Monensin, structure

Since 1950 a number of polyether antibiotics have been discovered using fermentation technol ogy They are characterized by the presence of sev eral cyclic ether structural units as illustrated for the case of monensm in Figure 16 3a Monensin and other naturally occurring polyethers are similar to crown ethers in their ability to form stable complexes... 

FIGURE 16 3 (a) The structure of monensin (b) The structure of the sodium salt of monensin showing coordination of Na yellow) to the six oxygens shown in red in the structural formula Flydrogen atoms have been omitted from the model for clarity... 

Other mobile carrier ionophores include monensin and nonaetin (Figure 10.39). The unifying feature in all these structures is an inward orientation of polar groups (to coordinate the central ion) and outward orientation of non-... 

Fig. 2. Chemical structures of monensin (a) and cholanic acid (b). (Cited from Ref.8))...

Cholanic acid also possesses the ability of transporting cations across a lipophilic membrane but the selectivity is not observed because it contains no recognition sites for specific cations. In the basic region, monensin forms a lipophilic complex with Na+, which is the counter ion of the carboxylate, by taking a pseudo-cyclic structure based on the effective coordination of the polyether moiety. The lipophilic complex taken up in the liquid membrane is transferred to the active region by diffusion. In the acidic region, the sodium cation is released by the neutralization reaction. The cycle is completed by the reverse transport of the free carboxylic ionophore. 

In 1967 Agtarap et al. disclosed the isolation and structure of monensic acid (1).3 Compound 1, now known as monensin, is produced by a strain of Streptomyces cinamonensis, and exhibits broad-spectrum anticoccidial activity. Since its introduction on the market in 1971, monensin has been used very successfully to combat coccidial infections in poultry and as an additive in cattle feed.4 In the polyether family, monensin occupies a position of some historical significance. Although monensin was the fifth polyether... 

Figure 1. X-ray crystal structure of the monensin-Ag complex (reprinted with permission from the American Chemical Society J. Am. Chem. Soc. 1967, 89, 5737).

Monensin belongs to the family of polyether ionophores. These compounds consist of a series of tetrahydrofuran and tetrahydro-pyran rings and have a carboxyl group that forms neutral salts with alkali metal cations. Their three-dimensional structure presents a lipophilic hydrocarbon exterior with the cation encircled in the oxygen-rich interior. They probably act by transporting cations through the lipid bi-layer of cell membranes, thereby preventing the concentration of potassium by the cells. Evidence for this is... 

Although the acidic antibiotics do not show the high selectivity characteristic of the neutral ones, there is still some preference, a strong one for monovalent as compared with divalent cations, and within the monovalent cations a variation from one acid to another. Monensin prefers sodium to potassium. The larger nigeridn, (X7), prefers potassium to sodium its silver, potassium, and sodium salts are isomorphous and anhydrous. Crystal structure determinations on the silver salt were carried out independently by workers in the U.S.A. (78) and in Japan... 

In addition to the structural effects due to the geometry of a substituted magnesium enolate, the stereochemistry of the reaction with a chiral aldehyde can be controlled, as described in equation 85. The aldol reaction based on the addition of magnesium enolate 56 to aldehyde 55 has been applied to the synthesis of monensin. The chiral center in the aldehyde induces the preferential approach of one diastereotopic face of the aldehyde by... 

The structural features described for monensin have been found in all the monovalent polyether antibiotic complexes studied. In some instances, e.g. nigericin568 and dianemycin,569... 

Because the stability constant of its complex with potassium is much greater than that with sodium, valinomycin is a relatively specific potassium ionophore. In contrast, the mushroom peptide antamanide has a binding cavity of a different geometry and shows a strong preference for sodium ions.388,390 The structure of the Na+-antamanide complex is also shown in Fig. 8-22B. The Streptomyces polyether antibiotic monensin (Fig. 8-22D),389,391 a popular additive to animal feeds, is also an ionophore. However, its mode of action, which involves disruption of Golgi functions, is uncertain 392... 

The structure and absolute configuration of a series of similar compounds, grisorixin (T9),487 monensin (80),488 X-206 (81),489, X-537A (82)490 and lysocellin (83),491 all antibiotics of the nigericin group, were then elucidated within a short period, again as their silver salts. 

ANTIBIOTICS POLYETHERS. The polvether antibiotics were first recognized as a separate class with the publication of the structure of monensin in 1967. Several members of the group have since found commercial application as anticoccidials in poultry farming and in improvement of feed efficiency for ruminants. 

Both monensin (24) and nigericin (25) complex Na+ and K+ strongly but not selectively. The crystal structures of the Na+, Tl+ and Ag+ complexes all show the metal ion to be in an O-rich cavity. The carboxylate group is not involved however.97 With the antibiotics (26), (27) and (28) the thermodynamic stabilities (Table 9) are greater for the divalent than for the monovalent metal ions.98 The conformations adopted in these complexes axe very solvent dependent, and the implication of these to the biological transportation of the cations has been discussed.99... 

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