Literature summary for 3.1.8.1 extracted from

Blaha-Nelson, D.; Krueger, D.M.; Szeler, K.; Ben-David, M.; Kamerlin, S.C.
Active site hydrophobicity and the convergent evolution of paraoxonase activity in structurally divergent enzymes the case of serum paraoxonase 1 (2017), J. Am. Chem. Soc., 139, 1155-1167 .

Search for more literature for 3.1.8.1

Activating Compound

Activating Compound	Comment	Organism	Structure
HDL	modulation of substrate selectivity and catalytic stimulation by HDL	Oryctolagus cuniculus

Application

Application	Comment	Organism
medicine	PON1 shows great promise as a biotherapeutic due to its role in atherosclerosis and because of its ability to hydrolyze a broad range of organophosphates, including pesticides and nerve agents such as sarin, soman, and VX	Oryctolagus cuniculus

Protein Variants

Protein Variants	Comment	Organism
additional information	modulating the active site hydrophobicity is a key element in facilitating the evolution of organophosphatase activity. Molecular dynamics simulations of wild-type and mutant PON1 enzymes, detailed overview	Oryctolagus cuniculus
Y71A	site-directed mutagenesis, the mutant shows an increased active site volume compared to the wild-type	Oryctolagus cuniculus
Y71F	site-directed mutagenesis, the mutant shows an increased active site volume compared to the wild-type	Oryctolagus cuniculus
Y71G	site-directed mutagenesis, the mutant shows reduced lactonase and paraoxonase activities compared to the wild-type enzyme, the mutant shows an increased active site volume compared to the wild-type	Oryctolagus cuniculus
Y71M	site-directed mutagenesis, the mutant shows reduced lactonase and paraoxonase activities compared to the wild-type enzyme, the mutant shows an increased active site volume compared to the wild-type	Oryctolagus cuniculus
Y71W	site-directed mutagenesis, the mutant shows an increased active site volume compared to the wild-type	Oryctolagus cuniculus
Y71X	site-saturation library screening. 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. Differential effect of mutating Y71 on the native and promiscuous activities of PON1, detailed overview	Oryctolagus cuniculus

Inhibitors

Inhibitors	Comment	Organism	Structure
2-hydroxyquinoline	enzyme-bound structure, overview	Oryctolagus cuniculus

KM Value [mM]

KM Value [mM]	KM Value Maximum [mM]	Substrate	Comment	Organism	Structure
additional information	-	additional information	Michaelis-Menten kinetics	Oryctolagus cuniculus

Metals/Ions

Metals/Ions	Comment	Organism	Structure
Ca2+	dependent on, catalytic Ca2+ ion	Oryctolagus cuniculus

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
diethyl-paraoxon + H2O	Oryctolagus cuniculus	-	diethyl phosphate + 4-nitrophenol	-	?

Organism

Organism	UniProt	Comment	Textmining
Oryctolagus cuniculus	P27170	-	-

Reaction

Reaction	Comment	Organism	Reaction ID
an aryl dialkyl phosphate + H2O = dialkyl phosphate + an aryl alcohol	reaction mechanism of lactonase activity and paraoxonase activity of the enzyme PON1, overview	Oryctolagus cuniculus	a

Source Tissue

Source Tissue	Comment	Organism	Textmining
serum	-	Oryctolagus cuniculus	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
diethyl-paraoxon + H2O	-	Oryctolagus cuniculus	diethyl phosphate + 4-nitrophenol	-	?
diethyl-paraoxon + H2O	both docking and molecular dynamics simulations suggest that the only way paraoxon can be accommodated in the PON1 active site is by pushing Y71 out of the active site, causing the active site loop to take on a partially open conformation	Oryctolagus cuniculus	diethyl phosphate + 4-nitrophenol	-	?
additional information	th enzyme is also active with the chromogenic lactone thiobutyl-gamma-butyric lactone (TBBL), cf. EC 3.1.1.81. It has both lactonase activity and paraoxonase activity. Empirical valence bond simulations of PON1-catalyzed hydrolyses of paraoxon and TBBL, overview	Oryctolagus cuniculus	?	-	?

Subunits

Subunits	Comment	Organism
More	enzyme PON1 is a six-bladed beta-propeller with a flexible loop (residues 70-81) covering the active site	Oryctolagus cuniculus

Synonyms

Synonyms	Comment	Organism
More	cf. EC 3.1.1.81	Oryctolagus cuniculus
paraoxonase 1	-	Oryctolagus cuniculus
PON1	-	Oryctolagus cuniculus
serum paraoxonase 1	-	Oryctolagus cuniculus

General Information

General Information	Comment	Organism
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	Oryctolagus cuniculus
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	Oryctolagus cuniculus
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	Oryctolagus cuniculus
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	Oryctolagus cuniculus

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Release 2023.1 (January 2023)