Uncouplers lipophilicity

Uncouplers of oxidative phosphorylation Compounds that uncouple oxidative phosphorylatiou from electron transport in the inner mitochondrial membrane. Most are weak lipophilic acids that can run down the proton gradient across this membrane. 

In the following a survey is given of the substances which have been found to alter intercellular coupling. First drugs will be considered which uncouple gap junctions. A number of lipophilic compounds have been described to reduce gap junctional coupling. These substances include alcohols like hep-tanol and octanol, saturated and unsaturated fatty acids, and alcohols and... 

Ovadia M, Burt JM Developmental modulation of susceptibility to arhythmogenesis in myocardial ischemia Reduced sensitivity of adult versus neonatal rat heart cells to uncoupling by lipophilic substances (abstract). Circulation 1991 84(suppl II) 324. 

The fact that uncouplers are lipophilic weak acids (see above) explains their ability to collapse transmembrane pH gradients. Their lipophilic character allows uncouplers to diffuse relatively freely through the phospholipid bilayer. Because they are weak acids, uncouplers can release a proton to the solution on one side of the membrane and then diffuse across the membrane to fetch another proton. The chemiosmotic theory thus provides a simple explanation of the effects of uncouplers on oxidative phosphorylation. 

The above results indicate that in order to maintain the high rate of transmembrane electron transfer, it is necessary to provide efficient neutralization of the arising polarization. For this purpose lipophilic ions and proton carriers were successfully used (see Table 1). These compounds are known to act as the uncouplers of the mitochondrial oxidative phosphorylation and are able to remove the gradients of electric fields across lipid membranes. 

One example is provided by the optical isomers of l-(a-methyl-benzy])-3-(3,4-dichlorophenyl)urea (17). This chemical is an inhibitory uncoupler. The S-isomer inhibits electron transport, but the R-isomer is noninhibitory. The inactive isomer does not compete with the active isomer at the photosystem II site. The phosphorylation site shows no optical specificity. The two isomers do not differ significantly in their lipophilicity. 

Ionophores (ion carriers) are lipophilic substances, capable of binding and carrying specific cations through the biological membranes. They differ from the uncouplers in that they promote the transport of cations other than H+ through the membrane. 

Phosphorylation of ADP to ATP by mitochondria is driven by an electrochemical proton gradient established across the inner mitochondrial membrane as a consequence of vectoral transport of protons from NADH and succinate during oxidation by the respiratory chain (see Chapter 17). Hence, lipophilic weak acids or bases (such as 2,4-dinitrophenol) that can shuttle protons across membranes will dissipate the proton gradient and uncouple oxidation from ADP phosphorylation. Intrami-tochondrial ADP can be rate-limiting as demonstrated by inhibition of the mitochondrial adenosine nucleotide carrier by atractyloside. Inhibition of ATP synthesis... 

The uncouplers which abolish the coupling of respiratory rate to ATP synthesis act as proton translocators, inducing net proton translocation across the membranes. In this way the proton circuit can be short-circuited , allowing the protons translocated by the generator of to cross back across the membrane without passing through the ATP synthase and producing ATP. The majority of the uncouplers are protonatable, lipophilic compounds with an extensive pi-orbital system which allows the electron of the anionic, de-protonated form to be delocalized [11]. This enhances the permeability of the anionic form in the hydrophobic membrane, and allows the proton translocators to permeate in both their neutral (protonated) and anionic (deprotonated) forms. In this way they can catalyze the net transport of protons... 

What remains is the possibility (4) that free fatty acids, also in brown fat mitochondria (under experimental conditions) function as classical uncouplers (i.e., as weak lipophilic acids). The reason for the higher sensitivity to free fatty acids of brown fat than of liver mitochondria — as well as the higher sensitivity of cold-acclimated than of control brown fat mitochondria — may then simply reside in the fact that the more sensitive mitochondria have more mitochondrial inner membrane [83] with which the free fatty acids can interact. This hypothesis has as yet not been experimentally tested. 

Uncoupling of oxidative phosphorylation by 2,4-dinitrophenol (2,4-DNP). The anionic form of 2,4-DNP is protonated in the intermembrane space, is lipid soluble, and crosses the inner membrane readily. In the matrix, the protonated form dissociates, abolishing the proton gradient established by substrate oxidation. The ionized form of 2,4-DNP is poorly soluble in the membrane lipids and therefore is not easily transported across the membrane (dashed arrow). It is lipophilic and capable of transporting protons from one side of the membrane to the other (a protonophore), thus abolishing the proton gradient. 

DNP is a lipophilic molecule that binds reversibly with protons. It dissipates that proton gradient in mitochondria by transferring protons across the inner membrane. The uncoupling of electron transport from oxidative phosphorylation causes the energy from food to be dissipated as heat. DNP causes liver failure because of insufficient ATP synthesis in a metabolically demanding organ. 

Highly lipophilic weak acids and bases that have the capacity to remain lipophilic in both their protonated and deprotonated forms can act as protonophores. Such compounds belong to another class of ionophores that are often referred to as mitochondrial uncouplers because of their unique ability to translocate protons across mitochondrial membranes, resulting in the subsequent loss of the mitochondrial proton gradient that is required to drive oxidative phosphorylation. While certain natural products act as mitochondrial uncouplers, most of the protonophores used as pharmacological probes are not natural products but are low-molecular-weight synthetic compounds (e.g., carbonyl cyanide -trifluoromethoxyphenylhydrazone (FCCP)). 

Other hand, H+-uptake, basal and uncoupled electron transport were not affected. The acetylation of 26a yielded piquerol diacetate (26b) increasing its lipophilicity and photophosphorylation capacity [53]. 

A limiting factor in the efficiency of the uncoupling cyde is the ability of the charged anionic form of the uncoupler to cross the lipophilic interior of the membrane bUayer. In some cases a bimolecular mechanism occurs, in which a neutral... 

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