycin, Calcium Ionophore, Antibiotic A23187 and Calcium Ionophore A23187. It is produced at fermentation of ' ...

) * Dodecyltriphenyl

phosphonium In chemistry, the term phosphonium (more obscurely: phosphinium) describes polyatomic cations with the chemical formula (where R is a hydrogen or an alkyl, aryl, organyl or halogen group). These cations have tetrahedral structures. The ...

(C₁₂TPP) *

Lasalocid Lasalocid is an antibacterial agent and a coccidiostat, which is produced by strains of ''Streptomyces ''Streptomyces'', from στρεπτός (''streptós''), meaning "twisted", and μύκης (''múkés''), meaning "fungus", is the larges ...

(X537A) * Long-chain fatty acids, such as

linoleic acid Linoleic acid (LA) is an organic compound with the formula . Both alkene groups () are ''cis''. It is a fatty acid sometimes denoted 18:2 (n−6) or 18:2 ''cis''-9,12. A linoleate is a salt or ester of this acid. Linoleic acid is a polyunsat ...

* MitoQ10 *

Nigericin Nigericin is an antibiotic derived from '' Streptomyces hygroscopicus''. Its isolation from soil from Nigeria was described in the 1950s, by R.L Harned (et. al), and in 1968 the structure could be elucidated by X-ray crystallography. The structure ...

Picric acid Picric acid is an organic compound with the formula (O2N)3C6H2OH. Its IUPAC name is 2,4,6-trinitrophenol (TNP). The name "picric" comes from (''pikros''), meaning "bitter", due to its bitter taste. It is one of the most acidic phenols. Like ot ...

(2,4,6-trinitrophenol) *

Sodium tetraphenylborate Sodium tetraphenylborate is the organic compound with the formula NaB(C6H5)4. It is a salt, wherein the anion consists of four phenyl rings bonded to boron. This white crystalline solid is used to prepare other tetraphenylborate salts, which are o ...

* SR4 (1,3-bis(dichlorophenyl)urea 13) *

Tetraphenylphosphonium chloride Tetraphenylphosphonium chloride is the chemical compound with the formula , abbreviated or or , where Ph stands for phenyl. Tetraphenylphosphonium and especially tetraphenylarsonium salts were formerly of interest in gravimetric analysis of perc ...

Valinomycin 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. It is a member o ...

Arsenate The arsenate is an ion with the chemical formula . Bonding in arsenate consists of a central arsenic atom, with oxidation state +5, double bonded to one oxygen atom and single bonded to a further three oxygen atoms. The four oxygen atoms orien ...

Notes

References

External links