Lonophores carboxylic

Carboxylic lonophores. Carboxylic ionophore-medlated transport is detailed on the left of Figure 2. The form assumed within the membrane at the start of the transport cycle is an electrically neutral zwltterlon, rf " anionic free I is presumably too polar to be stable at that locus. When this species diffuses to the membrane Interface, it is subject to solvation the cation can be hydrated and removed from the complex. The resultant highly polar I is obliged to remain at the interface until a new charge partner, represented by IT H20, arrives. Once in position,... 

Monensln Is another member of this family of carboxylic polyether lonophores. The kinetics of sodium binding (k ) and... 

The lonophores thus far described lack lonlzable groups and are collectively classified as neutral lonophores their complexes acquire the net charge of whatever ion is complexed. We shall now examine two representatives of the carboxylic subclass of lonophores. Only the anionic form of these lonophores complex cation hence they form electrically neutral zwitterlonic complexes. This distinction is fundamental for explaining the profound differences in biological behavior of the lonophore subclasses, hence we prefer carboxylic lonophore to the term polyether antibiotic used by Westley O). The latter term, furthermore, leads to functional ambiguity with the ethereal macrolide nactlns and crown polyethers which are neutral lonophores. 

X-ray crystallographic studies confirm that all cationic complexes of carboxylic lonophores have their llgandlng atoms oriented toward a central cavity. The extent to which this conformation would be altered in the absence of a bound cation due to the mutual electrostatic repulsion of the dipolar oxygen atoms would, in turn, be modulated by the mobility of the backbone supporting the ligands. 

We conclude that the dynamics of molecular conformation associated with sallnomycin complexatlon In all likelihood extend at least to the other naturally occurring carboxylic lonophores. The influence of lonophore environment, e.g. solvent, on lonophore conformation Is particularly significant when considering the environmental continuum encountered by an lonophore when trans-versing a biological membrane. 

Pharmacological Effects. Although both neutral and carboxylic lonophores have been extensively employed as tools for In vitro studies of biological systems for the reasons detailed previously, only the carboxylic lonophores are sufficiently tolerated by intact animals to produce well defined pharmacological responses. We initially examined the cardiovascular effects of lasalocld because of its ability to transport the key biological control agents, Ca2+ and catecholamines (20,21). However, we later discovered that carboxylic lonophores selective for alkali ions were even more potent in evoking the same responses (22). 

Carboxylic lonophores and Efficiency of Feed Conversion by Livestock. A strong note of relevance to studies of the chemical and pharmacological properties of carboxylic lonophores derives from the large scale use of monensin as a livestock feed additive. The rationale is that carboxylic lonophores control endemic coccidiosis in the poultry gut (30) and promote a more favorable fermentation of cellulose in the bovine rumen (31). In either case, the net result is the economically important Increased efficiency of conversion of feed into meat. 

Pharmacokinetics of lonophore Absorption. We have developed a sensitive chemical assay for carboxylic lonophores (which will be published elsewhere) based on their ability to form lipid soluble complexes with cations. We can detect as little as 1 part per billion (ppb) monensin in 2 ml of blood plasma or tissue. For a comparison yardstick, current feeding regimens call for ca. 30 parts per million (ppm) in cattle feed (32) and as much as 100 ppm in poultry feed (33). 

The Need for Increased Surveillance of the Exposure of Man to lonophores. From the lipid soluhllity of monensln and other lonophores, we would predict they should have no trouble equilibrating across biological membrane systems including the gut. This Is certainly the case for the two diverse species observed, the dog, a carnivore, and the rabbit, a herbivore. Accordingly, we infer that there Is ample opportunity for monensln and other carboxylic lonophores administered orally to livestock to distribute systemically and exert a pharmacological effect on the recipient animal. Furthermore, the resultant physiological effects may be part of the mechanism by which lonophores produce their Improved feed conversion efficiency. 

We have long been Interested in the possibility that the cardiovascular effects of carboxylic lonophores could be harnessed to provide new drugs for the treatment of disease states such as heart failure and shock. There may, however, be subpopulations of man for whom lonophores may be particularly toxic. For example, a toxic Interaction between monensln and digitalis on the dog heart has been reported (37). Our oral absorption data do Indicate that If a useful human therapeutic application can be established, lonophores could be administered as drugs orally. 

Cation Complexes of the Monovalent and Polyvalent Carboxylic lonophores Lasalocid (X-537A), Monensin, A-23187 (Calcimycin) and Related Antibiotics... 

Carboxylic lonophore Conformational Dynamics During Transport. . 99... 

Painter, G. R Pressman, B. C. The Conformational Dynamics of the Carboxylic lonophore Lasalocid A Underlying Cation Complexation-Cecomplexation and Membrane Transport. Submitted to Biochemistry, May, 1981... 

ENHANCEMENT OF THE RATE OF PHOTOPHOSPHORYLATION IN SpiNACH CHLOROPLASTS BY LOW CONCENTRATIONS OF CARBOXYLIC lONOPHORES AND AMINES... 

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