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Ionophores

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Ionophores
Page 211
TABLE 5.6 Major Transport Systems in Mammalian Cellsa
Substance Transported
Mechanism of Transport
Tissues
Sugars
Glucose
Fructose
Passive
Widespread
Active symport with Na+
Small intestines and renal tubular cells
Passive
Intestines and liver
Amino acid­specific transporters
Active symport with Na+
Intestines, kidney, and liver
All amino acids except proline
Active group translocation
Liver
Specific amino acids
Passive
Small intestine
ATP–ADP
Antiport transport of nucleotides; can be active transport
Mitochondria
Ascorbic acid
Active symport with Na+
Widespread
Biotin
Active symport with Na+
Liver
Cholic acid, deoxycholic acid, and taurocholic acid
Active symport with Na+
Intestines
Dicarboxylic acids
Active symport with Na+
Kidney
Folate
Amino acids
Other organic molecules
Active
Widespread
Lactate and monocarboxylic acids
Active symport with H+
Widespread
Neurotransmitters (e.g., g­amino butyric acid, norepinephrine, glutamate, dopamine)
Active symport with Na+
Brain
Organic anions (e.g., malate, a­ketoglutarate, glutamate)
Antiport with counterorganic anion
Mitochondria
Peptides (2 to 4 amino acids)
Active symport with H+
Intestines
Urea
Passive
Erythrocytes and kidney
H+
Active
Mitochondria
H+
Active; vacuolar ATPase
Widespread; lysosomes, endosomes, and Golgi complex
Na+
Passive
Distal renal tubular cells
Na+, H+
Active antiport
Proximal renal tubular cells and small intestines
Na+, K+
Active: ATP driven
Plasma membrane of all cells
Na+, HPO42–
Active cotransport
Kidney
Ca2+
Active: ATP driven
Plasma membrane and endoplasmic (sarcoplasmic) reticulum
Active antiport
Widespread
Active antiport
Parietal cells of gastric mucosa secreting H+
Passive antiport
Erythrocytes and other cells
Inorganic ions
Ca2+, Na+
+
+
H , K
Cl–/HCO3
–
a The transport systems are only indicative of the variety of transporters known; others responsible for a variety of substances have been proposed. Most systems have been studied in only a few tissues and their localization may be more extensive than indicated.
5.9— Ionophores
An interesting class of antibiotics of bacterial origin facilitates the movement of monovalent and divalent inorganic ions across biological and synthetic lipid membranes. These molecules, called ionophores, are not large macromolecules such as proteins but are relatively small molecular weight compounds (up to several thousand daltons). Ionophores are divided into two major groups:
Page 212
CLINICAL CORRELATION 5.4 Diseases Due to Loss of Membrane Transport Systems
A number of pathological conditions are due to an alteration in the transport systems for specific cellular components. Some of these are discussed in the appropriate sections describing the metabolism of the intermediates. Individuals have been observed with a decrease in glucose uptake from the intestinal tract due to a loss of the specific sodium­
coupled glucose–galactose transporter. Fructose malabsorption syndromes have been observed, which are due to an alteration in the activity of the transport system for fructose. In Hartnup's disease there is a decrease in the transport of neutral amino acids in the epithelial cells of the intestine and renal tubules.
In cystinuria, renal reabsorption of cystine and the basic amino acids lysine and arginine is abnormal, resulting in formation of cystine kidney stones. In hypophosphatemic, vitamin D resistant rickets, renal absorption of phosphate is abnormal. Little is known concerning possible changes of transport activities in tissues such as muscle, liver, and brain but it has been suggested that there may be a number of pathological states due to the loss of specific transport mechanisms.
Evans, L., Grasset, E., Heyman, M., et. al. Congenital selective malabsorption of glucose and galactose. J. Pediatr. Gastroenterol. Nutr. 4:878, 1985.
TABLE 5.7 Major Ionophores
Compound
Major Cations Transported
Action
Valinomycin
K+ or Rb+
Uniport, electrogenic
Nonactin
NH4+, K+
Uniport, electrogenic
A23187
Ca2+/2 H+
Antiport, electroneutral
Nigericin
K+/H+
Antiport, electroneutral
Monensin
Na+/H+
Antiport, electroneutral
Gramicidin
H+, Na+, K+, Rb+
Forms channels
Alamethicin
K+, Rb+
Forms channels
(1) mobile carriers are those ionophores that diffuse back and forth across the membrane carrying the ion from one side of the membrane to the other, and (2) ionophores that form a channel that transverses the membrane and through which ions can diffuse. With both types, ions are translocated by a passive mediated transport mechanism. The ionophores that diffuse back and forth across the membrane are more affected by changes in the fluidity of the membrane than those that form a channel. Some major ionophores are listed in Table 5.7.
Each ionophore has a definite ion specificity; valinomycin, whose structure is given in Figure 5.50, has an affinity for K+ that is 1000 times greater than that for Na+ and the antibiotic A23187 (Figure 5.51) translocates Ca2+ 10 times more actively than Mg2+. Several of the diffusion type ionophores have a cyclic structure. The metal ion is coordinated to several oxygen atoms in the core of the ionophore; the periphery of the molecule consists of hydrophobic groups. The interaction of the ionophore leads to a chelation of the ion, stripping away its surrounding water shell and encompassing the ion by a hydrophobic shell. The ionophore­ion complex freely diffuses across the membrane. Since the interaction of ion and ionophore is an equilibrium reaction, a steady state develops in the concentration of ions on both sides of the membrane. The specificity of the ionophore is due in part to the size of the pore into which the ion fits and to the attraction of the ionophore for the ion in competition with water molecules.
Valinomycin transports K+ by an electrogenic uniport mechanism and can create an electrochemical gradient across a membrane as it carries a positively charged K+ across the membrane. Nigericin is an electrically neutral antiporter; its carboxyl group when dissociated binds a positive ion, such as K+, leading to a neutral molecule that crosses a membrane. On diffusion back through the
Figure 5.50 Structure of the valinomycin–K+ complex. Abbreviations: D­Val, D­valine; L­Val, L­valine; L, L­lactate; and H, D­hydroxyisovalerate.
Figure 5.51 Structure of A23187, a Ca2+ ionophore.
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