Inference of macromolecular assemblies from crystalline state.

https://pubs.rsc.org/en/content/articlepdf/2019/NP/C8NP00092A

Marine natural products.

1.1. Discovery of the Phospholipase A2 Superfamily
Phospholipases represent one of the earliest enzyme activities to be identified and studied and the phospholipase A2 (PLA2) superfamily (see defining specificity1 in Figure 1) traces its roots to the identification of lytic actions of snake venom at the end of the 19th century. The enzyme was first purified and characterized from cobra venom and later from rattlesnake venom. As protein sequencing methodologies advanced in the 1970’s, it became apparent that these enzymes had an unusually large number of cysteines (over 10% of the amino acids) and as secreted enzymes, that they were all in the form of disulfide bonds. It was further recognized that in the case of PLA2, cobras and rattlesnakes had six disulfides in common, but one disulfide bond is located in distinctly different locations. This led to the designation of Type 1 and Type 2 for cobras (old world snakes) and rattlesnakes (new world snakes), respectively.2 During that same period, studies on the porcine pancreatic digestive enzyme that hydrolyzes phospholipids led to the determination that this mammalian enzyme (and also the human pancreatic enzyme) had the same disulfide bonding pattern as cobras and hence the designation as IB with the cobra enzyme as IA.






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Figure 1


The specific reaction catalyzed by phospholipase A2 at the sn-2 position of the glycerol backbone is shown. X, any of a number of polar headgroups; R1, fatty acids, or alkyl, or alkenyl groups and R2, fatty acids or acyl moieties.

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Phospholipase A2 enzymes: physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention.

Areas of general agreement: Total creatine kinase (CK) levels depend on age, gender, race, muscle mass, physical activity and climatic condition. High levels of serum CK in apparently healthy subjects may be correlated with physical training status, as they depend on sarcomeric damage: strenuous exercise that damages skeletal muscle cells results in increased total serum CK. The highest postexercise serum enzyme activities are found after prolonged exercise such as ultradistance marathon running or weight-bearing exercises and downhill running, which include eccentric muscular contractions. Total serum CK activity is markedly elevated for 24 h after the exercise bout and, when patients rest, it gradually returns to basal levels. Persistently increased serum CK levels are occasionally encountered in healthy individuals and are also markedly increased in the pre-clinical stages of muscle diseases. Areas that are controversial: Some authors, studying subjects with high levels of CK at rest, observed that, years later, subjects developed muscle weakness and suggested that early myopathy may be asymptomatic. Others demonstrated that, in most of these patients, hyperCKemia probably does not imply disease. In many instances, the diagnosis is not formulated following routine examination with the patients at rest, as symptoms become manifest only after exercise. Some authors think that strength training seems to be safe for patients with myopathy, even though the evidence for routine exercise prescription is still insufficient. Others believe that, in these conditions, intense prolonged exercise may produce negative effects, as it does not induce the physiological muscle adaptations to physical training given the continuous loss of muscle proteins. Growing points: High CK serum levels in athletes following absolute rest and without any further predisposing factors should prompt a full diagnostic workup with special regards to signs of muscle weakness or other simple signs that, in both athletes and sedentary subjects, are not always promptly evident. These signs may indicate subclinical muscle disease, which training loads may evidence through the onset of profound fatigue. It is probably safe to counsel athletes with suspected myopathy to continue to undertake physical activity at a lower intensity, so as to prevent muscle damage from high intensity exercise and allow ample recovery to favour adequate recovery.

Creatine kinase monitoring in sport medicine

In the last three decades the discovery of metabolites with biological activities from macroalgae has increased significantly. However, despite the intense research effort by academic and corporate institutions, very few products with real potential have been identified or developed. Based on Silverplatter MEDLINE and Aquatic Biology, Aquaculture & Fisheries Resources databases, the literature was searched for natural products from marine macroalgae in the Rhodophyta, Phaeophyta and Chlorophyta with biological and pharmacological activity. Substances that currently receive most attention from pharmaceutical companies for use in drug development, or from researchers in the field of medicine-related research include: sulphated polysaccharides as antiviral substances, halogenated furanones from Delisea pulchra as antifouling compounds, and kahalalide F from a species of Bryopsis as a possible treatment of lung cancer, tumours and AIDS. Other substances such as macroalgal lectins, fucoidans, kainoids and aplysiatoxins are routinely used in biomedical research and a multitude of other substances have known biological activities. The potential pharmaceutical, medicinal and research applications of these compounds are discussed.

Medicinal and pharmaceutical uses of seaweed natural products: A review

Phospholipase A2 myotoxins from Bothrops snake venoms

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/j.febslet.2009.03.029

Venoms, venomics, antivenomics

An overview of lysine-49 phospholipase A2 myotoxins from crotalid snake venoms and their structural determinants of myotoxic action.

As part of the characterization of the host reactivity to the venom ofBothrops asper, we investigated the inflammatory responses in the mouse footpad model. The subcutaneously injected venom induced a rapid increase of serum IL-6 concentration, which peaked between 3 and 6 h and returned to normal values at 12 h. In contrast, serum TNF-α and IL-1α were not detectable at any time point studied. A myotoxic phospholipase A2 isoform purified from this venom, myotoxin II, was also able to induce a systemic IL-6 release when injected into the footpad. Both venom and myotoxin induced local edema and a leukocyte infiltrate accumulating in the muscle and subdermal tissue within 6 h. The infiltrate consisted predominantly of neutrophils at 6 and 24 h, but at later times, mononuclear cells also appeared. The edema, leukocyte infiltration, and IL-6 responses did not depend on the hemorrhagic activity of venom, since all three effects were seen after injection of (1) preneutralized venom, devoid of hemorrhagic activity, and (2) purified myotoxin II. Circulating platelet numbers were significantly decreased 30 min after venom injection and returned to normal after 12 h. The venom also induced a rapid inversion in the ratio of neutrophils to lymphocytes in peripheral blood, which did not normalize until 12 h later. The present observations suggest that venom, besides its cytotoxic properties, induces early hematologic and immunologic alterations. These findings may be of relevance in future treatment modalities.

Host response to Bothrops asper snake venom. Analysis of edema formation, inflammatory cells, and cytokine release in a mouse model.

A large variety of snake toxins evolved from PLA2 digestive enzymes through a process of ‘accelerated evolution’. These toxins have different tissue targets, membrane receptors and mechanisms of alteration of the cell plasma membrane. Two of the most commonly induced effects by venom PLA2s are neurotoxicity and myotoxicity. Here, we will discuss how these snake toxins achieve a similar cellular lesion, which is evolutionarily highly conserved, despite the differences listed above. They cause an initial plasma membrane perturbation which promotes a large increase of the cytosolic Ca2+ concentration leading to cell degeneration, following modes that we discuss in detail for muscle cells and for the neuromuscular junction. The different systemic pathophysiological consequences caused by these toxins are not due to different mechanisms of cell toxicity, but to the intrinsic anatomical and physiological properties of the targeted tissues and cells.

Bruno Lomonte

Papers

Phospholipase A2 myotoxins from Bothrops snake venoms

Venoms, venomics, antivenomics

An overview of lysine-49 phospholipase A2 myotoxins from crotalid snake venoms and their structural determinants of myotoxic action.

Host response to Bothrops asper snake venom. Analysis of edema formation, inflammatory cells, and cytokine release in a mouse model.

Cellular pathology induced by snake venom phospholipase A2 myotoxins and neurotoxins: common aspects of their mechanisms of action