Solute translocation

A large number of plant compounds interact with the ATP-dependent, multidrug resistance transporter (MDR transporter or P glycoprotein transporter). This belongs to the ATP-binding cassette family of solute transporters (ABC transporters) and functions to remove unwanted chemicals of xenobiotic origin (notably compounds from plants). 

The MDR transporter is of importance in drug resistance in antiprotozoal and anticancer chemotherapy and hence compounds that inhibit this transporter are potentially very useful as adjuncts to chemotherapy to overcome such drug resistance (Table 13.7). This chapter also deals with numerous plant-derived compounds that inhibit various other enzymes (Table 13.8). 

Biochemical target inhibited (other targets) / in vivo effects/ 

Calystegine B4 (tetrahydroxy nortropane) Calystegine C1 (tetrahydroxy nortropane) 

Castanospermum australe (Fabaceae) [seed] Castanospermum australe (Fabaceae) [seed] Castanospermum australe (Fabaceae) [seed] Castanospermum australe (Fabaceae) [seed] 

---

In series with a desolvation energy barrier required to disrupt aqueous solute hydrogen bonds [14], the lipid bilayer offers a practically impermeable barrier to hydrophilic solutes. It follows that significant transepithelial transport of water-soluble molecules must be conducted paracellularly or mediated by solute translocation via specific integral membrane proteins (Fig. 6). Transcellular permeability of lipophilic solutes depends on their solubility in GI membrane lipids relative to their aqueous solubility. This lumped parameter, membrane permeability,... 

Most of the early work on membranes was based on experiments with erythrocytes. These cells were first described by Swammerdam in 1658 with a more detailed account being given by van Leeuwenhoek (1673). The existence of a cell (plasma) membrane with properties distinct from those of protoplasm followed from the work of Hamburger (1898) who showed that when placed in an isotonic solution of sodium chloride, erythrocytes behaved as osmometers with a semipermeable membrane. Hemolysis became a convenient indication of the penetration of solutes and water into the cell. From 1900 until the early 1960s studies on cell membranes fell into two main categories increasingly sophisticated kinetic analyses of solute translocation, and rather less satisfactory examinations of membrane composition and organization. 

Gryns (1896), Hedin (1897), and especially Overton (1900) looked at the permeability of a wide range of different compounds, particularly non-electrolytes, and showed that rates of penetration of solutes into erythrocytes increased with their lipid solubility. Overton correlated the rate of penetration of the solute with its partition coefficient between water and olive oil, which he took as a model for membrane composition. Some water-soluble molecules, particularly urea, entered erythrocytes faster than could be attributed to their lipid solubility—observations leading to the concept of pores, or discontinuities in the membrane which allowed water-soluble molecules to penetrate. The need to postulate the existence of pores offered the first hint of a mosaic structure for the membrane. Jacobs (1932) and Huber and Orskov (1933) put results from the early permeability studies onto a quantitative basis and concluded molecular size was a factor in the rate of solute translocation. 

As a class of tissue, epithelia demarcate body entry points, predisposing a general barrier function with respect to solute entry and translocation. The intestine is lined with enterocytes, which are polarized cells with their apical membrane facing the intestinal lumen that is separated by tight junctions from the basolateral membrane that faces the subepithelial tissues. In addition to their barrier function, the epithelia that line the GI tract serve specialized functions that promote efficient nutrient digestion and absorption and support other organs of the body in water, electrolyte, and bile salt homeostasis. The homeostatic demand on GI tissue that results from this dual function may pose special transport consideration compared with solute translocation across biologically inert barriers. 

The difference between the energy requirement of chloroplasts and mitochondria for import is unclear. It may be the result of the difference in the nature of the membranes that are being crossed (a membrane with electron transport and oxidative phosphorylation activities in mitochondria and a membrane which mainly functions in solute translocation in chloroplasts). If this is the explanation, one may predict that plastocyanin, which is located in the cistemae of the thylakoids [91], would be imported in two steps the first dependent on ATP and the final transthylakoid movement dependent on a membrane potential. 

The original definition of facilitated diffusion given by Danielli related to solute translocation through non-aqueous membranes, but there is no difference in principle between facilitated diffusion in aqueous and non-aqueous media. Eqns. 4-6 are therefore of general interest as a summary of... 

Our discussion of translocation catalysis has so far been confined to solute translocation, but the same general principles apply to the translocation of other types of chemical particle. 

A) In primary translocation reactions, primary bonds are exchanged or electrons are transferred between different pairs of chemical groups. This class of reactions may be divided into two sub-classes (7) In group translocation reactions, chemical groups or electrons pass from one side of an osmotic barrier to the other . (2) In enzyme-linked solute translocation reactions, the translocation of one or more solutes through the osmotic barrier is coupled to the translocation of chemical groups or electrons otherwise than across the osmotic barrier . 

B) In secondary translocation reactions, primary bond exchanges or the transfer of electrons do not occur. This class of reactions may be divided into three sub-classes (7) In non-coupled solute translocation, or facilitated diffusion, or uniport reactions, a single solute equilibrates across an osmotic barrier. (2) In sym-coupled solute translocation, or cotransport" , or symport reactions, two solutes equilibrate across an osmotic barrier, and the translocation of one solute is coupled to the translocation of the other in the same direction, (i) In anti-coupled solute translocation, or counter-transport , or antiport reactions, two solutes equilibrate across an osmotic barrier, and the translocation of one solute is coupled to the translocation of the other in the opposite direction. 

Vrlji6 M, Garg J, BeUmann A,Wachi S, Freudl R, Malecki MJ, et al.The LysE super frunily topology of the lysine, exporter LysE of Corynebacterium glutamicum, a paradigm for a novel super fiunily of, transmembrane solute translocators. J Mol Microbiol Biotechnol 1999 1 327-36. 

Vrljic, M., Garg, J., Bellmann, A., Wachi, S., Freudl, R., Malecki, M.J. et al (1999) The LysE superlamily topology of the lysine exporter LysE of Corynehacterium glutamicum, a paradyme for a novel superfamily of transmembrane solute translocators. 

Typically, the length ofa simulation varies between 1 and 10 ns. Even though such a simulation requires approximately 10 -10 time steps, it is not a sufficiently long time to collect complete, direct statistics about solute translocation. Thus, special techniques, described below, must be used to calculate both the distribution of a solute in the bilayer and the membrane permeability to a solute. The temperature of the system is usually held at a value in the 300-350 K range. Two considerations motivate the choice of the temperature. First, in some studies e.g., on anesthetic solutes) it is desired to simulate physiological conditions. Second, since the membrane permeability depends sensitively on the lipid phase, it is usually required that the bilayer be clearly above the gel-to-liquid-crystal transition temperature. 

---