Active transport across membranes

Energy for maintenance is the energy required for survival, or non-growth related purposes. It includes activities such as active transport across membranes and turnover (replacement synthesis) of macromolecules. 

Many solute properties are intertwined with those of the ubiquitous solvent, water. For example, the osmotic pressure term in the chemical potential of water is due mainly to the decrease of the water activity caused by solutes (RT In aw = —V ri Eq. 2.7). The movement of water through the soil to a root and then to its xylem can influence the entry of dissolved nutrients, and the subsequent distribution of these nutrients throughout the plant depends on water movement in the xylem (and the phloem in some cases). In contrast to water, however, solute molecules can carry a net positive or negative electrical charge. For such charged particles, the electrical term must be included in their chemical potential. This leads to a consideration of electrical phenomena in general and an interpretation of the electrical potential differences across membranes in particular. Whether an observed ionic flux of some species into or out of a cell can be accounted for by the passive process of diffusion depends on the differences in both the concentration of that species and the electrical potential between the inside and the outside of the cell. Ions can also be actively transported across membranes, in which case metabolic energy is involved. 

The placenta is both a transport and a metabolizing organ. Transport is accomplished by simple diffusion, facilitated diffusion, active transport across membranes, and by special processes such as pinocytosis, phagocytosis, specific transport molecules, and channels in the barrier . The placenta also contains a full complement of mixed function oxidases located in the microsomal and mitochondrial subcellular fractions capable of induction and metabolism of endogenous and exogenous chemicals. 

There are three major points to be stressed. First, the Hquid/ceUular interface may contribute significantly to mass transfer limitations. Second, when mass transfer Hmitations exist the intrinsic biokinetics parameters cannot be determined. In biochemical reactor design, intrinsic parameters are essential to model adequately the system performance. Furthermore, without an understanding of the intrinsic biokinetics, one cannot accurately study transport mechanisms across biological membranes. The determination of passive or active transport across membranes is strongly affected by the extent of the Hquid/ceUular interfacial resistance. 

In subsequent studies attempting to find a correlation of physicochemical properties and antimicrobial activity, other parameters have been employed, such as Hammett O values, electronic distribution calculated by molecular orbital methods, spectral characteristics, and hydrophobicity constants. No new insight on the role of physiochemical properties of the sulfonamides has resulted. Acid dissociation appears to play a predominant role, since it affects aqueous solubiUty, partition coefficient and transport across membranes, protein binding, tubular secretion, and reabsorption in the kidneys. An exhaustive discussion of these studies has been provided (10). 

Alternatively, one interesting drug delivery technique exploits the active transport of certain naturally-occurring and relatively small biomacromolecules across the cellular membrane. For instance, the nuclear transcription activator protein (Tat) from HIV type 1 (HlV-1) is a 101-amino acid protein that must interact with a 59-base RNA stem-loop structure, called the traus-activation region (Tar) at the 5 end of all nascent HlV-1 mRNA molecules, in order for the vims to replicate. HIV-Tat is actively transported across the cell membrane, and localizes to the nucleus [28]. It has been found that the arginine-rich Tar-binding region of the Tat protein, residues 49-57 (Tat+9 57), is primarily responsible for this translocation activity [29]. 

Unlike mass transport across membranes, which relates to chemical structure in predictable ways, the potencies of drugs as seen in pharmacological, pharmacodynamic, or other tests are highly structurally specific within a class of drugs and are without commonality across classes. A drug s activity involves a complex merging of these separate structural influences, with bioavailability always one of the concerns. Such concern is minimal when a truly superficial effect is involved, however. For example, the most potent antiseptic as measured in the test tube is likely to have... 

While both paracellular and passive transcellular pathways are available to a solute, the relative contribution of each to the observed transport will depend on the properties of the solute and the membrane in question. Generally, polar membrane-impermeant molecules diffuse through the paracellular route, which is dominated by tight junctions (Section III.A). Exceptions include molecules that are actively transported across one or both membrane domains of a polarized cell (Fig. 2). The tight junction provides a rate-limiting barrier for many ions, small molecules, and macromolecules depending on the shape, size, and charge of the solute and the selectivity and dimensions of the pathway. 

The uptake of siderophore-iron complexes by Gram-negative bacteria is energy dependent and occurs via specific outer membrane proteins. In the periplasmic space, it binds to its cognate periplasmic binding protein and is then actively transported across the cytoplasmic membrane by an ATP-trans-porter protein. Three principal mechanisms for transport through the outer membrane have been described ... 

During the process of nutrient assimilation, DIN is first actively transported across the cell membrane. This transport is mediated by species-specific enzymes called permeases that are present in the cell membrane. Once the inorganic nitrogen has crossed the cell membrane, it can participate in anabolic reactions. For example, ammonium helps build amino acids by first reacting with a-ketoglutaric acid to generate glutamic acid ... 

As lithium is an alkaline earth metal which readily exchanges with sodium and potassium, it is actively transported across cell membranes. The penetration of kidney cells is particularly rapid, while that of bone, liver and brain tissue is much slower. The plasma CSE ratio in man has been calculated to be between 2 1 and 3 1, which is similar to that found for the plasma red blood cell (RBC) ratio. This suggests that the plasma RBC ratio might be a useful index of the brain concentration and may be predictive of the onset of side effects, as these appear to correlate well with the intracellular concentration of the drug. 

The nuclear envelope is perforated with huge macromolecular assemblies of 30 different proteins that form nuclear pore complexes with a central channel of 25-30 nm in diameter. This channel allows proteins smaller than 30 kDa to passively traverse the outer and inner nuclear membranes. Larger proteins are actively transported across the nuclear envelope and contain nuclear localization signal (NLS) sequence motifs. These signals consist of one or two clusters of four or five basic residues localized usually within the polypeptide chain. The import of proteins with NLS through the channel is facilitated by the carrier heterodimer of importin-a ( > (Gorlich and Kutay 1999 Pemberton and Paschal... 

Passive diffusion, carrier-mediated, or active transport across sinusoidal membrane... 

Once mobilized in the hepatocyte, chemicals can contact and interact with biotransformation enzymes (Chapter 7). These enzymes generally increase the polarity of the chemical, thus reducing its ability to passively diffuse across the sinusoidal membrane back into the blood. Bio transformation reactions also typically render the xenobiotics susceptible to active transport across the canalicular membrane into the bile canaliculus and, ultimately, the bile duct (Figure 10.3). The bile duct delivers the chemicals, along with other constituents of bile, to the gall bladder that excretes the bile into the intestines for fecal elimination. 

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