抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

BIOE 402. Medical Technology Assessment. 2 or 3 hours. Bioentrepreneur course. Assessment of medical technology in the context of commercialization. Objectives, competition, market share, funding, pricing, manufacturing, growth, and intellectual property; many issues unique to biomedical products. Course Information: 2 undergraduate hours. 3 graduate hours. Prerequisite(s): Junior standing or above and consent of the instructor.

“Bioinformatics” 특집을 내면서

Access to unified datasets of protein and genetic interactions is critical for interrogation of gene/protein function and analysis of global network properties. BioGRID is a freely accessible database of physical and genetic interactions available at http://www.thebiogrid.org. BioGRID release version 2.0 includes >116 000 interactions from Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster and Homo sapiens. Over 30 000 interactions have recently been added from 5778 sources through exhaustive curation of the Saccharomyces cerevisiae primary literature. An internally hyper-linked web interface allows for rapid search and retrieval of interaction data. Full or user-defined datasets are freely downloadable as tab-delimited text files and PSI-MI XML. Pre-computed graphical layouts of interactions are available in a variety of file formats. User-customized graphs with embedded protein, gene and interaction attributes can be constructed with a visualization system called Osprey that is dynamically linked to the BioGRID.

/pdf/biogrid-a-general-repository-for-interaction-datasets-3ul1ct2q6g.pdf

BioGRID: a general repository for interaction datasets

P2X receptors are membrane ion channels that open in response to the binding of extracellular ATP. Seven genes in vertebrates encode P2X receptor subunits, which are 40–50% identical in amino acid ...

Molecular Physiology of P2X Receptors

Four adenosine receptors have been cloned and characterized from several mammalian species. The receptors are named adenosine A(1), A(2A), A(2B), and A(3). The A(2A) and A(2B) receptors preferably interact with members of the G(s) family of G proteins and the A(1) and A(3) receptors with G(i/o) proteins. However, other G protein interactions have also been described. Adenosine is the preferred endogenous agonist at all these receptors, but inosine can also activate the A(3) receptor. The levels of adenosine seen under basal conditions are sufficient to cause some activation of all the receptors, at least where they are abundantly expressed. Adenosine levels during, e.g., ischemia can activate all receptors even when expressed in low abundance. Accordingly, experiments with receptor antagonists and mice with targeted disruption of adenosine A(1), A(2A), and A(3) expression reveal roles for these receptors under physiological and particularly pathophysiological conditions. There are pharmacological tools that can be used to classify A(1), A(2A), and A(3) receptors but few drugs that interact selectively with A(2B) receptors. Testable models of the interaction of these drugs with their receptors have been generated by site-directed mutagenesis and homology-based modelling. Both agonists and antagonists are being developed as potential drugs.

https://pharmrev.aspetjournals.org/content/pharmrev/53/4/527.full.pdf

International Union of Pharmacology. XXV. Nomenclature and Classification of Adenosine Receptors

Summary Intracellular amino acid levels and the characteristics of amino acid transport were investigated in red blood cells of a primitive vertebrate, the Pacific hagfish (Eptatretus stouti Lockington). In contrast to red cells from euryhaline teleosts and elasmobranchs, which contain high concentrations of /?-amino acids, those from hagfish exhibited an intracellular amino acid pool (approx. lOOmmolP'cell water) composed almost entirely of conventional a'-amino acids. Red cell:plasma distribution ratios for individual amino acids ranged from 219, 203 and 173 for alanine, a--amino-«-butyrate and proline, respectively, to 11 and 13 for lysine and arginine. Corresponding distribution ratios for Na + , K + and Cl~ were 0.043, 21 and 0.32, respectively. The cellular uptake of amino acids, with the exception of Lproline and glycine, was Na + -independent. Compared with mammalian and avian red cells, those from hagfish exhibited 10

Characterisation of Amino Acid Transport in Red Blood Cells of a Primitive vertebrate, the Pacific Hagfish (Eptatretus Stouti)

The potential role of plasma nucleosides as metabolic energy substrates for pig erythrocytes, which are impermeable to glucose, was investigated in vivo by infusion of anesthetized pigs with nitrobenzylthioinosine phosphate (NBMPR-P), a soluble prodrug form of the specific nucleoside transport inhibitor, nitrobenzylthioinosine. NBMPR-P administration (1 or 10 mg X kg-1 X h-1) led to complete in vivo blockade of erythrocyte nucleoside transport activity and was associated with a dramatic decrease in the erythrocyte [ATP]-to-[ADP] ratio from 11.4 at time 0 to 2.9 after 4 h (mean results from 3 animals). Plasma inosine concentrations increased progressively from 2-4 microM at time 0 to 20-70 microM after 4 h of drug administration. In contrast, plasma adenosine concentrations remained less than 0.4 microM in all samples. These data suggest that pig erythrocytes utilize plasma inosine as their physiological energy substrate.

Nitrobenzylthioinosine: an in vivo inhibitor of pig erythrocyte energy metabolism.

Pharmacologically important drugs were examined as potential inhibitors or permeants of human concentrative nucleoside transporters 1 (hCNT1)- and 2 (hCNT2)-producing stable transfectants by assessing their abilities to inhibit uridine transport. hCNT1 exhibited high affinities for uridine analogs (5-fluorouridine, 2′-deoxyuridine, 5-fluoro-2′-deoxyuridine, and 5-fluoro-5′-deoxyuridine) with K i values of 22 to 33 μM, whereas hCNT2 exhibited moderate affinities for 5-fluoro-2′-deoxyuridine, high affinities for 2′-deoxyuridine and 5-fluorouridine, and low affinity for 5-fluoro-5′-deoxyuridine. The uridine analogs were transported at 2-fold higher rates (at 10 μM) by hCNT1 than by hCNT2. Enantiomeric configuration and the 3′-hydroxyl group of the ribose ring were important determinants for interaction with hCNTs, whereas the 2′-hydroxyl group was less important. Both transporters bound N 6-( p -aminobenzyl)adenosine with affinities similar to those of adenosine ( K i = 28-39 μM). Other adenosine receptor ligands, including caffeine, bound better to hCNT1 than to hCNT2 ( K i = 46 versus 103 μM, respectively), whereas 2-chloroadenosine bound better to hCNT2 than to hCNT1 ( K i = 37 and 101 μM, respectively). There was a greater than 3-fold difference in binding affinities between hCNT1 and hCNT2 for nicotine ( K i = 63 versus 227 μM). However, direct measurements of nicotine and caffeine uptake rates (10 μM) failed to demonstrate mediated uptake by either transporter. Although hCNT1 bound several adenosine analogs relatively well, it did not transport 2-chloro-2′-deoxyadenosine (cladribine) or 2-fluoro-9-β-d-arabinofuranosyladenine (fludarabine), whereas hCNT2 transported both, albeit with low activities. The results indicated that although hCNT1 and hCNT2 possess some overlap in transport of several uridine and adenosine analogs, they also exhibit distinct differences in capacity to interact with some adenosine receptor ligands, adenosine-based drugs, and nicotine.

Interactions of Nucleoside Analogs, Caffeine, and Nicotine with Human Concentrative Nucleoside Transporters 1 and 2 Stably Produced in a Transport-Defective Human Cell Line

Nucleoside transport in human erythrocytes: nitrobenzylthioinosine binding and uridine transport activities have similar radiation target sizes

Human concentrative nucleoside transporters 1, 2, and 3 (hCNT1, hCNT2, and hCNT3) exhibit different functional characteristics, and a better understanding of their permeant selectivities is critical for development of nucleoside analog drugs with optimal pharmacokinetic properties. In this study, the sensitivity of a high-throughput yeast expression system used previously for hCNT1 and hCNT3 was improved and used to characterize determinants for interaction of uridine (Urd) with hCNT2. The observed changes of binding energy between hCNT2 and different Urd analogs suggested that it interacts with C(3′)-OH, C(5′)-OH, and N(3)-H of Urd. The C(2′) and C(5) regions of Urd played minor but significant roles for Urd-hCNT2 binding, possibly through Van der Waals interactions. Because the yeast assay only provided information about potential transportability, the permeant selectivities of recombinant hCNT1, hCNT2, and hCNT3 produced in Xenopus laevis oocytes were investigated using a two-electrode voltage clamp assay. hCNT1-mediated transport was sensitive to modifications of the N(3), C(3′), and C(5′) positions of Urd. hCNT2 showed some tolerance for transporting Urd analogs with C(2′) or C(5) modifications, little tolerance for N(3) modifications, and no tolerance for any modifications at C(3′) or C(5′) of Urd. Although hCNT3 was sensitive to C(3′) modifications, it transported a broad range of variously substituted Urd analogs. The transportability profiles identified in this study, which reflected the binding profiles well, should prove useful in the development of anticancer and antiviral therapies with nucleoside drugs that are permeants of members of the hCNT protein family.

James D. Young

Papers

Characterisation of Amino Acid Transport in Red Blood Cells of a Primitive vertebrate, the Pacific Hagfish (Eptatretus Stouti)

Nitrobenzylthioinosine: an in vivo inhibitor of pig erythrocyte energy metabolism.

Interactions of Nucleoside Analogs, Caffeine, and Nicotine with Human Concentrative Nucleoside Transporters 1 and 2 Stably Produced in a Transport-Defective Human Cell Line

Nucleoside transport in human erythrocytes: nitrobenzylthioinosine binding and uridine transport activities have similar radiation target sizes

Uridine Binding and Transportability Determinants of Human Concentrative Nucleoside Transporters