Transport mechanisms nucleotide

Angerer, A., Gaisser, S. and Braun, V. (1990). Nucleotide sequences of the sfuA, sfuB, and sfuC genes of Serratia marcescens suggest a periplasmic-binding-protein-dependent iron transport mechanism, J. Bacteriol., 172, 572-578. 

Etoposide and teniposide are synthetic derivatives of the extract of the American mandragora plant (May Apple). The mechanism of their action has not been completely explained however, they act on the enzyme topoisomerase II, which disturbs the twisting of DNA. In addition, they inhibit DNA and RNA synthesis, as well as transport of nucleotides to cells. Cytotoxic action on normal cells is observed only in very high doses. These drugs exhibit significant activity in lymphomas, leukemia, Kaposi s sarcomas, and in testicular cancer. 

Kaever, V., and Resch, K. (1990). Role of cyclic nucleotides in lymphocyte activation. In Current Topics in Membranes and Transport Mechanisms of Leukocyte Activation (S. Grinstein and O. D. Rotstein, ed.), Vol. 35, pp. 375-398. Academic Press, San Diego. 

The brain needs the influx of nucleosides because the brain is deficient in de novo nucleotide synthesis (102). Purine and pyrimidine nucleosides are necessary for the synthesis of DNA and RNA, but nucleosides also influence many other biological processes. In addition, nucleosides play an important role in the treatment of diseases, such as cardiac diseases, brain cancers, and infections [parasitic and viral (103)]. Nucleosides are hydrophilic compounds, and the influx and efflux of these compounds is therefore mediated by a number of distinct transporters (104). Nucleoside transporters are membrane-fixed transporters and are classified by their transport mechanisms (e = equilibrative, c = concentrative), their sensitivity to the transport inhibitor nitrobenzylmercaptopurine riboside (NBMPR s = sensitive, i = insensitive), and their substrates. Presently, there are two equilibrative transporters (ENTs es and ei) and six concentrative nucleoside transporters [CNTs cif (concentrative, NBMPR insensitive, broad specificity Nl), cit (concentrative, NBMPR insensitive, common permeant thymidine N2), cib (concentrative, NBMPR insensitive, broad specificity N3), cib (concentrative, MBMPR insensitive, broad specificity N4), cs (concentrative, NBMPR sensitive N5), and csg (concentrative, NBMPR sensitive, accepts guanosine as permeant N6) (104)]. The equilibrative es and ei nucleoside transporters are widely expressed in mammalian cells and are present at cultured endothelial cells and brain capillaries (105). In these cells, the expression of concentrative transporter cit (N2) was demonstrated also. In other parts of the rat brain, ei and es nucleoside transport systems have... 

In order to interact with their target enzyme, the reverse transcriptase, pharmacologically effective levels of 2, 3 -dideoxynucleoside-5 -triphosphates have to be generated. This implies that the candidate 2, 3 -dideoxynucleoside has to enter the cell, using the nucleoside transport mechanisms or by passive diffusion. The 2, 3 -dideoxynucleoside must also be transformed to the corresponding 5 -triphosphate by cellular kinases, because HIV does not appear to encode for nucleoside kinases. The efficiency of this phosphorylation strongly depends on the type of compound and the nature of the cells. The susceptibility of the nucleosides and nucleotides involved in this process to metabolic enzymes such as deaminases, hydrolases and phosphatases is another important factor to reach and maintain effective levels of dideoxynucleoside triphosphates. 

The enzymes from the pancreas, called nucleases, split the nucleic acids into nucleotides. Then the nucleotides are split into nucleosides and phosphoric acid by other enzymes in the intestine. Finally, the nucleosides are split into their (1) constituent sugars (deoxyribose or ribose), (2) purine bases (adenine and guanine), and (3) pyrimidine bases (cytosine, thymine, and uracil). These bases are then absorbed into the blood via active transport. The sugars are absorbed slowly, and, as far as is known, there is no specific transport mechanism. 

Incorporation of the modified nucleotide bases enables us to modulate the DNA properties that are extremely important to the charge transport efficiency. The data obtained by these experiments provides a much deeper insight and understandingof the mechanism of DNA mediated charge transport. 

Methemoglobinemia arises from poisoning with MHb-forming substances and from the hereditary deficiency of an enzyme system which either provides reduced pyridine nucleotides for MHb reduction or is involved itself in the MHb reduction mechanism (e.g., electron transport system). (See Section II of the Addendum, page 280.)... 

V3. Vennesland, B., and Westheimer, F. H., Hydrogen transport and steric specificity in reactions catalyzed by pyridine nucleotide dehydrogenases. In The Mechanism of Enzyme Action (W. D. McElroy, and B. Glass, eds.), pp. 357-379. Johns Hopkins Press, Baltimore, Maryland, 1954. 

Flavonoids are now regarded as a class of MDR modulators that directly interact with nucleotide and steroid binding domains of P-gp. However, the molecular mechanism leading to inhibition of MRP1 transport activity by these compounds is still far from being fully understood. Apart from interaction with NBD or substrate binding sites, the stimulation of GSH transport carried by MRP1 and depletion of cellular GSH was also proposed as a possible mechanism of MRPl-mediated resistance reversal by flavonoids [223]. 

Fig. 4 Mechanisms involved in the extracellular inactivation of nucleotides (a, b and c) and adenosine (d) and their influence on purine concentration in the P2Y and PI receptor biophases, (a) NT-PDasel hydrolyses ATP and ADP very efficiently, thus preventing their action on P2Y receptors (b) NTPDase2 metabolizes ATP preferentially, allowing an accumulation of ADP and thus favouring activation of P2Yi, 12,13 receptors (c) NTPDase3 hydrolyses both ATP and ADP slowly, giving them time to activate both P2Y2,4 and P2Y 1,12,13 receptors. Formation of adenosine depends on the activity of ecto 5 -nucleotidase (CD73). Adenosine inactivation systems also influence adenosine concentration in the PI receptor biophase (d) the nucleoside transporters take up adenosine adenosine deaminase (ADA) regulates both the concentration of adenosine in the Ai receptor biophase and the functionality of Ai receptors.

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