Biochemical Processes In Cells Research Articles

The Aurora kinase inhibitors in cancer research and therapy.

Compounds that affect enzymatic function of kinases are valuable for the understanding of the complex biochemical processes in cells. Aurora kinases (AURKs) play a key role in the control of the mitosis. These kinases are frequently deregulated in different human cancers: overexpression, amplifications, translocations and deletions were reported in many cancer cell lines as well as patient tissues. These findings steered a rigorous hunt for small-molecule AURK inhibitors not only for research purposes as well as for therapeutic uses. In this review, we describe a number of AURK inhibitors and their use in cancer research and/or therapy. We hope to assist researchers and clinicians in deciding which inhibitor is most appropriate for their specific purpose. The review will also provide a broad overview of the clinical studies performed with some of these inhibitors (if such studies have been performed).

Computational analysis of the roles of biochemical reactions in anomalous diffusion dynamics**Project supported by the Thailand Research Fund and Mahidol University (Grant No. TRG5880157), the Thailand Center of Excellence in Physics (ThEP), CHE, Thailand, and the Development Promotion of Science and Technology.

Most biochemical processes in cells are usually modeled by reaction–diffusion (RD) equations. In these RD models, the diffusive process is assumed to be Gaussian. However, a growing number of studies have noted that intracellular diffusion is anomalous at some or all times, which may result from a crowded environment and chemical kinetics. This work aims to computationally study the effects of chemical reactions on the diffusive dynamics of RD systems by using both stochastic and deterministic algorithms. Numerical method to estimate the mean-square displacement (MSD) from a deterministic algorithm is also investigated. Our computational results show that anomalous diffusion can be solely due to chemical reactions. The chemical reactions alone can cause anomalous sub-diffusion in the RD system at some or all times. The time-dependent anomalous diffusion exponent is found to depend on many parameters, including chemical reaction rates, reaction orders, and chemical concentrations.

Dynamics of elongation factor 2 kinase regulation in cortical neurons in response to synaptic activity.

The rapid regulation of cell signaling in response to calcium in neurons is essential for real-time processing of large amounts of information in the brain. A vital regulatory component, and one of the most energy-intensive biochemical processes in cells, is the elongation phase of mRNA translation, which is controlled by the Ca(2+)/CaM-dependent elongation factor 2 kinase (eEF2K). However, little is known about the dynamics of eEF2K regulation in neurons despite its established role in learning and synaptic plasticity. To explore eEF2K dynamics in depth, we stimulated synaptic activity in mouse primary cortical neurons. We find that synaptic activity results in a rapid, but transient, increase in eEF2K activity that is regulated by a combination of AMPA and NMDA-type glutamate receptors and the mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin complex 1 (mTORC1) pathways. We then used computational modeling to test the hypothesis that considering Ca(2+)-coordinated MEK/ERK, mTORC1, and eEF2k activation is sufficient to describe the observed eEF2K dynamics. Although such a model could partially fit the empirical findings, it also suggested that a crucial positive regulator of eEF2K was also necessary. Through additional modeling and empirical evidence, we demonstrate that AMP kinase (AMPK) is also an important regulator of synaptic activity-driven eEF2K dynamics in neurons. Our combined modeling and experimental findings provide the first evidence that it is necessary to consider the combined interactions of Ca(2+) with MEK/ERK, mTORC1, and AMPK to adequately explain eEF2K regulation in neurons.

Building Bio‐Inspired Artificial Functional Nanochannels: From Symmetric to Asymmetric Modification

Over millions of years, complex processes of intelligent control have evolved in nature. Learning from nature is a continuing theme in the development of smart materials and intelligent systems. For example, biological nanochannels, which are typically ion channels, play a very important role in basic biochemical processes in cells. Inspired by ion channels, in which the components are asymmetrically distributed between the membrane surfaces, the generation of biomimetic smart nanochannels is a broad and varied scientific research field. The design and development of new biomimetic channels includes the use of different shapes of channels, different stimuli-responsive molecules, and different symmetric/asymmetric modification methods. In this Minireview, we summarize recent developments in building functional nanochannels by applying various symmetric and asymmetric modifications.

Channelpedia: An Integrative and Interactive Database for Ion Channels

Ion channels are membrane proteins that selectively conduct ions across the cell membrane. The flux of ions through ion channels drives electrical and biochemical processes in cells and plays a critical role in shaping the electrical properties of neurons. During the past three decades, extensive research has been carried out to characterize the molecular, structural, and biophysical properties of ion channels. This research has begun to elucidate the role of ion channels in neuronal function and has subsequently led to the development of computational models of ion channel function. Although there have been substantial efforts to consolidate these findings into easily accessible and coherent online resources, a single comprehensive resource is still lacking. The success of these initiatives has been hindered by the sheer diversity of approaches and the variety in data formats. Here, we present “Channelpedia” (http://channelpedia.net), which is designed to store information related to ion channels and models and is characterized by an efficient information management framework. Composed of a combination of a database and a wiki-like discussion platform Channelpedia allows researchers to collaborate and synthesize ion channel information from literature. Equipped to automatically update references, Channelpedia integrates and highlights recent publications with relevant information in the database. It is web based, freely accessible and currently contains 187 annotated ion channels with 45 Hodgkin–Huxley models.

Studies of chemical fixation effects in human cell lines using Raman microspectroscopy

The in vitro study of cellular species using Raman spectroscopy has proven a powerful non-invasive modality for the analysis of cell constituents and processes. This work uses micro-Raman spectroscopy to study the chemical fixation mechanism in three human cell lines (normal skin, normal bronchial epithelium, and lung adenocarcinoma) employing fixatives that preferentially preserve proteins (formalin), and nucleic acids (Carnoy's fixative and methanol-acetic acid). Spectral differences between the mean live cell spectra and fixed cell spectra together with principal components analysis (PCA), and clustering techniques were used to analyse and interpret the spectral changes. The results indicate that fixation in formalin produces spectral content that is closest to that in the live cell and by extension, best preserves the cellular integrity. Nucleic acid degradation, protein denaturation, and lipid leaching were observed with all fixatives and for all cell lines, but to varying degrees. The results presented here suggest that the mechanism of fixation for short fixation times is complex and dependent on both the cell line and fixative employed. Moreover, important spectral changes occur with all fixatives that have consequences for the interpretation of biochemical processes within fixed cells. The study further demonstrates the potential of vibrational spectroscopy in the characterization of complex biochemical processes in cells at a molecular level.

Lipid Exchange during Contact between Oppositely Charged Lipid Bilayers

The mechanistic details of processes occurring in and during contact between lipid bilayers are still poorly understood due to their complexity on the mesoscopic scale. Here, we analyze lipid exchange during contact of oppositely charged lipid bilayers. Specifically, we explore a generic mechanism, where this process occurs via diffusion of individual lipids between the layers. Our estimates indicate that this scenario is feasible on the time scale of conventional experiments and also on the time scale of biochemical processes in cells.

Identification of functional modules in a PPI network by clique percolation clustering

Large-scale experiments and data integration have provided the opportunity to systematically analyze and comprehensively understand the topology of biological networks and biochemical processes in cells. Modular architecture which encompasses groups of genes/proteins involved in elementary biological functional units is a basic form of the organization of interacting proteins. Here we apply a graph clustering algorithm based on clique percolation clustering to detect overlapping network modules of a protein–protein interaction (PPI) network. Our analysis of the yeast Sacchromyces cerevisiae suggests that most of the detected modules correspond to one or more experimentally functional modules and half of these annotated modules match well with experimentally determined protein complexes. Our method of analysis can of course be applied to protein–protein interaction data for any species and even other biological networks.

Systematic analysis of biochemical processes in cells by applying graphical diagrams

A method for systematically analyzing biochemical reactions in a cell was proposed. One of the characteristic features of biochemical reactions in a cell is that many components are participating and that quite many reactions are taking place. Also bio-separation processes are observed. We applied material-utilization diagrams to systematically grasp such a biochemical process. We used two diagrams. In the first diagram, the change in concentration for each component was presented, whereas in the second diagram, the deviation of each biochemical reaction from the equilibrium condition was displayed. Those diagrams suggested the possibility to improve the biochemical process, since they revealed the exergy losses caused by changes in concentration or biochemical reactions.

Self-assembly properties of a model RING domain.

RING domains act in a variety of essential cellular processes but have no general function ascribed to them. Here, we observe that purified arenaviral protein Z, constituted almost entirely by its RING domain, self-assembles in vitro into spherical structures that resemble functional bodies formed by Z in infected cells. By using a variety of biophysical methods we provide a thermodynamic and kinetic framework for the RING-dependent self-assembly of Z. Assembly appears coupled to substantial conformational reorganization and changes in zinc coordination of site II of the RING. Thus, the rate-limiting nature of conformational reorganization observed in the folding of monomeric proteins can also apply to the assembly of macromolecular scaffolds. These studies describe a unique mechanism of nonfibrillar homogeneous self-assembly and suggest a general function of RINGs in the formation of macromolecular scaffolds that are positioned to integrate biochemical processes in cells.

Salicylates: Molecular Mechanism of Therapeutic Action

This chapter presents the analysis of the molecular mechanism of action of salicylates with the aim of interpreting the therapeutic effects of these drugs in terms of their interactions with biochemical processes in cells or tissues. It is expected that such interactions might result from the binding of the drug molecule with one or more types of macromolecule that conducts such processes. Such binding might be expected to occur—for example, at the active site of an enzyme, at the receptor for a neurohumoral transmitter, or at some comparable point. The primary task, however, was to identify the biochemical process or processes whose modification by salicylates led to the therapeutic effects of these drugs and to examine how these effects occurred. This task was pursued along two main lines, emerging from the questions: (1) what is the character of the therapeutic actions of salicylates and (2) what potent effect(s) of salicylates at a molecular level might give rise to actions of this character? Inhibition of the cyclooxygenase of prostaglandin synthetase explains those actions of salicylates in which aspirin is more potent than sodium salicylate, including certain forms of analgesia, inhibition of platelet aggregation, antagonism of bradykinin-induced bronchoconstriction in the guinea pig, and possibly antipyresis.

Biochemical Mechanisms of Drug Toxicity

It has long been known that many drugs can be converted in the body to various metabolites that evoke therapeutic and toxicologic responses. In most instances these metabolites are chemically inert and bring about their effects by combining reversibly with action sites in tissues. In some instances, however, drugs and other foreign compounds can be converted in the body to chemically reactive metabolites which either uncouple integrated biochemical processes in cells or combine cova­ lently with various tissue macromolecules, such as DNA, RNA, protein, and glyco­ gen. During the past several years it has become increasingly evident that chemically reactive metabolites mediate many different kinds of serious toxicity, including carcinogenesis, mutagenesis, cellular necrosis, hypersensitivity reactions, methemo­ globinemia, hemolytic anemia, blood dyscrasias, and fetotoxicities. This review is devoted mainly to the mechanisms by which various kinds of toxicities are mediated by chemically reactive metabolites of drugs and the factors that affect the severity of the toxicities. Since the pioneering work of the Millers in Wisconsin and of Magee and co­ workers in England, it has become increasingly evident that most if not all chemical carcinogens bring about their effects by combining covalently with DNA and other tissue macromolecules or by being transformed to chemically reactive metabolites that in turn combine covalently with tissue macromolecules (1-4). The many studies on the mechanism of formation of carcinogenic metabolites in the body have revealed that chemically inert substances can be converted to chemi­ cally reactive metabolites by a variety of different reactions (Figure I). For example,