Stereochemical and steric control of enzymatic glucuronidation : A rational approach for the design of novel Inhibitors for the human UDP-glucuronosyltransferase 2B7

The UDP-glucuronosyltransferases (UGTs) are enzymes of the phase II metabolic system. These enzymes catalyze the transfer of α-D-glucuronic acid from UDP-glucuronic acid to aglycones bearing nucleophilic groups affording exclusively their corresponding β-D-glucuronides to render lipophilic endobiotics and xenobiotics more water soluble. This detoxification pathway aids in the urinary and biliary excretion of lipophilic compounds thus preventing their accumulation to harmful levels. The aim of this study was to investigate the effect of stereochemical and steric features of substrates on the glucuronidation catalyzed by UGTs 2B7 and 2B17. Furthermore, this study relates to the design and synthesis of novel, selective inhibitors that display high affinity for the key enzyme involved in drug glucuronidation, UGT2B7. The starting point for the development of inhibitors was to assess the influence of the stereochemistry of substrates on the UGT-catalyzed glucuronidation reaction. A set of 28 enantiomerically pure alcohols was subjected to glucuronidation assays employing the human UGT isoforms 2B7 and 2B17. Both UGT enzymes displayed high stereoselectivity, favoring the glucuronidation of the (R)-enantiomers over their respective mirror-image compounds. The spatial arrangement of the hydroxy group of the substrate determined the rate of the UGT-catalyzed reaction. However, the affinity of the enantiomeric substrates to the enzymes was not significantly influenced by the spatial orientation of the nucleophilic hydroxy group. Based on these results, a rational approach for the design of inhibitors was developed by addressing the stereochemical features of substrate molecules. Further studies showed that the rate of the enzymatic glucuronidation of substrates was also highly dependent on the steric demand in vicinity of the nucleophilic hydroxy group. These findings provided a rational approach to turn high-affinity substrates into true UGT inhibitors by addressing stereochemical and steric features of substrate molecules. The tricyclic sesquiterpenols longifolol and isolongifolol were identified as high-affinity substrates which displayed high selectivity for the UGT isoform 2B7. These compounds served therefore as lead structures for the design of potent and selective inhibitors for UGT2B7. Selective and potent inhibitors were prepared by synthetically modifying the lead compounds longifolol and isolongifolol taking stereochemical and steric features into account. The best inhibitor of UGT2B7, β-phenyllongifolol, displayed an inhibition constant of 0.91 nM.no abstract availabl

Full Electric Helicopter Anti-Torque

On the way to complete electric flight, the electrification of helicopter subsystems is an essential milestone. This paper discusses the design of an electric helicopter anti-torque system, which uses Kopter's AW09 helicopter as a platform and shall be tested in ground tests. Analysis of state of the art anti-torque devices for helicopters has helped to identify concepts, which are suitable to be combined with electric propulsion and actuation. Engineering models are used to estimate the power benefits of varied tail rotor RPM, enlarged and steerable vertical stabilizers and drag reducing devices, which cover the rotor in forward flight. In connection with operational benefits viewed from the OEMs perspective, an architecture is proposed which consists of an electric driven shrouded tail rotor, an electric pitch actuation system and additional aerodynamic surfaces, like a steerable vertical stabilizer and a drag optimized tail rotor cover. The systems were developed according to the results of a safety analysis to meet the requirements of CS-27. The electric tail rotor drive is designed with an internal level of redundancy that allows to compensate for subsystem failures

Parken 2025 : die Entwicklung der Parkraumbewirtschaftung und das Potential der Sonderimmobilie: Garage

Der Immobilienmarkt boomt und es werden jährlich viele Milliarden in diese Assetklassen investiert. Jedes Vermögen veranlagt seine Werte zu einem Großteil in Immobilien und die letzten Jahre haben gezeigt, dass auf Grund der steigenden Immobilienpreise diese Vermögen ebenfalls stetig wachsen. Sowie Wohnraum ist auch Parkraum ein knappes Gut welches auf Grund von steigenden Bevölkerungszahlen, der generellen höheren Lebenserwartung, durch die Verjüngung der älteren Generationen und durch das Wachstum des Fahrzeugbestandes, wird es in diesem Segment immer einen Nachfrage geben. Das Investmentobjekt Parkhaus ist bereit für viele Anleger interessant geworden allerdings kommen solche Objekt äußerst selten auf den Markt. Die gesteigerte Mobilität der Bevölkerung erfordert auch ein gesteigertes Bewusstsein für organisiertes Parkverhalten. Diese Arbeit stellt die Entstehungsgeschichte und die aktuelle Parkraumbewirtschaftung sowie die Sonderimmobilie: Garage in all ihren Facetten dar und analysiert die unterschiedlichen Immobilien- und Nutzungsarten. Es wird ein Überblick über die Parkraumsituation verschafft und auf bereits umgesetzte Lösungsansätze und deren Ergebnisse eingegangen. Die Maßnahmen der letzten Jahrzehnte die für einen geregelten und geordneten ruhenden Verkehr sorgen, haben längst einen Beitrag zu Verbesserung der Verkehrssituation geleistet. Ohne diesen, wäre es in Ballungszentren längst zu einem Verkehrsinfarkt gekommen. Die Manifestierung der Parkplatzproblematik bei Stadt- und Immobilienentwicklung war ein wichtiger Schritt für die Weiterentwicklung unserer Städte und Gesellschaft und trägt zu einem gesteigerten Umweltbewusst sein bei.5

Gemeente Molenort

Design of a cohousing project based on partially existing structure of a former 50ies shopping mall. The existing structure is evaluated and freely approached with the open mindset of the bricoleur. The bricoleur as defined by Claude Levi Strauss works with the existing and uses what is at hand. The result is the formation of a new urban neighbourhood on the site of the former Molenpoort in Nijmegen.Architecture, Urbanism and Building Sciences | Building Technolog

First molecular barcoding and record of the Indo Pacific punctuated flatworm Maritigrella fuscopunctata (Newman & Cannon 2000), (Polycladida : Euryleptidae) from the Mediterranean Sea

A first record of the punctuated flatworm Maritigrella fuscopunctata (Newman & Cannon 2000) from Maltese waters in the Mediterranean Sea during marine research surveys in summer 2015 is reported in detail. This platyhelminth species is alien to the Mediterranean, as it is native to the Indo Pacific region. The abundance of this non indigenous flatworm was observed to be highest in Exiles Bay followed by Spinola Bay (St. Julians) and St. George’s Bay with a few others found elsewhere along the North eastern coast of Malta between the Valletta Harbour and St. George’s Bay. A sample of these specimens observed were photographed and measured (n=40). A few (n=5) were collected to undertake a first molecular barcode for this euryleptid flatworm Total body length of the specimens observed in the field varied from 20 to 6 0 mm . Observations in the field indicate that a growing population has been established especially in the presence of the colonial ascidian Ecteinascidia turbinata , found among the various fouling organisms Molecular genetics of euryleptid flatworm species is still scarce and was missing for this species. The present study also contributed toward filling this gap.peer-reviewe

First molecular barcoding and record of the Indo-Pacific punctuated flatworm Maritigrella fuscopunctata (Newman & Cannon 2000), (Polycladida: Euryleptidae) from the Mediterranean Sea

International audienceA first record of the punctuated flatworm Maritigrella fuscopunctata (Newman & Cannon 2000) from Maltese waters in the Mediterranean Sea during marine research surveys in summer 2015 is reported in detail. This platyhelminth species is alien to the Mediterranean, as it is native to the Indo-Pacific region. The abundance of this non-indigenous flatworm was observed to be highest in Exiles Bay followed by Spinola Bay (St. Julians) and St. George's Bay with a few others found elsewhere along the North eastern coast of Malta between the Valletta Harbour and St. George's Bay. A sample of these specimens observed were photographed and measured (n=40). A few (n=5) were collected to undertake a first molecular barcode for this euryleptid flatworm. Total body length of the specimens observed in the field varied from 20 to 60mm. Observations in the field indicate that a growing population has been established especially in the presence of the colonial ascidian Ecteinascidia turbinata, found among the various fouling organisms. Molecular genetics of euryleptid flatworm species is still scarce and was missing for this species. The present study also contributed toward filling this gap

UDP-glucuronosyltransferases (UGTs) 2B7 and UGT2B17 display converse specificity in testosterone and epitestosterone glucuronidation, whereas UGT2A1 conjugates both androgens similarly. Drug Metab Dispos 37:417–423.

ABSTRACT: Testosterone and epitestosterone are endogenous steroids that differ in the configuration of the hydroxyl-bearing carbon at C-17. Testosterone is the predominant male sex hormone, whereas the role of epitestosterone is largely unclear. In humans, both androgens are excreted mainly as glucuronide conjugates and the urinary ratio of testosterone to epitestosterone (T/E), used to expose illicit testosterone abuse by male athletes, indicates the relative concentrations of the respective glucuronides. Some male athletes have T/E values greater than the accepted threshold value (4.0), even without testosterone abuse. We have analyzed athletes' urine samples and found that the main reason for such false-positive results in doping tests was a low epitestosterone glucuronide concentration not a high level of testosterone glucuronide. Sulfate conjugates of both testosterone and epitestosterone were also detected in the different urine samples. Glucuronidation assays with the 19 human UDP-glucuronosyltransferases (UGTs) of subfamilies UGT1A, UGT2A, and UGT2B revealed that UGT2B17 is the most active enzyme in testosterone glucuronidation. UGT2B17 does not glucuronidate epitestosterone, but inhibition studies revealed that it binds epitestosterone with affinity similar to that of testosterone. Epitestosterone glucuronidation is catalyzed mainly by UGT2B7, and the K m of this reaction is significantly lower than the K m of UGT2B17 for testosterone. Although UGT2B7 and UGT2B17 exhibited high, although converse, stereoselectivity in testosterone and epitestosterone glucuronidation, UGT2A1, an extrahepatic enzyme that is expressed mainly in the nasal epithelium, catalyzed the glucuronidation of both steroids at considerable rates and similar kinetics. The results shed new light on the substrate specificity and stereoselectivity of human UGTs