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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.