Current Chemical Biology - Volume 5, Issue 1, 2011

The aim of this study was the introduction of an artificial copper center at the surface of carbonic anhydrase II (CA II) which subsequently might be used by azide and alkyne building blocks to catalyze triazole formation following 2+3 dipolar cycloaddition. Several mutants were produced to introduce favorable copper coordinating residues taking model copper-proteins from nature as reference templates. Unfortunately, the embarked rational design strategy remained unsuccessful which underlines that our still rather limited understanding of amino acid exchanges on the architecture of proteins might provoke unpredictable effects while tampering with complex biological systems such as a highly functionalized proteins. Finally, more by serendipity than design the formation of an artificial Cu center at the surface of CA II could be achieved. The metal ion is coordinated by two histidines and a serine residue in square planar coordination geometry.

Dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEAS) and tetrahydrocortisol (THC) with apolipoprotein A-I form the biologically active complexes able to interact specifically with eukaryotic DNA. This conjugate is highly cooperative and results in local splitting of DNA. Specific binding sites of steroid-apoA-I complexes are the (GCC/GGC)n sequences. At the sites of splitting, single-stranded regions sensitized to the action of S1-nuclease form. These regions are irregularly distributed over DNA. The formation of single-stranded DNA regions can promote the interaction with RNA-polymerase. Formation of the biologically active THC (DHEA)-apoA-I complexes is related with resident macrophages having 5α- and 5 β-reductase activity. These complexes greatly enhance the rate of protein biosynthesis in hepatocytes. The cortisol-apoA-I complex does not show such effect. So, the reduced forms of fascicular zone and reticular cortex adrenal zone hormones have synergism of action toward gene expression and protein biosynthesis. The intensification of tissues regeneration during the stress period as a result of given mechanism is discussed.

The mechanism used by proteins to maintain their thermostability throughout a wide range of temperature has been extensively investigated. Different aspects have been reported which explain protein thermal stability such as protein flexibility, loops length, number of charged residues, hydrophobic and ionic interactions, electrostatic interactions and their pathways, number and dimension of internal cavities. All these features have an effect on the protein global structure, but they are not the unique mechanism which explains the protein thermal stability. The molecular mechanisms of adaptation to the environment of an organism are reflected on different levels, with regards to DNA, genes and proteins expression, which are intrinsically adapted to the particular physical/chemical state. Amino acid composition is strictly related to environmental adaptation and, in this review, we present an up to date overview on thermal adaptation of esterases and lipases belonging to the HSL family. In particular, we discuss results obtained by different analyses on these enzymes and we re-analyze them from a statistical standpoint.

Chlamydial interactions with host cells rely on chlamydia-secreted proteins, including preexisting and newly synthesized proteins. The preexisting proteins released from EBs participate in both chlamydial entry and intracellular survival at the early stage while the newly synthesized proteins secreted from RBs can both manipulate host cell signaling pathways and promote chlamydial reinfection. Despite the significant progresses made in the past decade, the precise mechanisms on what and how chlamydia-secreted proteins interact with host cells remain largely unknown, and will therefore still represent major research directions of the chlamydial field in the foreseeable future. Development of more effective methodologies will aid in discovery of new secretion molecules and novel mechanisms utilized in chlamydial interactions with host cells. The continuing accumulation of knowledge on chlamydia-secreted proteins and their mechanism of action may lead to discovery of novel prevention and therapeutic reagents for preventing and controlling chlamydial infection and pathologies.

BCL-2 protein controls the intrinsic pathway of apoptosis and plays a crucial role in governing apoptotic cell death. It regulates mitochondrial outer membrane permeability, leading to the initiation of Caspase cascade. Till date there are 25 genes known to be the members of BCL-2 family. Some of them are pro-apoptotic and some are anti-apoptotic. Over expression of anti-apoptotic BCL-2 proteins has been observed in 80% of beta cell lymphomas and 90% of colorectal adenocarcinomas. Hence, BCL-2 proteins are valuable targets in designing anti-cancer agents. Peptides, Peptidomimetics and non-peptide antagonists are designed to trigger apoptosis by BCL-2 pathway. These drugs have exhibited promising results at pre-clinical and clinical levels. It is well known that apoptosis is also related to inflammatory responses; it will be interesting to explore the area of BCL-2 to design some drugs having anti-inflammatory action. This review gives an account of development of BCL-2 family of proteins as potential target in the varieties of diseases including special focus on cancer.

Signal transducer and activator of transcription 3 (STAT3) is a transcriptional factor and has been implicated in cell proliferation, survival and differentiation. Recent studies demonstrate that STAT3 activity is persistently elevated in patients with some chronic disorders, and required for the development and progression of fibrosis in a variety of tissues including kidney, bone marrow and skin. On the other hand, STAT3 is implicated in tissue protection against fibrosis in the heart following acute injury. Moreover, STAT3 can either promote or protect against tissue fibrosis in chronic liver disease models, depending on etiologies. The underlying mechanisms by which STAT3 mediates those cellular events are not fully understood, but the profibrotic action of STAT3 is mostly associated with activation and proliferation of fibroblasts, deposition of excessive extracellular matrix proteins, and overproduction of some cytokines. In this review article, we discuss the role of STAT3 in tissue fibrosis and the effect of the STAT3 pathway inhibition on the proliferation and activation of fibroblasts in vitro and fibrogenesis in various animal models.

Tuberculosis and some other mycobacterial infections remain a tremendous threat to mankind. Pathogenic mycobacteria are able to survive within the hosts even for years, and a chemical and biological basis for their adaptation mechanisms is now beginning to be unraveled. The lipid-rich cell wall of mycobacteria contains structurally diverse glycolipids that comprise the outermost layer and interact directly with the environments. Recent studies have revealed that production of these surface-exposed glycolipids is mediated by enzymes utilized typically for biosynthesis of secondary metabolites. As for defined secondary metabolites in plants, bacteria and fungi that are often produced in response to environmental stresses and play a critical role in protection from their enemies, production of these cell wall glycolipids is influenced significantly by external factors to which mycobacteria are exposed. Identification of lipidic secondary metabolites in mycobacteria and elucidation of their biosynthetic pathways and biological functions now provide a clue to how mycobacteria have evolved to survive and grow both in host tissues as well as in natural environments. Further, what is learned from these studies is of important medical implications, including the development of a novel type of vaccines and therapeutic agents against human mycobacterial infections.

Plant cytosolic glutathione transferases (GSTs) are an ancient enzyme superfamily with multiple and diverse functions which are important in counteracting biotic and abiotic stresses. GSTs play an important role in catalyzing the conjugation of xenobiotics and endogenous electrophilic compounds with glutathione (GSH), such as pesticides, chemical carcinogens, environmental pollutants, which leads to their detoxification. GSTs not only catalyze detoxification reactions but they are also involved in GSH-dependent isomerization reactions, in GSH-dependent reduction of organic hydroperoxides formed during oxidative stress, biosynthesis of sulfur-containing secondary metabolites, and exhibit thioltransferase and dehydroascorbate reductase activity. This review focuses on plant GSTs, and attempts to give an overview of the new insights into the catalytic function and structural biology of these enzymes.