The Measurement of Territorial Differences in the Information Society

Glutamine synthetase (GS, EC 6.3.1.2; also known as γ-glutamyl:ammonia ligase) catalyzes the ATP-dependent condensation of glutamate and ammonia to form glutamine. The enzyme has essential roles in different tissues and species, which have led to its consideration as a drug or an herbicide target. In this article, we describe studies aimed at the discovery of new antimicrobial agents targeting Mycobacterium tuberculosis, the causative pathogen of tuberculosis. A number of distinct classes of GS inhibitors with an IC50 of micromolar value or better were identified via high-throughput screening. A commercially available purine analogue similar to one of the clusters identified (the diketopurines), 1-[(3,4-dichlorophenyl)methyl]-3,7-dimethyl-8-morpholin-4-yl-purine-2,6-dione, was also shown to inhibit the enzyme, with a measured IC50 of 2.5 ± 0.4 μM. Two X-ray structures are presented: one is a complex of the enzyme with the purine analogue alone (2.55-Å resolution), and the other includes the compound together with methionine sulfoximine phosphate, magnesium and phosphate (2.2-Å resolution). The former represents a relaxed, inactive conformation of the enzyme, while the latter is a taut, active one. These structures show that the compound binds at the same position in the nucleotide site, regardless of the conformational state. The ATP-binding site of the human enzyme differs substantially, explaining why it has an ∼ 60-fold lower affinity for this compound than the bacterial GS. As part of this work, we devised a new synthetic procedure for generating l-(SR)-methionine sulfoximine phosphate from l-(SR)-methionine sulfoximine, which will facilitate future investigations of novel GS inhibitors

Structural basis for the inhibition of Mycobacterium tuberculosis glutamine synthetase by novel ATP-competitive inhibitors

Glutamine synthetase (GS, EC 6.3.1.2; also known as γ-glutamyl:ammonia ligase) catalyzes the ATP-dependent condensation of glutamate and ammonia to form glutamine. The enzyme has essential roles in different tissues and species, which have led to its consideration as a drug or an herbicide target. In this article, we describe studies aimed at the discovery of new antimicrobial agents targeting Mycobacterium tuberculosis, the causative pathogen of tuberculosis. A number of distinct classes of GS inhibitors with an IC50 of micromolar value or better were identified via high-throughput screening. A commercially available purine analogue similar to one of the clusters identified (the diketopurines), 1-[(3,4-dichlorophenyl)methyl]-3,7-dimethyl-8-morpholin-4-yl-purine-2,6-dione, was also shown to inhibit the enzyme, with a measured IC50 of 2.5 ± 0.4 μM. Two X-ray structures are presented: one is a complex of the enzyme with the purine analogue alone (2.55-Å resolution), and the other includes the compound together with methionine sulfoximine phosphate, magnesium and phosphate (2.2-Å resolution). The former represents a relaxed, inactive conformation of the enzyme, while the latter is a taut, active one. These structures show that the compound binds at the same position in the nucleotide site, regardless of the conformational state. The ATP-binding site of the human enzyme differs substantially, explaining why it has an ∼ 60-fold lower affinity for this compound than the bacterial GS. As part of this work, we devised a new synthetic procedure for generating l-(SR)-methionine sulfoximine phosphate from l-(SR)-methionine sulfoximine, which will facilitate future investigations of novel GS inhibitors

Trisubstituted Imidazoles as Mycobacterium tuberculosis Glutamine Synthetase Inhibitors

Mycobacterium tuberculosis glutamine synthetase (MtGS) is a promising target for antituberculosis drug discovery. In a recent high-throughput screening study we identified several classes of MtGS inhibitors targeting the ATP-binding site. We now explore one of these classes, the 2-tert-butyl-4,5-diarylimidazoles, and present the design, synthesis, and X-ray crystallographic studies leading to the identification of MtGS inhibitors with submicromolar IC(50) values and promising antituberculosis MIC values

Poetically coded individual experience of artist in Taras Shevchenko’s «Fate. Muse. Glory»

(uk) У статті йдеться про основні аспекти шевченкознавчих досліджень стосовно триптиху «Доля. Муза. Слава». Висвітлено особливості літературознавчого осмислення лейтмотиву митця в межах художнього світу Кобзаря. З’ясовано, що авторське самозображення презентоване постатями «сіроми», зосередженого на своїй життєвій незреалізованості, та «Я-митця», що переймається виключно творчою самореалізацією. Обґрунтовано самооцінку автора з позиції статусу в суспільстві, творчої зреалізованості, повноти богемного життя. Дійшли висновку, що поетично закодовані авторські самоочікування передають сподівання досягти певного життєвого і творчого успіху, настирливе прагнення бути володарем вічного натхнення, впливати на духовну ауру суспільства. У результаті розкодування, систематизації та узагальнення індивідуального досвіду автора в триптиху «Доля. Муза. Слава» було увиразнено мотив митця і мистецтва в поетичній спадщині Шевченка останніх років творчості, а також висвітлено окремі штрихи презентованого в ній образу автора.(en) Speech the question is in the article about the basic aspects of Shevchenko researches concerning to the triptych «Fate. Muse. Glory». Highlighted features of the literary interpretation of the motif of the artist within the art world poet. The expediency of application of the triptych «Fate. Muse. Glory» of Taras Shevchenko concept of an integrated approach to the image of the author: need a proper generalization and systematization of disparate efforts of researchers; the need for a concept or methodology, which will represent a systematic approach to the theme of the artist and art in a separate text in the whole heritage of the poet. Defined the concept of a comprehensive analysis of the image of the author that involves the study of using linguistic, literary, psychological tools artistically expressed the author' s individual picture of the world: vision, comprehension, attitude to the environment and to their own «I» in it (interdependent images of the external and internal worlds). Focus on the main aim of this article is to explore the triptych «Fate. Muse. Glory» of Taras Shevchenko in accordance with the «self-concept » poetically expressed system presentation author (the image itself, score yourself, expectations of yourself) as evidence acquired and the expected life experience. Found that the author the image itself presents figures «poor», focused on his failure to, and I am the artist that deals exclusively with creative self-realization. I n the process of determining the mental state and sensual palette of the above images focused on the features artistically Express author: emotion, sensitiveness, the sincerity, the unique existential readiness for self-improvement. Reasonably score yourself of the author from a position of status in society, creative treats, completeness Bohemian life. It is noted that the shape «poor» adds new nuances based Shevchenko back in the early works of folklore and romantic image, «I am miserable orphan-slave in a foreign land». Came to the conclusion that poetically encoded copyright expectations of yourself convey hope to achieve a certain life and creative success, persistent desire to be the owner of eternal inspiration, influence of the spiritual aura of the society. In the decoding, systematization and generalization of the personal experience of the author in the triptych «Fate. Muse. Glory» was expressive motive of the artist and art in poetic heritage Shevchenko last years of creativity as well as highlights some finishing touches presented in her image of the author

Design, Synthesis, and X-ray Crystallographic Studies of alpha-Aryl Substituted Fosmidomycin Analogues as Inhibitors of Mycobacterium tuberculosis 1-Deoxy-D-xylulose 5-Phosphate Reductoisomerase

The natural antibiotic fosmidomycin acts via inhibition of 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR), an essential enzyme in the non-mevalonate pathway of isoprenoid biosynthesis. Fosmidomycin is active on Mycobacterium tuberculosis DXR (MtDXR), but it lacks antibacterial activity probably because of poor uptake. alpha-Aryl substituted fosmidomycin analogues have more favorable physicochemical properties and are also more active in inhibiting malaria parasite growth. We have solved crystal structures of MtDXR in complex with 3,4-dichlorophenyl substituted fosmidomycin analogues; these show important differences compared to our previously described forsmidomycin-DXR complex. Our best inhibitor has an IC(50) = 0.15 mu M on MtDXR but still lacked activity in a mycobacterial growth assay (MIC > 32 mu g/mL). The combined results, however, provide insights into how DXR accommodates the new inhibitors and serve as an excellent starting point for the design of other novel and more potent inhibitors, particularly against pathogens where uptake is less of a problem, such as the malaria parasite

DXR Inhibition by Potent Mono- and Disubstituted Fosmidomycin Analogues

The antimalarial compound fosmidomycin targets DXR, the enzyme that catalyzes the first committed step in the MEP pathway producing the universally essential isoprenoid precursors, isopentenyl diphosphate and dimethylallyl diphosphate. The MEP pathway is used by a number of pathogens, including Mycobacterium tuberculosis and apicomplexan parasites, and differs from the classical mevalonate pathway that is essential in humans. Using a structure-based approach, we designed a number of analogues of fosmidomycin, including a series that are substituted in both the Cα and the hydroxamate positions. The latter proved to be a stable framework for the design of inhibitors that extend from the cramped substrate-binding site and can, for the first time, bridge the substrate and cofactor binding sites. A number of these compounds are more potent than fosmidomycin in terms of killing Plasmodium falciparum in an in vitro assay; the best has an IC50 of 40 nM.De tre (3) första författarna delar förstaförfattarskapet.</p

Trisubstituted Imidazoles as <i>Mycobacterium tuberculosis</i> Glutamine Synthetase Inhibitors

<i>Mycobacterium tuberculosis</i> glutamine synthetase (<i>Mt</i>GS) is a promising target for antituberculosis drug discovery. In a recent high-throughput screening study we identified several classes of <i>Mt</i>GS inhibitors targeting the ATP-binding site. We now explore one of these classes, the 2-<i>tert</i>-butyl-4,5-diarylimidazoles, and present the design, synthesis, and X-ray crystallographic studies leading to the identification of <i>Mt</i>GS inhibitors with submicromolar IC₅₀ values and promising antituberculosis MIC values

DXR Inhibition by Potent Mono- and Disubstituted Fosmidomycin Analogues

The antimalarial compound fosmidomycin targets DXR, the enzyme that catalyzes the first committed step in the MEP pathway, producing the essential isoprenoid precursors, isopentenyl diphosphate and dimethylallyl diphosphate. The MEP pathway is used by a number of pathogens, including Mycobacterium tuberculosis and apicomplexan parasites, and differs from the classical mevalonate pathway that is essential in humans. Using a structure-based approach, we designed a number of analogues of fosmidomycin, including a series that are substituted in both the Cα and the hydroxamate positions. The latter proved to be a stable framework for the design of inhibitors that extend from the polar and cramped (and so not easily druggable) substrate-binding site and can, for the first time, bridge the substrate and cofactor binding sites. A number of these compounds are more potent than fosmidomycin in terms of killing Plasmodium falciparum in an in vitro assay; the best has an IC₅₀ of 40 nM