Non-zinc mediated inhibition of carbonic anhydrases: coumarins are a new class of suicide inhibitors.

The X-ray crystal structure of the adduct between the zinc metalloenzyme carbonic anhydrase II (CA, EC 4.2.1.1) with the recently discovered natural product coumarin derivative 6-(1S-hydroxy-3-methylbutyl)-7-methoxy-2H-chromen-2-one showed the coumarin hydrolysis product, a cis-2-hydroxy-cinnamic acid derivative, and not the parent coumarin, bound within the enzyme active site. The bound inhibitor exhibits an extended, two-arm conformation that effectively plugs the entrance to the enzyme active site with no interactions with the catalytically crucial zinc ion. The inhibitor is sandwiched between Phe131, with which it makes an edge-to-face stacking, and Asn67/Glu238sym, with which it makes several polar and hydrogen bonding interactions. This unusual binding mode, with no interactions between the inhibitor molecule and the active site metal ion is previously unobserved for this enzyme class and presents a new opportunity for future drug design campaigns to target a mode of inhibition that differs substantially from classical inhibitors such as the clinically used sulfonamides and sulfamates. Several structurally simple coumarin scaffolds were also shown to inhibit all 13 catalytically active mammalian CA isoforms, with inhibition constants ranging from nanomolar to millimolar. The inhibition is time dependent, with maximum inhibition being observed after 6 h.No Full Tex

Phosph(on)ate as a zinc-binding group in metalloenzyme inhibitors: X-ray crystal structure of the antiviral drug foscarnet complexed to human carbonic anhydrase I

Foscarnet (phosphonoformate trisodium salt), an antiviral used for the treatment of HIV and herpes virus infections, also acts as an activator or inhibitor of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Interaction of the drug with 11 CA isozymes has been investigated kinetically, and the X-ray structure of its adduct with isoform I (hCA I-foscarnet complex) has been resolved. The first CA inhibitor possessing a phosphonate zinc-binding group is thus evidenced, together with the factors governing recognition of such small molecules by a metalloenzyme active site. Foscarnet is also a clear-cut example of modulator of an enzyme activity which can act either as an activator or inhibitor of a CA isozyme

Critical assessment of enhancement factor measurements in surface-enhanced raman scattering on different substrates

The SERS enhancement factor (SERS-EF) is one of the most important parameters that characterizes the ability of a given substrate to enhance the Raman signal for SERS applications. The comparison of SERS intensities and SERS-EF values across different substrates is a common practice to unravel the performance of a given substrate. In this study, it is shown that such a comparison may lack significance if we compare substrates of very distinct nature and optical properties. It is specifically shown that the SERS-EF values for static substrates (e.g. immobilized metallic nanostructures) cannot be compared to those of dynamic ones (e.g. colloidal metal nanoparticle solutions), and that the optical properties for the latter show strong dependence on the metal-molecule interaction dynamics. The most representative experimental results concerning the dynamic substrates have been supported by generalized Mie theory simulations, which are tools used to describe the substrate complexity and the microscopic information not usually taken into account17332129421301CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE MINAS GERAIS - FAPEMIGFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPES

Converting simulated total dry matter to fresh marketable yield for field vegetables at a range of nitrogen supply levels

Simultaneous analysis of economic and environmental performance of horticultural crop production requires qualified assumptions on the effect of management options, and particularly of nitrogen (N) fertilisation, on the net returns of the farm. Dynamic soil-plant-environment simulation models for agro-ecosystems are frequently applied to predict crop yield, generally as dry matter per area, and the environmental impact of production. Economic analysis requires conversion of yields to fresh marketable weight, which is not easy to calculate for vegetables, since different species have different properties and special market requirements. Furthermore, the marketable part of many vegetables is dependent on N availability during growth, which may lead to complete crop failure under sub-optimal N supply in tightly calculated N fertiliser regimes or low-input systems. In this paper we present two methods for converting simulated total dry matter to marketable fresh matter yield for various vegetables and European growth conditions, taking into consideration the effect of N supply: (i) a regression based function for vegetables sold as bulk or bunching ware and (ii) a population approach for piecewise sold row crops. For both methods, to be used in the context of a dynamic simulation model, parameter values were compiled from a literature survey. Implemented in such a model, both algorithms were tested against experimental field data, yielding an Index of Agreement of 0.80 for the regression strategy and 0.90 for the population strategy. Furthermore, the population strategy was capable of reflecting rather well the effect of crop spacing on yield and the effect of N supply on product grading

Theoretical studies of Mefenamic Acid Polymorphs: Solid-state 13C carbon-NMR and vibrational (IR and Raman) Spectroscopies.

The two polymorphs of mefenamic acid (MEF) or 2-[(2,3-(dimethyphenyl)amino] benzoic acid polymorphs (known as I and II forms) were studies in the framkework of density functional theory (DFT). The DFT calculations were performed using the Gaussian03 package and these results were compared with experimental data of solid-state 13C Nuclear Magnetic Resonance (NMR), vibrational Raman and infrared spectroscopies.CAPESCNPqFAPES

O comportamento do consumidor de vinho no mercado português

A presente investigação resultou da necessidade de perceber as razões que motivam e que eventualmente poderão condicionar a frequência de consumo de vinho em Portugal. Deste modo, o principal objetivo deste trabalho é compreender as motivações de compra e consumo, dependendo da situação de uso e de caraterísticas pessoais. A literatura existente sobre as motivações de consumo de vinho salienta a existência de efeitos diretos sobre as motivações do género do comprador e da ocasião de consumo. Este estudo introduz uma formulação alternativa destes efeitos, considerando-os indiretos, i.e. completamente mediados pelo conhecimento subjetivo do comprador e pelas emoções que ele associa ao respetivo consumo. Foram desenvolvidos dois modelos, um para explicar as motivações, outro a frequência de consumo, os quais foram posteriormente validados numa amostra de 523 compradores entrevistados no momento da compra em grandes superfícies retalhistas da Grande Lisboa e do Grande Porto. Os resultados apresentados no primeiro modelo apontam para a rejeição dos efeitos diretos, sendo o conhecimento subjetivo o mediador mais importante. Sugere-se que a autoconfiança e a eficácia na decisão, que aparecem associadas ao conhecimento subjetivo, justifiquem que os homens se sintam mais motivados para o consumo. Este efeito positivo do conhecimento na motivação é ainda mais importante nas ocasiões regulares. No segundo modelo, verificou-se que a frequência de consumo é explicada predominantemente pela motivação por gratificação sensorial e, também, pela ocasião de consumo no contexto de refeição normal (efetuada no dia-a-dia). O conhecimento subjetivo revelou-se também como elemento fundamental no comportamento do consumidor, quer pela sua influência sobre as motivações, quer pela sua influência sobre a frequência de consumo. As conclusões retiradas desta investigação salientam a importância do conhecimento subjetivo no consumo de vinho. Realçam também que os efeitos de fatores como o género e a ocasião sobre as motivações para consumir vinho, reportados na literatura, poderão dever-se a mediadores de ordem psicográfica, como o conhecimento subjetivo. Esta conclusão tem implicações no marketing de vinhos para compradores regulares, nomeadamente pelo reconhecimento da necessidade de reforçar a perceção de confiança e de eficácia de decisão que costumam ser associadas aos elevados níveis de conhecimento percebido numa categoria de produto