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Literature summary extracted from

  • Zhang, H.; Yang, L.; Ma, Y.Y.; Zhu, C.; Lin, S.; Liao, R.Z.
    Theoretical studies on catalysis mechanisms of serum paraoxonase 1 and phosphotriesterase diisopropyl fluorophosphatase suggest the alteration of substrate preference from paraoxonase to DFP (2018), Molecules, 23, 1660.
    View publication on PubMedView publication on EuropePMC

Cloned(Commentary)

EC Number Cloned (Comment) Organism
3.1.8.1 gene PON1, phylogenetic analysis Oryctolagus cuniculus
3.1.8.2 phylogenetic analysis Loligo vulgaris

Protein Variants

EC Number Protein Variants Comment Organism
3.1.8.1 D269N site-directed mutagenesis, the mutant possesses measurable lactonase and paraoxonase activity Oryctolagus cuniculus
3.1.8.1 D270X site-directed mutagenesis, mutation of the residue stabilizes the PON1-paraoxon substrate binding reducing the leaving group elimination rate. Effects of Asn270 mutation on enzymatic structure, overview Oryctolagus cuniculus
3.1.8.1 E53Q site-directed mutagenesis, the mutant possesses measurable lactonase and paraoxonase activity Oryctolagus cuniculus

Localization

EC Number Localization Comment Organism GeneOntology No. Textmining
3.1.8.1 extracellular
-
Oryctolagus cuniculus
-
-

Metals/Ions

EC Number Metals/Ions Comment Organism Structure
3.1.8.1 Ca2+ dependent on, 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. PTE Ca2+ binding structure comparisons Oryctolagus cuniculus
3.1.8.1 Zn2+ required Oryctolagus cuniculus
3.1.8.2 Ca2+ dependent on, PTE Ca2+ binding structure comparisons Loligo vulgaris
3.1.8.2 Zn2+ required Loligo vulgaris

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
3.1.8.1 dimethyl-paraoxon + H2O Oryctolagus cuniculus
-
dimethyl phosphate + 4-nitrophenol
-
?
3.1.8.2 diisopropyl fluorophosphate + H2O Loligo vulgaris
-
diisopropyl phosphate + fluoride
-
?

Organism

EC Number Organism UniProt Comment Textmining
3.1.8.1 Oryctolagus cuniculus P27170
-
-
3.1.8.2 Loligo vulgaris Q7SIG4
-
-

Reaction

EC Number Reaction Comment Organism Reaction ID
3.1.8.1 an aryl dialkyl phosphate + H2O = dialkyl phosphate + an aryl alcohol catalytic reaction mechanism involving residue Asp269, and role of Asp270 for the catalytic function, molecular dynamics and modelling, overview. The reaction is supposed to proceed by a two-step addition-elimination (An + Dn) mechanism, which goes through a common pentavalent intermediate observed in phosphoryl transfer reactions. The first step is the activation of H2O by Asp269 and Glu53 to form a nucleophile hydroxide and a metastable pentavalent complex. Both the residues Asn168 and Asn224 help the leaving group leave through hydrogen bonds Oryctolagus cuniculus
3.1.8.2 diisopropyl fluorophosphate + H2O = diisopropyl phosphate + fluoride catalytic reaction mechanism involving residue Asp269, molecular dynamics and modelling, overview Loligo vulgaris

Source Tissue

EC Number Source Tissue Comment Organism Textmining
3.1.8.1 serum
-
Oryctolagus cuniculus
-
3.1.8.2 central nervous system
-
Loligo vulgaris
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
3.1.8.1 dimethyl-paraoxon + H2O
-
Oryctolagus cuniculus dimethyl phosphate + 4-nitrophenol
-
?
3.1.8.1 additional information the mammalian serum paraoxonase 1 (PON1) is a calcium-dependent serum esterase which catalyzes the hydrolysis of a broad range of organic esters and organophosphorous (OP) compounds. PON1 is a lactonase with native substrates gamma- and delta-lactones which have long alkyl side chains, and PON1 possesses promiscuous OP hydrolase activity, particularly on paraoxon, which is attributed to its considerable plasticity of catalytic structure Oryctolagus cuniculus ?
-
?
3.1.8.2 (RS)-propan-2-yl methylphosphonofluoridate + H2O i.e. sarin Loligo vulgaris isopropyl phosphate methylphosphonate + fluoride
-
?
3.1.8.2 3-[fluoro(methyl)phosphoryl]oxy-2,2-dimethylbutane + H2O i.e. soman Loligo vulgaris 3,3-dimethylbutan-2-yl methylphosphonate + fluoride
-
?
3.1.8.2 cyclohexyl methylphosphonofluoridate + H2O i.e. cyclosarin Loligo vulgaris cyclohexyl methylphosphonate + fluoride
-
?
3.1.8.2 diisopropyl fluorophosphate + H2O
-
Loligo vulgaris diisopropyl phosphate + fluoride
-
?
3.1.8.2 ethyl dimethylphosphoramidocyanidate + H2O i.e. tabun Loligo vulgaris ?
-
?
3.1.8.2 additional information the squid phosphotriesterase diisopropyl fluorophosphatase (DFPase) from Loligo vulgaris shows relatively specific substrate preference, efficiently catalyzing the hydrolysis of diisopropyl fluorophosphate (DFP) and G-type nerve agents, including tabun (GA), sarin (GB), soman (GD), and cyclohexyl sarin (GF). The detoxification of the organophosphorous agent is achieved by the hydrolytic reaction producing a phosphate or phosphonate and a fluoride ion. The DFPase from squid central nervous system shows strong preference for the hydrolysis of P-F or P-CN bonds, which are absent in natural compounds Loligo vulgaris ?
-
?

Synonyms

EC Number Synonyms Comment Organism
3.1.8.1 paraoxonase 1
-
Oryctolagus cuniculus
3.1.8.1 PON1
-
Oryctolagus cuniculus
3.1.8.2 DFPase
-
Loligo vulgaris
3.1.8.2 diisopropyl fluorophosphatase
-
Loligo vulgaris
3.1.8.2 phosphotriesterase
-
Loligo vulgaris

General Information

EC Number General Information Comment Organism
3.1.8.1 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 Oryctolagus cuniculus
3.1.8.1 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 Oryctolagus cuniculus
3.1.8.1 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 Oryctolagus cuniculus
3.1.8.2 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 Loligo vulgaris
3.1.8.2 additional information the phosphotriesterase diisopropyl fluorophosphatase (DFPase) is a calcium-dependent beta-propeller protein. 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 DFPase (PDB ID 2GVW) and substrate docking Loligo vulgaris
3.1.8.2 physiological function the squid phosphotriesterase diisopropyl fluorophosphatase (DFPase) from Loligo vulgaris shows relatively specific substrate preference, efficiently catalyzing the hydrolysis of diisopropyl fluorophosphate (DFP) and G-type nerve agents, including tabun (GA), sarin (GB), soman (GD), and cyclohexyl sarin (GF). The detoxification of the organophosphorous (OP) agent is achieved by the hydrolytic reaction producing a phosphate or phosphonate and a fluoride ion Loligo vulgaris