Antibiotics valinomycin

These substances include primarily depsipeptides (compounds whose structural units consist of alternating amino acid and ar-hydroxy acid units). Their best-known representative is the cyclic antibiotic, valinomycin, with a 36-membered ring [L-Lac-L-Val-D-Hy-i-Valac-D-Val]3, which was isolated from a culture of the microorganism, Streptomyces fulvissimus. Figure 6.13 depicts the structure of free valinomycin and its complex with a potassium ion, the most important of the coordination compounds of valinomycin. 

The transport of K+ ions through cell membranes by antibiotics (valinomycin) has been a very important example. Addition of K+ ions to the subphase of a valinomycin monolayer showed that the surface potential became positive. This clearly indicates the ion-specific binding of K+ to valinomycin (Birdi, 1989). 

Impetus was given to work in the field of selective cation complex-ation by the observation of Moore and Pressman (5) in 1964 that the macrocyclic antibiotic valinomycin is capable of actively transporting K+ across mitochondrial membranes. This observation has been confirmed and extended to numerous macrocyclic compounds. There is now an extensive literature on the selective complexation and transport of alkali metal ions by various macrocyclic compounds (e.g., valinomycin, mo-nactin, etc.) (2). From solution spectral (6) and crystal X-ray (7) studies we know that in these complexes the alkali metal cation is situated in the center of the inwardly oriented oxygen donor atoms. Similar results are found from X-ray studies of cyclic polyether complexes of alkali metal ions (8) and barium ion (9). These metal macrocyclic compound systems are especially noteworthy since they involve some of the few cases where alkali metal ions participate in complex ion formation in aqueous solution. 

Transport through Membranes. Transport antibiotics Valinomycin, Nonactin, Monensin and Their Mimics... 

Effects of Valinomycin on Oxidative Phosphorylation When the antibiotic valinomycin is added to actively respiring mitochondria, several things happen the yield of ATP decreases, the rate of 02 consumption increases, heat is released, and the pH gradient across the inner mitochondrial membrane increases. Does valinomycin act as an uncoupler or an inhibitor of oxidative phosphorylation Explain the experimental observations in terms of the antibiotic s ability to transfer K+ ions across the inner mitochondrial membrane. 

This additive procedure was applied for the study of a number of cases including the interaction of cations with the carrier antibiotics valinomycin 184> and nonac-tin 185), the interaction of CH3NH3+ and (CH3)4N+ with amino acids mimicking the active site of a phosphorylcholine antibody186), the interaction of guanine and cytosine with amino acids 181), the interaction of Ca2+ and Mg2-1- with two serine phosphates 188), and the interaction of the channel-forming antibiotic gramicidin A with different cations 189 191>. 

For examfde, cydic dodecadepsipeptide antibiotic valinomycin (18) is refure-sented as Cydo-(D-Val-Lac-Val-D-Ifyv)3 where Lac and Hyv re esent lactic add and cr-oxyisobutyric add, re ctively. ValinonQrcin selectively binds K, when it acts as an antibiotic. As shown in Fig. 31, valinomycin takes a bracelet structure and has a cavity in the middle with a diameter of 6—7A. Sizes of hydrated cations are... 

This Na+/K+ selectivity is of paramount importance since many physiological functions depend upon its maintenance. The selective transport of K+ across cell membranes is achieved by the natmal antibiotic valinomycin (10), which contains a crownlike cycle of ether oxygens, but also a number of amide linkages. The cycle would seem too large to bind K+... 

How ionophotes like the antibiotic valinomycin transport ions across a cell membrane (Section 3.7B)... 

A relevant example of a suitable ionophore is the antibiotic valinomycin, which specifically binds K. Other ionophores have been developed for measurement of, for example, NHj, Ca, Cl . In addition, electrodes have been developed for organic species by using specific ion-pairing reagents in the membrane that interact with ionic forms of the organic compound, e.g. with drugs such as 5,5-diphenylhydantoin. 

When the cyclic antibiotic valinomycin forms a complex with K"", Rb" or Cs"" ions, the carbonyl C signals are shifted 4-5 ppm downfield [116]. The shift differences upon complexation with Na are much less pronounced, which is presumably related to the ability of the antibiotic to distinguish between Na" and K. ... 

A major breakthrough in the development and routine application of PVC type ISEs was the discovery by Simon and co-workers that the neutral antibiotic valinomycin could be incorporated into organic liquid membranes (and later plasticized PVC membranes), resulting in a sensor with high selectivity for K over Na (Kk/ns = 2.5 X 10 ), The ISE based on valinomycin was the first example of a neutral carrier ISE and is extensively used today for the routine measurement of in blood. Figure 4-2 shows the response of the... 

The antibiotics valinomycin and gramicidin A operate by acting, within the cell membrane as ion carriers and ion channels respectively (see Chapter 10). 

Thylakoid membrane as a Molecular Voltmeter and Ammeter. The antibiotic valinomycin was found in 1964 by Moore and Pressman to affect ion transport across the mitochondrial membrane. Subsequently, Pressman and coworkers proposed that valinomycin is an ionophore and acts as a mobile ion carrier across the lipid membrane [cf. sectionlll.B. above]. Since the light-induced FIAC in thylakoid membrane appears to be an electrochromic band shift in pigments produced by an electric field, Boeck and Witt °, Junge and Schmid used this unique effect to probe the effect of compounds such as the ionophore, valinmycin, on the voltage and current density generated across the membrane. 

Without question, sodium and potassium have been the analytes receiving the most attention in conjunction with the development of new analyzers. Almost all instruments on the market utilize the potassium-selective membrane system based on the antibiotic valinomycin in a PVC membrane matrix. For blood measurements, such a membrane is quite adequate. However, in undiluted urine samples, a negative error in the measurement of potassium has been reported (KIO). Apparently, this interference comes from a negatively charged lipophilic component of the urine which can partition into the PVC membrane, reducing the membrane potential (i.e., the membrane is not permselective). Fortunately, this problem can be overcome by incorporating the valinomycin in a silicone rubber-based membrane matrix (A4) into which the unknown anionic component apparently has a less favorable partition coefficient. 

We have already introduced the hole-fit concept for a macrocyclic ligand in Chapter 4 (see Figure 4.38), which effectively means that the most stable complexes form where the internal diameter of the ring cavity matches the size of the entering cation. The effect can be significant for example, the natural antibiotic valinomycin is a macrocycle that binds potassium ion to form a complex 104 times more stable than that formed with the smaller... 

Potassium ions are assayed with a selective membrane electrode employing a poly(vinyl-chloride)-membrane doped with a specific ionophore. The classical carrier is the antibiotic valinomycin. Active research is going on at many places to develop synthetic ionophores for both cations, sodium and potassium. 

For examfde, cyclic dodecadepsipeptide antibiotic valinomycin (18) is represented as Cyclo D-Val-Lac-Val-D-ifyv)3 where Lac and Hyv re esent lactic acid and a-oxyisobutyric add, re ctively. ValinoiiQrcin selectively binds K, when it acts as an antibiotic. As shown in Fig. 31, valinomycin takes a bracelet structure and has a cavity in the middle with a diameter of 6—7A. Sizes of hydrated cations are 4.5—5.0 A for K, Rb, and Cs and 5.5—7.4 A for Na and Li . It is understandable that the cavity fits in with K. Carbonyl groups are distributed along the inside wall of the cavity which is necessarily polar. Alifdiatic side chains form the outside wall of the bracelet whidi is necessarily nonpolar. Valinomycin binds in the hydro-0ulic interior of the cavity and transports the ion across the lipid bilayer of the cell... 

NaCl from water. Moore and Pressman s discovery that the antibiotic valinomycin exhibits alkali metal cation selectivity in rat liver mitochondria then provided a starting point for studies in the area of selectivity by biological and model systems. ... 

Since the discovery in 1964 that the antibiotic valinomycin exhibited alkali cation specificity in rat liver mitochondria, a new area of research has developed, based not only on biological systems but also on model systems such as crown ethers. The ability of neutral compounds to form lipid-soluble alkali and alkaline earth complexes was observed in 1951. The structure of the corresponding ligand, the anion of the antibiotic nigeridn (78), was characterized as its silver salt in 1968. Silver was used as a heavy atom crystdlographically, since the Ag" cation had a radius between that of Na" and K, which were the two alkali cations with which nigericin was most active. 

Li, ]., Jaitzig, ]., Hillig, E, Siissmuth, R., and Neubauer, R (2014) Enhanced production of the nonribosomal peptide antibiotic valinomycin in Escherichia coli through small-scale high cell density fed-batch cultivation. Appl. Microbiol. Biotechnol, 98, 591-601. 

The earliest work with ISEs based on electrically neutral ionophores was inspired by the observation of Moore and Pressman that the antibiotic valinomycin (Fignre 3), K+-I, cansed the nptake of K+ into and the release of H+ from mitochondria. Simon and Stefanac showed in 1966 that thin films of water-immiscible organic solvents doped with antibiotics exhibited responses to monovalent cations with selectivities similar to those observed in biological... 

---