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metabolism
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the enzyme exhibits promiscuous phosphotriesterase activity for the degradation of organophosphorous chemicals including insecticides and chemical warfare agents
evolution
enzyme SsoPox belongs to the phosphotriesterase-like lactonase (PLL) family of enzymes. SsoPox shares only about 30% sequence identity with phosphotriesterases (PTEs) but all amino acids coordinating the binuclear metal-centre are conserved. The coexistence of lactonase and phosphotriesterase activities has been already reported for many members of PLL family
evolution
serum paraoxonase 1 (PON1) is a native lactonase capable of promiscuously hydrolyzing a broad range of substrates, including organophosphates, esters, and carbonates. Comparison of PON1 to other organophosphatases demonstrates that either a similar gating loop or a highly buried solvent excluding active site is a common feature of these enzymes
evolution
Sphingobium fuliginis acquired OPH coding opd gene through lateral gene transfer
evolution
the enzyme is a member of phosphotriesterase-like lactonase family. The phosphotriesterase activities of phosphotriesterases (PTEs) are considered to derive from the lactonase-activities during the evolution, and phosphotriesterase-like lactonase family (PLL), is the closest protein family to PTE family based on protein-protein blast results. But members of PLL family exhibit higher lactonase activities than the phosphotriesterase activities, while the best substrates for PTEs are phosphotriesters. Enzyme mPHP is a dimer with a typical distorted (beta/alpha)8 barrel structure like other structures of PLL family and PTE family
evolution
the phosphotriesterase activity development between PON1, EC 3.1.8.1, and DFPase, EC 3.1.8.2, is investigated by using the hybrid density functional theory method B3LYP. Structure comparisons of evolutionarily related enzymes show that the mutation of Asn270 leads to the catalytic Ca2+ ion indirectly connecting the buried structural Ca2+ ion via hydrogen bonds in DFPase. It can reduce the plasticity of enzymatic structure, and possibly change the substrate preference from paraoxon (preferred substrate of PON1) to DFP (preferred substrate of DFPase), which implies an evolutionary transition from mono- to dinuclear catalytic centers, enzyme catalysis mechanism from an evolutionary perspective, overview
evolution
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the enzyme is a member of phosphotriesterase-like lactonase family. The phosphotriesterase activities of phosphotriesterases (PTEs) are considered to derive from the lactonase-activities during the evolution, and phosphotriesterase-like lactonase family (PLL), is the closest protein family to PTE family based on protein-protein blast results. But members of PLL family exhibit higher lactonase activities than the phosphotriesterase activities, while the best substrates for PTEs are phosphotriesters. Enzyme mPHP is a dimer with a typical distorted (beta/alpha)8 barrel structure like other structures of PLL family and PTE family
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evolution
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the enzyme is a member of phosphotriesterase-like lactonase family. The phosphotriesterase activities of phosphotriesterases (PTEs) are considered to derive from the lactonase-activities during the evolution, and phosphotriesterase-like lactonase family (PLL), is the closest protein family to PTE family based on protein-protein blast results. But members of PLL family exhibit higher lactonase activities than the phosphotriesterase activities, while the best substrates for PTEs are phosphotriesters. Enzyme mPHP is a dimer with a typical distorted (beta/alpha)8 barrel structure like other structures of PLL family and PTE family
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malfunction
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paraoxonase 1 knockout mice are dramatically more sensitive than wild type mice to the toxicity of chlorpyrifos oxon and diazoxon and to a lesser extent the parent phosphorothioates, chlorpyrifos and diazinon
malfunction
decrease of serum PON1 activities is usually related to many chronic diseases, such as atherosclerosis, diabetes, cancers, migraine, pulmonary tuberculosis, polycystic ovary syndrome, gastroesophageal malignancies, depression, nephritic syndrome, hemodialysis, metabolic syndrome, and liver disease. Determination of PON1 activity has a significant diagnostic value in predicting disease status
malfunction
insufficient organophosphate-hydrolyzing activity of native enzyme affirms the urgent need to develop improved variant(s) having enhanced organophosphate-hydrolyzing activity. Enzyme mutants show altered substrate specificity with increased activity against paraoxon and lactone substrates, overview
malfunction
opd null mutants of Brevundimonas diminuta fail to grow using the organophosphate insecticide methyl parathion as sole source of phosphate
malfunction
prenatal exposure to organophosphate insecticides are not associated with autism spectrum disorders and related behaviors. It is not modified by single nucleotide polymorphisms in the paraoxonase (PON1) enzyme. Analysis of the relationship of prenatal organophosphate insecticide biomarkers with reciprocal social, repetitive, and stereotypic behaviors in 8-year old children, and modification of this relationship by child PON1 polymorphisms, overview
malfunction
the impact of Y71 mutational substitutions on PON1's lactonase activity is minimal, whereas the kcat for the paraoxonase activity is negatively perturbed by up to 100fold, suggesting greater mutational robustness of the native activity. Additionally, while these substitutions modulate PON1's active site shape, volume, and loop flexibility, their largest effect is in altering the solvent accessibility of the active site by expanding the active site volume, allowing additional water molecules to enter. This effect is markedly more pronounced in the organophosphatase activity than the lactonase activity
physiological function
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after 6 months of anti-tumour necrosis factor therapy, initial improvement of PON-1 activity parallels a decrease in the inflammatory status
physiological function
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basal and salt-stimulated paraoxonase activity is significantly lower in patients with gestational diabetes mellitus compared to controls, while lipid hydroperoxide levels are significantly higher. Among gestational diabetes patients, serum paraoxonase activity is inversely correlated with lipid hydroperoxide levels. Decreased serum paraoxonase activity may play a role in the potential early pathogenesis for atherosclerotic heart disease in gestational diabetes mellitus beyond its antioxidant properties
physiological function
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caterpillar of the Trichoplusia ni moth can be used as an expression system to produce large quantities of functional recombinant PON1
physiological function
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paraoxonase 1 functions as an efficient catalytic bioscavenger against nerve agents
physiological function
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paraoxonase 1 functions as an efficient catalytic bioscavenger against nerve agents
physiological function
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paraoxonase 1 modulates the toxicity of organophosphorous mixtures (paraoxon, chlorpytifoy oxon, diazoxon) by altering the activity of another detoxication enzyme, carboxylesterase
physiological function
the presence of a particular amino acid residue at position 192 differentially alters the effect of the H115W substitution, and the H115 residue is not always needed for the lactonase and arylesterase activities of the enzyme. The amino acid residues at position 192 and 115 act in conjunction in modulating the hydrolytic activities of the enzyme
physiological function
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evaluation of protective effect of the enzyme in plasma of rats against in vitro challenge of intoxication with parathion or paraoxon in rats, effectiveness of the enzyme as bioscavenger in vivo, overview
physiological function
evaluation of protective effect of the enzyme in plasma of rats against in vitro challenge of intoxication with parathion or paraoxon in rats, effectiveness of the enzyme as bioscavenger in vivo, overview
physiological function
evaluation of protective effect of the enzyme in plasma of rats against in vitro challenge of intoxication with parathion or paraoxon in rats, effectiveness of the enzyme as bioscavenger in vivo, overview
physiological function
evaluation of protective effect of the enzyme in plasma of rats against in vitro challenge of intoxication with parathion or paraoxon in rats, effectiveness of the enzyme as bioscavenger in vivo, overview
physiological function
human paraoxonase 1 (h-PON1) is a serum enzyme that can hydrolyze a variety of substrates, including organophosphate (OP) compounds. PON1 can hydrolyze and inactivate a variety of organophosphate (OP) compounds, including certain OP pesticides and nerve agents (NAs). It is a potential candidate for the development of antidote against OP poisoning in humans. The enzyme possesses anti-inflammatory, anti-oxidative, anti-diabetic and quorum sensor-hydrolyzing activities, it is proposed that the lactonase activity of the enzyme is important for these defensive roles, cf. EC 3.1.1.81
physiological function
organophosphate hydrolase (OPH) hydrolyzes the triester bond found in a variety of organophosphate insecticides and nerve agents. Membrane-bound OPH interacts with the outer membrane efflux protein TolC and with PstS, the periplasmic component of the ABC transporter complex (PstSACB) involved in phosphate transport. Interaction of enzyme OPH with PstS appears to facilitate transport of phosphate generated from organophosphates due to the combined action of OPH and periplasmically located phosphatases. Enzyme OPH supports Brevundimonas diminuta growth with methyl-parathion as sole phosphate source
physiological function
organophosphate hydrolase interacts with Ton components and is targeted to the membrane only in the presence of the ExbB/ExbD complex. Proton motif force (PMF) is required for efficient uptake and utilization of dimethyl-parathion as sole source of phosphate, no growth is observed in cultures having PMF inhibitor CCCP
physiological function
paraoxonase 1 (PON1) is a calcium-dependent lactonase synthesized primarily in the liver and secreted into the plasma, where it is associates with high density lipoproteins (HDL). PON1 acts as antioxidant preventing low-density lipoprotein (LDL) oxidation, a process considered critical in the initiation and progression of atherosclerosis. Additionally, PON1 hydrolyzes and detoxifies some toxic metabolites of organophosphorus compounds (OPs). Modulation of PON1 expression by many factors is due to interaction with nuclear receptors (NRs)
physiological function
paraoxonase 1 (PON1) is an physiologically important hydrolase. The enzyme activity decreases in patients with liver disease, diabetes, coronary heart disease, etc. Recombinant human PON1 shows selectivity over other serum esterases such as lipase, acetylcholinesterase, and esterase D more than 300folds. PON1 can prevent lipid oxidation in low-density lipoprotein and thus decrease the levels of oxidized lipids that are associated with aging, anoxia-reoxygenation injury, and atherosclerosis. Additionally, some evidences demonstrates its key role in metabolism of drugs
physiological function
serum paraoxonase 1 (PON1) is a native lactonase capable of promiscuously hydrolyzing a broad range of substrates, including organophosphates, esters, and carbonates. PON1 is a calcium-dependent hydrolytic enzyme that is found in all mammalian species. In vivo, this enzyme forms complexes with the membrane-like surface of high-density lipoprotein (HDL) and contributes to HDL's antioxidant properties. Modulation of substrate selectivity and catalytic stimulation by HDL
physiological function
SsoPox is a thermostable phosphotriesterase-like lactonase (PLL) that hydrolyses lactones (primary activity) and, at a lower rate, neurotoxic organophosphorus compounds (promiscuous activity)
physiological function
the enzyme catalyzes the hydrolysis of organophosphorus (OP) compounds and enhances hydrolysis of various nerve agents. PON1's native function is likely to be a lactonase which hydrolyzes the lactones from the oxidized lipids
physiological function
The enzyme exhibits anti-inflammatory, anti-oxidative, anti-atherogenic, anti-diabetic, anti-microbial and organophosphate-hydrolyzing activities
physiological function
the serum enzyme can hydrolyze (and inactivate) a wide range of substrates. It is a multifaceted enzyme and exhibit anti-inflammatory, anti-oxidative, anti-atherogenic, anti-diabetic, anti-microbial, and organophosphate (OP)-detoxifying properties
physiological function
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thermostable phosphotriesterase-like lactonases (PLLs) are able to degrade organophosphates and act as bioscavengers
additional information
active site residues are Y99, L228, F229 and W263. Structure-activity analysis of wild-type and mutant enzymes, overview
additional information
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active site residues are Y99, L228, F229 and W263. Structure-activity analysis of wild-type and mutant enzymes, overview
additional information
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analysis of the hydrogen bonding of the catalytic triad, mechanism by which Asp137 confers catalytic activity to enzyme LcalphaE7. In LcalphaE7 Gly137Asp:OP, the only other residues that sampled alternative conformations with significant frequency are Met308 and Phe309, which are adjacent to Asp137. These residues are in different conformations in the structure of the Gly137Asp variant relative to the wild-type enzyme
additional information
enzyme homology modeling and molecular dynamics simulations, overview. The active site contains two divalent metal ions essential for its catalytic activity and also 6 amino acids, including four histidine, one aspartic acid and one lysine. Disulfide bridge confirmation in the enzyme structure
additional information
enzyme PON1 is a six-bladed beta-propeller with a flexible loop (residues 70-81) covering the active site. This loop contains a functionally critical Tyr at position 71, mutational analysis of the role of Y71 in PON1's lactonase and organophosphatase activities. The side chain of Y71 is highly mobile and has been shown to adopt various conformational substrates that have been suggested to differentially affect PON1's native and promiscuous functions. Residue Y71 does not play an active role in PON1's lactonase activity in general, and specifically not on the HDL-induced simulation. Molecular dynamics simulations of PON1, e.g. using crystal structure of RePON1 in complex with the inhibitor 2-hydroxyquinoline (2HQ) and obtained at pH 6.5 (PDB ID 3SRG). In the wild-type enzyme Y71 forms a hydrogen-bonding interaction with the side chain of D183, which is itself part of a hydrogen-bonding network that leads from N168 on the catalytic Ca2+ ion to the outer periphery of the protein. D183 is central to this hydrogen-bonding network, as in addition to the hydrogen bond it forms with the side chain of Y71, it also forms hydrogen-bonding interactions with the side chains of S166, N168, and H184, the backbone carbonyl group of S166, and an active site water molecule. Therefore, D183 acts as an anchor, keeping this hydrogen-bonding network together. Active site hydrophobicity and the role of the active site loop in determining substrate selectivity, active site structure, structure-function relationship, overview
additional information
enzyme struture homology modelling, overview
additional information
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enzyme struture homology modelling, overview
additional information
enzyme three-dimensional structure homology model is used for interaction analysis in silico predictions of biopolymer transport protein ExbD with enzyme OPH, protein-protein docking studies on different variants of OPH and ExbD, overview. Residues R91 and R96 of OPH do contribute to interactions with recombinant N-terminally His6-tagged ExbD. Formation of a four-component Ton complex due to OPH interactions with proton motive force (ExbB/ExbD) and energy harvesting (TonB) components
additional information
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enzyme three-dimensional structure homology model is used for interaction analysis in silico predictions of biopolymer transport protein ExbD with enzyme OPH, protein-protein docking studies on different variants of OPH and ExbD, overview. Residues R91 and R96 of OPH do contribute to interactions with recombinant N-terminally His6-tagged ExbD. Formation of a four-component Ton complex due to OPH interactions with proton motive force (ExbB/ExbD) and energy harvesting (TonB) components
additional information
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h-PON1 is a polymorphic enzyme. Molecular docking analysis, homology modelling, overview
additional information
h-PON1 is a polymorphic enzyme. Molecular docking analysis, homology modelling, overview
additional information
identification of the OPH interactome using purified native wild-type enzyme. Protein-protein interactions study using the bacterial two-hybrid system
additional information
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identification of the OPH interactome using purified native wild-type enzyme. Protein-protein interactions study using the bacterial two-hybrid system
additional information
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protective ratio in mice pretreated i.v. with catalytic scavengers and challenged i.v. with tabun, paraoxon, O,O-diethyl fluorophosphate, and the cyclosarin surrogate, Sp-CMP, pH 8.0, 25°C or 38°C
additional information
the architecture of active pocket of enzyme mPHP coordinates with two metal ions, substrate binding structure, structre comparisons, overview
additional information
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the deduced amino acid sequences of OpdD show a potential serine hydrolase motif such as G-H-S116-Q-G
additional information
the serum paraoxonase 1 (PON1) is a calcium-dependent beta-propeller protein. PON1 has a six-blade beta-propeller fold with two calcium ions in its central tunnel. The structural Ca2+ is completely embedded inside the protein, and the catalytic Ca2+ is located at the bottom of the active site cavity. PON1, EC 3.1.8.1, and DFPase, EC 3.1.8.2, seem to employ similar catalytic mechanisms as phosphotriesterase, due to their structural similarities of active sites. The attacking nucleophile for phosphotriester hydrolysis is identified to be an activated water molecule, with the nucleophile attacking the phosphorus center. The E53Q and D269N mutants in PON1 both possess measurable lactonase and paraoxonase activity, and mutation studies combined with related molecular dynamics simulations suggest that the water activated by Glu53 and Asp269 is the most likely attacking nucleophile. Analysis of the rate-determining reaction step of the organophosphorus compound hydrolysis catalyzed both by DFPase and PON1. Structure-function relationship, overview. Active site structure of PON1 (PDB ID 3SRE) and substrate docking
additional information
the serum paraoxonase 1 (PON1) is a calcium-dependent beta-propeller protein. PON1 has a six-blade beta-propeller fold with two calcium ions in its central tunnel. The structural Ca2+ is completely embedded inside the protein, and the catalytic Ca2+ is located at the bottom of the active site cavity. PON1, EC 3.1.8.1, and DFPase, EC 3.1.8.2, seem to employ similar catalytic mechanisms as phosphotriesterase, due to their structural similarities of active sites. The attacking nucleophile for phosphotriester hydrolysis is identified to be an activated water molecule, with the nucleophile attacking the phosphorus center. The E53Q and D269N mutants in PON1 both possess measurable lactonase and paraoxonase activity, and mutation studies combined with related molecular dynamics simulations suggest that the water activated by Glu53 and Asp269 is the most likely attacking nucleophile. Analysis of the rate-determining reaction step of the organophosphorus compound hydrolysis catalyzed both by DFPase and PON1. Structure-function relationship, overview. Active site structure of PON1 (PDB ID 3SRE) and substrate docking
additional information
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the architecture of active pocket of enzyme mPHP coordinates with two metal ions, substrate binding structure, structre comparisons, overview
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additional information
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the architecture of active pocket of enzyme mPHP coordinates with two metal ions, substrate binding structure, structre comparisons, overview
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additional information
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the deduced amino acid sequences of OpdD show a potential serine hydrolase motif such as G-H-S116-Q-G
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