Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:6.2.1.1 (ACS)
 78,556 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phase II results of the trials of two phospholipase A2 inhibitors which may be of value in the treatment of atherosclerosis and cardiovascular disease have been reported in the past year. Darapladib (GlaxoSmithKline) is an inhibitor of lipoprotein-associated phospholipase A2 and varespladib (Anthera) inhibits several forms of the secreted phospholipase A2s. Despite the apparent similarity of mechanism, which is also built into the compounds' names, the role of the two types of phospholipase in atherogenesis is very different. Evidence for this comes from a range of preclinical studies and from epidemiological data which are summarised here. These data provide a basis for the Phase II studies and support decisions to move into Phase III, a decision which in the case of darapladib has been made and studies commenced (STABILITY trial). For varespladib the FRANCIS-ACS trial in acute coronary syndrome patients is in progress.
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PMID:Phospholipase A2 inhibitors in the treatment of atherosclerosis: a new approach moves forward in the clinic. 1969 42

Viral capsid dynamics are often observed during infectious events such as cell surface attachment, entry and genome release. Structural analysis of adeno-associated virus (AAV), a helper-dependent parvovirus, revealed a cluster of surface-exposed tyrosine residues at the icosahedral two-fold symmetry axis. We exploited the latter observation to carry out selective oxidation of Tyr residues, which yielded cross-linked viral protein (VP) subunit dimers, effectively "stitching" together the AAV capsid two-fold interface. Characterization of different Tyr-to-Phe mutants confirmed that the formation of cross-linked VP dimers is mediated by dityrosine adducts and requires the Tyr704 residue, which crosses over from one neighboring VP subunit to the other. When compared to unmodified capsids, Tyr-cross-linked AAV displayed decreased transduction efficiency in cell culture. Surprisingly, further biochemical and quantitative microscopy studies revealed that restraining the two-fold interface hinders externalization of buried VP N-termini, which contain a phospholipase A2 domain and nuclear localization sequences critical for infection. These adverse effects caused by tyrosine oxidation support the notion that interfacial dynamics at the AAV capsid two-fold symmetry axis play a role in externalization of VP N-termini during infection.
ACS Chem Biol 2012 Jun 15
PMID:Tyrosine cross-linking reveals interfacial dynamics in adeno-associated viral capsids during infection. 2245 29

Studies indicate that elevated plasma concentrations of lipoprotein-associated phospholipase A2 (Lp-PLA2) is associated with increased risk of cardiovascular disease. Lp-PLA2 seems to play a crucial role in the formation of plaques and acute inflammation, and plasma Lp-PLA2 could therefore potentially be used as a predictor of long-term outcome in ACS patients. To evaluate this, data concerning Lp-PLA2 as a predictor in ACS patients was gathered through a systematic literature review, and studies on this issue were extracted from relevant databases, incl. PubMed and Cochrane. A total of 14 articles were retrieved, but after thorough evaluation and elimination of irrelevant articles only seven studies were eligible for the literature review. All studies except two showed significant correlation between Lp-PLA2 and CV events in ACS patients. Only one study found an independent value to predict CV events 30 days after ACS. Altogether, there was inconsistency in the findings regarding the potential use of Lp-PLA2 and a lack of knowledge on several issues. Lp-PLA2 seems to give valuable information on which ACS patients are prone to new events and also provides important information on plaque size. However, more focused studies concerning genetic variations, time-window impact, patients with and without CV risk factors (e.g. diabetes), and treatment effects are needed. In conclusion, Lp-PLA2 offers new insight in the pathophysiological development of ACS, but until the aforementioned issues are addressed the biomarker will mainly be of interest in a research setting, not as a predictive parameter in a clinical setting.
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PMID:Can lipoprotein-associated phospholipase A2 be used as a predictor of long-term outcome in patients with acute coronary syndrome? 2431 41

Supported lipid bilayer platforms have been used for various biological applications. However, the lipid bilayers easily delaminate and lose their natural structure after being exposed to an air-water interface. In this study, for the first time, we demonstrated that physical confinement can be used instead of chemical modifications to create air-stable membranes. Physical confinement was generated by the obstacle network induced by a peripheral enzyme, phospholipase A2. The enzyme and reacted lipids could be washed away from the obstacle network, which was detergent-resistant and strongly bonded to the solid support. On the basis of these properties, the obstacle framework on the solid support was reusable and lipid bilayers with the desired composition could be refilled and formed in the region confined by the obstacle framework. The results of fluorescence recovery after photobleaching (FRAP) indicate that the diffusivities of the lipid bilayers before drying and after rehydration were comparable, indicating the air stability of the physically confined membrane. In addition, we observed that the obstacles could trap a thin layer of water after the air-water interface passed through the lipid bilayer. Because the obstacles were demonstrated to be several times higher than a typical lipid membrane on a support, the obstacles may act as container walls, which can trap water above the lipid membrane. The water layer may have prevented the air-water interface from directly contacting the lipid membrane and, therefore, buffered the interfacial force, which could cause membrane delamination. The results suggest the possibility of using physical confinement to create air-stable membranes without changing local membrane rigidity or covering the membrane with protecting molecules.
ACS Appl Mater Interfaces 2014 May 14
PMID:Creating air-stable supported lipid bilayers by physical confinement induced by phospholipase A2. 2475 6

A rapid and highly sensitive point-of-care (PoC) lateral flow assay for phospholipase A2 (PLA2) is demonstrated in serum through the enzyme-triggered release of a new class of biotinylated multiarmed polymers from a liposome substrate. Signal from the enzyme activity is generated by the adhesion of polystreptavidin-coated gold nanoparticle networks to the lateral flow device, which leads to the appearance of a red test line due to the localized surface plasmon resonance effect of the gold. The use of a liposome as the enzyme substrate and multivalent linkers to link the nanoparticles leads to amplification of the signal, as the cleavage of a small amount of lipids is able to release a large amount of polymer linker and adhesion of an even larger amount of gold nanoparticles. By optimizing the molecular weight and multivalency of these biotinylated polymer linkers, the sensitivity of the device can be tuned to enable naked-eye detection of 1 nM human PLA2 in serum within 10 min. This high sensitivity enabled the correct diagnosis of pancreatitis in diseased clinical samples against a set of healthy controls using PLA2 activity in a point-of-care device for the first time.
ACS Nano 2015 Mar 24
PMID:Multivalent nanoparticle networks enable point-of-care detection of human phospholipase-A2 in serum. 2575 26

Phospholipases A2 (PLA2) are a diverse group of enzymes that hydrolyze membrane phospholipids into arachidonic acid and lysophospholipids. Arachidonic acid is metabolized to eicosanoids (prostaglandins, leukotrienes, thromboxanes), and lysophospholipids are converted to platelet-activating factors. These lipid mediators play critical roles in the initiation, maintenance, and modulation of neuroinflammation and oxidative stress. Neurological disorders including excitotoxicity; traumatic nerve and brain injury; cerebral ischemia; Alzheimer's disease; Parkinson's disease; multiple sclerosis; experimental allergic encephalitis; pain; depression; bipolar disorder; schizophrenia; and autism are characterized by oxidative stress, inflammatory reactions, alterations in phospholipid metabolism, accumulation of lipid peroxides, and increased activities of brain phospholipase A2 isoforms. Several old and new synthetic inhibitors of PLA2, including fatty acid trifluoromethyl ketones; methyl arachidonyl fluorophosphonate; bromoenol lactone; indole-based inhibitors; pyrrolidine-based inhibitors; amide inhibitors, 2-oxoamides; 1,3-disubstituted propan-2-ones and polyfluoroalkyl ketones as well as phytochemical based PLA2 inhibitors including curcumin, Ginkgo biloba and Centella asiatica extracts have been discovered and used for the treatment of neurological disorders in cell culture and animal model systems. The purpose of this review is to summarize information on selective and potent synthetic inhibitors of PLA2 as well as several PLA2 inhibitors from plants, for treatment of oxidative stress and neuroinflammation associated with the pathogenesis of neurological disorders.
ACS Chem Neurosci 2015 Jun 17
PMID:Synthetic and natural inhibitors of phospholipases A2: their importance for understanding and treatment of neurological disorders. 2589 85

Advancement in the understanding of biomolecular interactions has benefited greatly from the development of surface-sensitive bioanalytical sensors. To further increase their broad impact, significant efforts are presently being made to enable label-free and specific biomolecule detection with high sensitivity, allowing for quantitative interpretation and general applicability at low cost. In this work, we have addressed this challenge by developing a waveguide chip consisting of a flat silica core embedded in a symmetric organic cladding with a refractive index matching that of water. This is shown to reduce stray light (background) scattering and thereby allow for label-free detection of faint objects, such as individual sub-20 nm gold nanoparticles as well as sub-100 nm lipid vesicles. Measurements and theoretical analysis revealed that light-scattering signals originating from single surface-bound lipid vesicles enable characterization of their sizes without employing fluorescent lipids as labels. The concept is also demonstrated for label-free measurements of protein binding to and enzymatic (phospholipase A2) digestion of individual lipid vesicles, enabling an analysis of the influence on the measured kinetics of the dye-labeling of lipids required in previous assays. Further, diffraction-limited imaging of cells (platelets) binding to a silica surface showed that distinct subcellular features could be visualized and temporally resolved during attachment, activation, and spreading. Taken together, these results underscore the versatility and general applicability of the method, which due to its simplicity and compatibility with conventional microscopy setups may reach a widespread in life science and beyond.
ACS Nano 2015 Dec 22
PMID:Evanescent Light-Scattering Microscopy for Label-Free Interfacial Imaging: From Single Sub-100 nm Vesicles to Live Cells. 2651 91