Structural Basis for Substrate Specificity in Human Monomeric Carbonyl Reductases

Carbonyl reduction constitutes a phase I reaction for many xenobiotics and is carried out in mammals mainly by members of two protein families, namely aldo-keto reductases and short-chain dehydrogenases/reductases. In addition to their capacity to reduce xenobiotics, several of the enzymes act on endogenous compounds such as steroids or eicosanoids. One of the major carbonyl reducing enzymes found in humans is carbonyl reductase 1 (CBR1) with a very broad substrate spectrum. A paralog, carbonyl reductase 3 (CBR3) has about 70% sequence identity and has not been sufficiently characterized to date. Screening of a focused xenobiotic compound library revealed that CBR3 has narrower substrate specificity and acts on several orthoquinones, as well as isatin or the anticancer drug oracin. To further investigate structure-activity relationships between these enzymes we crystallized CBR3, performed substrate docking, site-directed mutagenesis and compared its kinetic features to CBR1. Despite high sequence similarities, the active sites differ in shape and surface properties. The data reveal that the differences in substrate specificity are largely due to a short segment of a substrate binding loop comprising critical residues Trp229/Pro230, Ala235/Asp236 as well as part of the active site formed by Met141/Gln142 in CBR1 and CBR3, respectively. The data suggest a minor role in xenobiotic metabolism for CBR3. ENHANCED VERSION: This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1

Performance characteristics of the PAW instrumentation on Beagle 2 (the astrobiology lander on ESA's Mars Express Mission)

The performance of the PAW instrumentation on the 60kg Beagle 2 lander for ESA’s 2003 Mars Express mission will be described. Beagle 2 will search for organic material on and below the surface of Mars in addition to a study of the inorganic chemistry and mineralogy of the landing site. The lander will utilize acquisition and preparation tools to obtain samples from below the surface, and both under and inside rocks. In situ analysis will include examination of samples with an optical microscope, Mossbauer and fluorescent X-ray spectrometers. Extracted samples will be returned to the lander for analysis, in particular a search for organics and a measurement of their isotopic composition. The PAW experiment performance data will be described along with the status of the project

Corruption and Related Socioeconomic Factors: A Time Series Study

This study examines corruption in relation to political, legal, and economic factors to see how these factors impact corruption over time and to test the direction of causality between these variables. To assess causality, cointegration analysis using an error correction model on data from over 100 countries spanning over 20 years was performed. Three antecedent variables are analyzed in relation to corruption. Over the long-term, increases in these variables result in decreases in corruption. However, there is no evidence that changes in corruption impact any of these same variables. Interestingly, increases in GDP per capita are found to increase corruption over the short-term while leading to a long-term reduction in corruption. Copyright 2007 Blackwell Publishing Ltd..