3d5e | pdb_00003d5e
Crystal structure of human plasma platelet activating factor acetylhydrolase covalently inhibited by paraoxon
Structural highlights
DiseasePAFA_HUMAN Defects in PLA2G7 are the cause of platelet-activating factor acetylhydrolase deficiency (PAFAD) [MIM:614278. An enzymatic deficiency that results in exacerbated bodily response to inflammatory agents. Asthmatic individuals affected by this condition may manifest severe respiratory symptoms.[1] [2] [3] [4] [5] Defects in PLA2G7 are a cause of susceptibility to asthma (ASTHMA) [MIM:600807. The most common chronic disease affecting children and young adults. It is a complex genetic disorder with a heterogeneous phenotype, largely attributed to the interactions among many genes and between these genes and the environment. It is characterized by recurrent attacks of paroxysmal dyspnea, with weezing due to spasmodic contraction of the bronchi. Note=PLA2G7 variants can be a risk factor for the development of asthma and PLA2G7 may act as a modifier gene that modulates the severity of this disease.[6] Defects in PLA2G7 are a cause of susceptibility to atopic hypersensitivity (ATOPY) [MIM:147050. A condition characterized by predisposition to develop hypersensitivity reactions. Atopic individuals can develop eczema, allergic rhinitis and allergic asthma.[7] FunctionPAFA_HUMAN Modulates the action of platelet-activating factor (PAF) by hydrolyzing the sn-2 ester bond to yield the biologically inactive lyso-PAF. Has a specificity for substrates with a short residue at the sn-2 position. It is inactive against long-chain phospholipids. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedHuman plasma platelet-activating factor (PAF) acetylhydrolase functions by reducing PAF levels as a general anti-inflammatory scavenger and is linked to anaphylactic shock, asthma, and allergic reactions. The enzyme has also been implicated in hydrolytic activities of other pro-inflammatory agents, such as sn-2 oxidatively fragmented phospholipids. This plasma enzyme is tightly bound to low and high density lipoprotein particles and is also referred to as lipoprotein-associated phospholipase A2. The crystal structure of this enzyme has been solved from x-ray diffraction data collected to a resolution of 1.5 angstroms. It has a classic lipase alpha/beta-hydrolase fold, and it contains a catalytic triad of Ser273, His351, and Asp296. Two clusters of hydrophobic residues define the probable interface-binding region, and a prediction is given of how the enzyme is bound to lipoproteins. Additionally, an acidic patch of 10 carboxylate residues and a neighboring basic patch of three residues are suggested to play a role in high density lipoprotein/low density lipoprotein partitioning. A crystal structure is also presented of PAF acetylhydrolase reacted with the organophosphate compound paraoxon via its active site Ser273. The resulting diethyl phosphoryl complex was used to model the tetrahedral intermediate of the substrate PAF to the active site. The model of interface binding begins to explain the known specificity of lipoprotein-bound substrates and how the active site can be both close to the hydrophobic-hydrophilic interface and at the same time be accessible to the aqueous phase. Crystal structure of human plasma platelet-activating factor acetylhydrolase: structural implication to lipoprotein binding and catalysis.,Samanta U, Bahnson BJ J Biol Chem. 2008 Nov 14;283(46):31617-24. Epub 2008 Sep 10. PMID:18784071[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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