ArticleBiochemistry2006
A bromoenol lactone suicide substrate inactivates group VIA phospholipase A2 by generating a diffusible bromomethyl keto acid that alkylates cysteine thiols.
Article in Biochemistry, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
31 citing papers in PubMed, 59 citations in OpenAlex.
- Specificity mechanism of Group VIA calcium-independent phospholipase ABiochimica et biophysica acta. Molecular and cell biology of lipids · 2025Article
- iPLA2 inhibition blocks LysoPC-induced TRPC6 externalization and promotes Re-endothelialization of carotid injuries in hypercholesterolemic mice.Cell calcium · 2023Article
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- The phospholipase iPLAThe Journal of biological chemistry · 2017Article
- Platelet Lipidomic Profiling: Novel Insight into Cytosolic Phospholipase A2α Activity and Its Role in Human Platelet Activation.Biochemistry · 2015Article
- Calcium-independent phospholipases A2 and their roles in biological processes and diseases.Journal of lipid research · 2015Review
- Regulation of the Ca(2+)-independent phospholipase A2 in liver mitochondria by changes in the energetic state.Journal of lipid research · 2014Article
- New potent and selective polyfluoroalkyl ketone inhibitors of GVIA calcium-independent phospholipase A2.Bioorganic & medicinal chemistry · 2013Article
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- Fluoroketone inhibition of Ca(2+)-independent phospholipase A2 through binding pocket association defined by hydrogen/deuterium exchange and molecular dynamics.Journal of the American Chemical Society · 2013Article
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- Smooth muscle-specific expression of calcium-independent phospholipase A2β (iPLA2β) participates in the initiation and early progression of vascular inflammation and neointima formation.The Journal of biological chemistry · 2012Article
- Group VIA PLA2 (iPLA2β) is activated upstream of p38 mitogen-activated protein kinase (MAPK) in pancreatic islet β-cell signaling.The Journal of biological chemistry · 2012Article
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- Bromoenol lactone inhibits voltage-gated Ca2+ and transient receptor potential canonical channels.The Journal of pharmacology and experimental therapeutics · 2011Article
- Phospholipase A2 enzymes: physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention.Chemical reviews · 2011Review
- Combination therapy of an inhibitor of group VIA phospholipase A2 with paclitaxel is highly effective in blocking ovarian cancer development.The American journal of pathology · 2011Article
- Platelet-activating factor and metastasis: calcium-independent phospholipase A2β deficiency protects against breast cancer metastasis to the lung.American journal of physiology. Cell physiology · 2011Article
- Activation of group VI phospholipase A2 isoforms in cardiac endothelial cells.American journal of physiology. Cell physiology · 2011Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Phospholipases A2 (PLA2) comprise a superfamily of enzymes that hydrolyze phospholipids to a free fatty acid, e.g., arachidonate, and a 2-lysophospholipid. Dissecting their individual functions has relied in large part on pharmacological inhibitors that discriminate among PLA2. Group VIA PLA2 (iPLA2beta) has a GTSTG serine lipase consensus sequence, and studies with a bromoenol lactone (BEL) suicide substrate inhibitor have been taken to suggest that iPLA2beta participates in a wide variety of biological processes. Such conclusions presume inhibitor specificity. Inhibition by BEL requires its hydrolysis by and results in uncharacterized covalent modification(s) of iPLA2beta. We performed mass spectrometric analyses of proteolytic digests of BEL-treated iPLA2beta to identify modifications associated with loss of activity. The GTSTG active site and large flanking regions of sequence are not modified by BEL treatment, but most iPLA2beta Cys residues are alkylated at various BEL concentrations to form a thioether linkage to a BEL keto acid hydrolysis product. Synthetic Cys-containing peptides are alkylated when incubated with iPLA2beta and BEL, which reflects iPLA2beta-catalyzed BEL hydrolysis to a diffusible bromomethyl keto acid product that reacts with distant thiols. The BEL concentration dependence of Cys651 alkylation closely parallels that of loss of iPLA2beta activity. No amino acid residues other than Cys were found to be modified, suggesting that Cys alkylation is the covalent modification of iPLA2beta responsible for loss of activity, and the alkylating species appears to be a diffusible hydrolysis product of BEL rather than a tethered acyl-enzyme intermediate.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.