Lipoxygenases – Structure and reaction mechanism

Lipid oxidation is a common metabolic reaction in all biological systems, appearing in developmentally regulated processes and as response to abiotic and biotic stresses. Products derived from lipid oxidation processes are collectively named oxylipins. Initial lipid oxidation may either occur by chemical reactions or is derived from the action of enzymes. In plants this reaction is mainly catalyzed by lipoxygenase (LOXs) enzymes and during recent years analysis of different plant LOXs revealed insights into their enzyme mechanism. This review aims at giving an overview of concepts explaining the catalytic mechanism of LOXs as well as the different regio- and stereo-specificities of these enzymes.     

The nonallosteric mechanism of enzyme activity regulation. Is it the only true mechanism?

The nonallosteric regulation mechanism of enzyme reaction velocity assumes that the substrate and enzyme interact via a metal cation and form simple and mixed, mono- and multi-nuclear complexes. A solution of equations for individual cases gives a function of initial reaction velocity at any given substrate or modifier concentration. This function can describe kinetic effects that are considered allosteric, as well as phenomena omitted by commonly-accepted models.     

Mitochondrial mechanism of cardiomyocyte apoptosis induced by stress

Stress induced the serious disorder of cardiac function and cardiovascular diseases. Apoptosis is the cellular basis in stress induced cardiac injury. In our previous study we found that many stressors resulted in mitochondrial damage. It is certain that mitochondria is important mediator in triggering apoptotic cell death, but the mechanism, by which the stress induced mitochondrial injury leads to cardiomyocyte apoptosis, remains unclear. We designed the present study to investigate the changes of the mitochondria in cardiomyocytes undergoing stress and its role in inducing apoptosis. Here we reported that stress changed the membrane fluidity of mitochondria and induced the lipid peroxidation of mitochondrial membrane in     

Can mechanism help explain insect host choice?

Evolutionary theory predicts that herbivorous insects should lay eggs on plants in a way that reflects the suitability of each plant species for larval development. Empirical studies, however, often fail to find any relationship between an adult insect's choice of host-plant and offspring fitness, and in such cases, it is generally assumed that other 'missing' factors (e.g. predation, host-plant abundance, learning and adult feeding sites) must be contributing to overall host suitability. Here, I consider an alternative theory - that a fitness cost inherent in the olfactory mechanism could constrain the evolution of insect host selection. I begin by reviewing current knowledge of odour processing in the insect antennal lobe with the aid of a simple schematic: the aim being to explain the workings of this mechanism to scientists who do not have prior knowledge in this field. I then use the schematic to explore how an insect's perception of host and non-host odours is governed by a set of processing rules, or algorithm. Under the assumptions of this mechanistic view, the perception of every plant odour is interrelated, and seemingly bad host choices can still arise as part of an overall adaptive behavioural strategy. I discuss how an understanding of mechanism can improve the interpretation of theoretical and empirical studies in insect behaviour and evolution.     

Is the philosophy of mechanism philosophy enough?

Recognition of the widespread use of the word 'mechanism' in bio-molecular research has resulted in the concept of 'mechanism' becoming a focal point for a highly visible group of philosophers of biology. Rather, however, than grasping and elucidating the situated aims and practices of biologists themselves, the philosophical investigation of the contemporary meaning of mechanism in biology has been commandeered by the needs of 'hard naturalists' to replace the old deductive-nomological model of the 'received view' with a new normative-explanatory gold-standard. It is argued that rather than an orientation toward an increasingly precise characterization of mechanisms as being an ultimate end in biological research, in actual biological practice 'mechanism' means different things in different contexts, pragmatically draws on our embodied know-how in the use of machines and is not, nor should be, an ultimate end of biological research. Further, it is argued, that classic work on low-level mechanisms became taken up qualitatively as parts of the scaffolding for investigating higher level regulatory processes and that in so doing, and in light of new findings such as that of the regulatory significance of 'pleiomorphic ensembles' and 'intrinsically unstructured proteins' the explanatory limits of the mechanism image have already come into view.     

IFN-γ-mediated neuronal defense mechanism targets Toxoplasma

Toxoplasma gondii encysts preferentially within neurons in the central nervous system, establishing lifelong persistence. Despite recent discoveries, this neuronal preference was thought, in part, to be secondary to a lack of neuronal cell-autonomous immunity. By showing that neurons can mount interferon-gamma (IFN-γ)-mediated cell-autonomous anti-T. gondii defenses, Chandrasekaran et al. have challenged long held assumptions.     

Understanding the mechanism of IL-1β secretion

The cytokine interleukin-1β (IL-1β) is a key mediator of the inflammatory response. Essential for the host-response and resistance to pathogens, it also exacerbates damage during chronic disease and acute tissue injury. It is not surprising therefore that there is a huge level of interest in how this protein is produced and exported from cells. However, the mechanism of IL-1β release has proven to be elusive. It does not follow the conventional ER-Golgi route of secretion. A literature full of disparate observations arising from numerous experimental systems, has contributed to a complicated mix of diverse proposals. Here we summarise these observations and propose that secretion of IL-1β occurs on a continuum, dependent upon stimulus strength and the extracellular IL-1β requirement.     

A molecular mechanism of aluminium-induced Alzheimer's disease?

An abundance of research has continued to link aluminium (Al) with Alzheimer's disease (AD) (Strong et al., J. Toxicol. Environ. Health 48 (1996) 599; Savory et al., J. Toxicol. Environ. Health 48 (1996) 615). Animals loaded with Al develop both symptoms and brain lesions that are similar to those found in AD. However, these animal models of Al intoxication are not representative of human exposure to Al. They have not addressed the significance of a truly chronic exposure to Al. If Al is a cause of AD it is effective at the level of our everyday exposure to the metal and AD will be one possible outcome of the life-long presence of a low, though burgeoning, brain Al burden. Individual susceptibility to AD will be as much to do with differences in brain physiology as with changes in our everyday exposure to the metal. There will be a chemical response and indeed biochemical/physiological response in the brain to Al. The question is whether brain Al homeostasis could impact upon brain function. In reviewing the recent literature covering the neurotoxicity of Al and, in particular, of the known and probable mechanisms involved in brain Al homeostasis I have identified a mechanism through which a truly chronic exposure to Al would bring about subtle and persistent changes in neurotransmission which, in time, could instigate the cascade of events known collectively as AD. This mechanism involves the potentiation of the activities of neurotransmitters by the action of Al-ATP at adenosine 5'-triphosphate (ATP) receptors in the brain.     

Slow-reacting substance from alveolar macrophages--a mechanism of asthma?

The effects of alveolar macrophages on bronchial reactivity were studied in vitro to determine whether these cells could provide a pathogenetic link between cellular components of the inflammatory response, chemical medication of smooth muscle contraction and possible local mechanism of asthma. Alveolar macrophages harvested from rabbit lungs produced consistent and prolonged contractile responses in guinea-pig tracheal rings. The contractile material had the pharmacological and physical properties of slow-reacting substance (SRS) and, in particular, it was completely antagonized by minute concentrations (5 ng/ml) of a specific SRS antagonist, FPL 55712. The average contractile response per 10(6) macrophages was quantitatively equivalent to that produced by 76 ng methacholine. These findings not only support the view that local mechanisms may be of relevance in the pathogenesis of asthma, but could also have possible implications for therapy.     

Evolutionary deimmunization: an ancillary mechanism for self-tolerance?

Self-proteins in the extracellular environment are constantly sampled and processed through the Class II antigen presentation pathway. Mechanisms responsible for central and peripheral tolerance reduce the chance of autoimmune responses to these proteins. However, tolerance can and does break down, leading to the development of autoimmune disease. In a preliminary analysis, we observed that common serum proteins have fewer HLA class II-restricted T-cell epitopes than expected, when compared to random protein sequences. We therefore performed a broader analysis of human proteins to determine whether the number of T-cell epitopes in extracellular proteins is reduced in comparison with non-secreted (intracellular) proteins. Here we document fewer putative HLA class II-restricted T-cell epitopes in extracellular proteins, compared to intracellular proteins. These data suggest that the diminished presence of T-cell epitopes may reduce the potential for autoimmunity. Over evolutionary timescales, immune pressure may have resulted in alterations in the inherent T-cell immunogenic potential of autologous proteins.     

Structure and catalytic mechanism of the β-carbonic anhydrases

The β-carbonic anhydrases (β-CAs) are a diverse but structurally related group of zinc-metalloenzymes found in eubacteria, plant chloroplasts, red and green algae, and in the Archaea. The enzyme catalyzes the rapid interconversion of CO₂ and H₂O to HCO₃⁻ and H⁺, and is believed to be associated with metabolic enzymes that consume or produce CO₂ or HCO₃⁻. For many organisms, β-CA is essential for growth at atmospheric concentrations of CO₂. Of the five evolutionarily distinct classes of carbonic anhydrase, β-CA is the only one known to exhibit allosterism. Here we review the structure and catalytic mechanism of β-CA, including the structural basis for allosteric regulation.     

α-Catenin uses a novel mechanism to activate vinculin

Vinculin, an actin-binding protein, is emerging as an important regulator of adherens junctions. In focal-adhesions, vinculin is activated by simultaneous binding of talin to its head domain and actin filaments to its tail domain. Talin is not present in adherens junctions. Consequently, the identity of the ligand that activates vinculin in cell-cell junctions is not known. Here we show that in the presence of F-actin, α-catenin, a cytoplasmic component of the cadherin adhesion complex, activates vinculin. Direct binding of α-catenin to vinculin is critical for this event because a point mutant (α-catenin L344P) lacking high affinity binding does not activate vinculin. Furthermore, unlike all known vinculin activators, α-catenin binds to and activates vinculin independently of an A50I substitution in the vinculin head, a mutation that inhibits vinculin binding to talin and IpaA. Collectively, these data suggest that α-catenin employs a novel mechanism to activate vinculin and may explain how vinculin is differentially recruited and/or activated in cell-cell and cell-matrix adhesions.     

Is there a unifying mechanism for protein folding?

Proteins appear to fold by diverse pathways, but variations of a simple mechanism - nucleation-condensation - describe the overall features of folding of most domains. In general, secondary structure is inherently unstable and its stability is enhanced by tertiary interactions. Consequently, an extensive interplay of secondary and tertiary interactions determines the transition-state for folding, which is structurally similar to the native state, being formed in a general collapse (condensation) around a diffuse nucleus. As the propensity for stable secondary structure increases, folding becomes more hierarchical and eventually follows a framework mechanism where the transition state is assembled from pre-formed secondary structural elements.