Understanding allostery in enzymes and tools to identify it, offer promising alternative strategies to inhibitor development. Through a combination of equilibrium and nonequilibrium molecular dynamics simulations, we identify allosteric effects and communication pathways in two prototypical class A β-lactamases, TEM-1 and KPC-2, which are important determinants of antibiotic resistance. The nonequilibrium simulations reveal pathways of communication operating over distances of 30 Å or more. Propagation of the signal occurs through cooperative coupling of loop dynamics. Notably, 50% or more of clinically relevant amino acid substitutions map onto the identified signal transduction pathways. This suggests that clinically important variation may affect, or be driven by, differences in allosteric behavior, providing a mechanism by which amino acid substitutions may affect the relationship between spectrum of activity, catalytic turnover and potential allosteric behavior in this clinically important enzyme family. Simulations of the type presented here will help in identifying and analyzing such differences.

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Curcumin (1) is a secondary metabolite of turmeric, derived from Curcuma longa L. and was shown to have many biological activities. One of the most interesting properties of curcumin (1) is the antitumour activity allied with the ability to act as a multidrug resistance (MDR) modulator. Several curcumin derivatives have been synthesized with the purpose of discovering more information about the mechanisms of action, to establish structure-activity relationships (SAR), and to overcome pharmacokinetic problems. Over the past few decades, more potent and more stable curcumin derivatives have emerged with potential as drug candidates. Some important SAR studies pointed out that the unstable α,β-unsaturated diketone linker present in curcumin (1) may not be necessary for the antitumour activity; generally, shorter linkers result in more potent compounds than curcumin (1); the type of substituents and their substitution pattern are crucial regarding the biological activities of interest. Overall, the structure of curcumin (1) may represent an important basis for the development of more effective therapeutic agents, particularly in chemotherapy, as reflected by ongoing clinical trials. This article aims to review the synthesis and biological activities of curcumin (1) and derivatives, highlighting the MDR modulation properties of curcumin (1), since these effects makes this natural product a promising lead compound for the development of new anticancer drugs.

Within the framework of the circular economy, there is a need for waste management alternatives that promote the reuse of materials produced in wastewater treatment plants (WWTP). An interesting option is the recovery of extracellular substances from sludge. The variability of characteristics of potential recovered bioproducts has to be assessed in full scale operational settings. In this study, aerobic granular sludge (AGS) from a full-scale WWTP treating urban wastewater was regularly collected for 4 months to assess variability in extracellular polymeric substances (EPS) composition and in granular morphology. Variations in the EPS composition occurred with time. Proteins and humic substances were the main EPS components (329-494 and 259−316 mg/g VSS of AGS, respectively), with polysaccharides and DNA representing minor components. The application of an extra purification step after extraction to obtain a purer EPS led to a decrease in the yield of each EPS component, particularly pronounced for the polysaccharides. The final product had a rather constant composition for the monthly samples. The granules showed morphological stability throughout the sampling period and the yield of EPS was correlated to the size of the granules, higher when there was a higher content of small granules (Deq < 150 μm) comparing to intermediate (150 ≤ Deq < 1500 μm) or large granules (Deq≥1500 μm). This is the first time that a potential valorization strategy for surplus AGS biomass is studied in a full-scale environment. Knowledge on yield and product homogeneity is important as these features are essential for downstream application of the recovered EPS. the conventional activated sludge systems. This is related to lower investment costs (10-30 %), around 30 % savings in energy consumption and ca. 70 % less space needed [2]. AGS is considered a special case of suspended biofilms in which self-immobilized microorganisms form spherical sludge aggregates. Microorganisms are embedded in a selfproduced extracellular polymeric substances (EPS) matrix thus avoiding the need for any carrier [3][4][5]. The formation of AGS can be accomplished using sequencing batch reactors (SBR), alternating between aerobic and anaerobic periods [6]. Interesting properties, such as high biomass retention, settling properties (increasing the amount of water that can be treated in a certain period), tolerance to chemical toxicity, high biosorption capacity, ability to remove organic carbon, nitrogen and phosphorus simultaneously, make this technology increasingly attractive over the conventional activated sludge systems

Allosteric effects control protein (e.g. enzyme) activity in ways that are not fully understood. Better understanding of allosteric effects, and tools to identify them, would offer promising alternative strategies to inhibitor development. Through a combination of equilibrium and nonequilibrium molecular dynamics simulations, we identify allosteric effects and communication pathways from two distant ligand binding sites to important active site structural elements that control enzymatic activity in two prototypical class A β-lactamases, TEM-1 and KPC-2. Both of these enzymes are important determinants of antibiotic resistance in widespread bacterial pathogens. The simulations show that the allosteric sites are connected to the active site in both enzymes, (e.g. affecting the conformation of the Ω-loop) highlighting how allosteric inhibitors may exert their effects. Nonequilibrium simulations reveal pathways of communication operating over distances of 30 Å or more. In these identified signaling pathways, the propagation of the signal occurs through cooperative coupling of loop dynamics. Notably, 50% or more clinically relevant amino acid substitutions in each enzyme map onto the identified signal transduction pathways. This suggests that clinically important variation may affect, or be driven by, differences in allosteric behavior, providing a mechanism by which amino acid substitutions may affect the relationship between spectrum of activity, catalytic turnover and potential allosteric behavior in this clinically important enzyme family. Simulations of the type presented here will help in identifying and analyzing such differences.