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Literature summary extracted from

  • Gorelik, A.; Gebai, A.; Illes, K.; Piomelli, D.; Nagar, B.
    Molecular mechanism of activation of the immunoregulatory amidase NAAA (2018), Proc. Natl. Acad. Sci. USA, 115, E10032-E10040 .
    View publication on PubMedView publication on EuropePMC

Cloned(Commentary)

EC Number Cloned (Comment) Organism
3.5.1.60 recombinant expression of enzyme NAAA in Spodoptera frugiperda Sf9 insect cells via baculovirus transfection method, the enzyme is secreted. The endogenous signal peptide is replaced by the melittin signal peptide MKFLVNVALVFMVVYISYIYA followed by a His6-tag DRHHHHHHKL. Construct encompasses residues 31-359 of NAAA of mouse enzyme Oryctolagus cuniculus
3.5.1.60 recombinant expression of wild-type and mutant enzymes NAAA in Spodoptera frugiperda Sf9 insect cells via baculovirus transfection method, the enzyme is secreted. The endogenous signal peptide comprising the first 28-33 residues is replaced by the melittin signal peptide MKFLVNVALVFMVVYISYIYA followed by a His6-tag DRHHHHHHKL. Constructs encompassed residues 29-359 of NAAA of human enzyme Homo sapiens
3.5.1.60 recombinant expression of wild-type and mutant enzymes NAAA in Spodoptera frugiperda Sf9 insect cells via baculovirus transfection method, the enzyme is secreted. The endogenous signal peptide is replaced by the melittin signal peptide MKFLVNVALVFMVVYISYIYA followed by a His6-tag DRHHHHHHKL. Constructs encompass residues 29-355 of NAAA of mouse enzyme Cavia porcellus
3.5.1.60 recombinant expression of wild-type and mutant enzymes NAAA in Spodoptera frugiperda Sf9 insect cells via baculovirus transfection method, the enzyme is secreted. The endogenous signal peptide is replaced by the melittin signal peptide MKFLVNVALVFMVVYISYIYA followed by a His6-tag DRHHHHHHKL. Constructs encompass residues 34-362 of NAAA of mouse enzyme Mus musculus

Crystallization (Commentary)

EC Number Crystallization (Comment) Organism
3.5.1.60 purified recombinant enzyme C116A mutant in complex with inhibitors ARN726, ARN19702, and with substrate myristate, and in presence of Triton X-100, X-ray diffraction structure determination and analysis at 2.7 A resolution Oryctolagus cuniculus
3.5.1.60 purified recombinant enzyme in complex with inhibitor ARN726, and in presence of Triton X-100, X-ray diffraction structure determination and analysis at 3.0. A resolution Cavia porcellus
3.5.1.60 purified recombinnat enzyme C116A mutant in complex with ARN19702 and in presence of Triton X-100, X-ray diffraction structure determination and analysis at 3.0 A resolution Homo sapiens

Protein Variants

EC Number Protein Variants Comment Organism
3.5.1.60 A47V site-directed mutagenesis Mus musculus
3.5.1.60 A75R site-directed mutagenesis Cavia porcellus
3.5.1.60 C116A site-directed mutagenesis, inhibition of disulfide bridge formation Homo sapiens
3.5.1.60 H142R site-directed mutagenesis Mus musculus
3.5.1.60 K95E site-directed mutagenesis Cavia porcellus
3.5.1.60 N112S site-directed mutagenesis, the mutation abolishes an N-linked glycosylation site Homo sapiens
3.5.1.60 N163D site-directed mutagenesis Mus musculus
3.5.1.60 N338S site-directed mutagenesis, the mutation abolishes an N-linked glycosylation site4 Homo sapiens

Inhibitors

EC Number Inhibitors Comment Organism Structure
3.5.1.60 4-cyclohexylbutyl-N-[(S)-2-oxoazetidin-3-yl]carbamate ARN726, enzyme-binding structure analysis. Nucleophilic attack on the carbonyl carbon of the strained beta-lactam moiety by the Cys126 side chain Cavia porcellus
3.5.1.60 4-cyclohexylbutyl-N-[(S)-2-oxoazetidin-3-yl]carbamate ARN726, a beta-lactam that irreversibly reacts with Cys126 Homo sapiens
3.5.1.60 4-cyclohexylbutyl-N-[(S)-2-oxoazetidin-3-yl]carbamate ARN726 Mus musculus
3.5.1.60 4-cyclohexylbutyl-N-[(S)-2-oxoazetidin-3-yl]carbamate ARN726, enzyme-binding structure analysis. Nucleophilic attack on the carbonyl carbon of the strained beta-lactam moiety by the Cys126 side chain Oryctolagus cuniculus
3.5.1.60 additional information NAAA inhibitors block the substrate-binding site Cavia porcellus
3.5.1.60 additional information NAAA inhibitors block the substrate-binding site Homo sapiens
3.5.1.60 additional information NAAA inhibitors block the substrate-binding site Mus musculus
3.5.1.60 additional information NAAA inhibitors block the substrate-binding site Oryctolagus cuniculus
3.5.1.60 [2-(ethylsulfonyl)phenyl][(2S)-4-(6-fluoro-1,3-benzothiazol-2-yl)-2-methylpiperazin-1-yl]methanone ARN19702, a noncovalent benzothiazole-piperazine derivative Homo sapiens

Localization

EC Number Localization Comment Organism GeneOntology No. Textmining
3.5.1.60 lysosome
-
Homo sapiens 5764
-
3.5.1.60 lysosome
-
Mus musculus 5764
-
3.5.1.60 lysosome
-
Oryctolagus cuniculus 5764
-
3.5.1.60 lysosome
-
Cavia porcellus 5764
-
3.5.1.60 membrane proposed membrane interactions via hydrophobic helices alpha3 and alpha6 Homo sapiens 16020
-
3.5.1.60 membrane proposed membrane interactions via hydrophobic helices alpha3 and alpha6 Mus musculus 16020
-
3.5.1.60 membrane proposed membrane interactions via hydrophobic helices alpha3 and alpha6 Oryctolagus cuniculus 16020
-
3.5.1.60 membrane proposed membrane interactions via hydrophobic helices alpha3 and alpha6 Cavia porcellus 16020
-

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
3.5.1.60 N-palmitoylethanolamide + H2O Homo sapiens
-
palmitate + ethanolamine
-
?
3.5.1.60 N-palmitoylethanolamide + H2O Mus musculus
-
palmitate + ethanolamine
-
?
3.5.1.60 N-palmitoylethanolamide + H2O Oryctolagus cuniculus
-
palmitate + ethanolamine
-
?
3.5.1.60 N-palmitoylethanolamide + H2O Cavia porcellus
-
palmitate + ethanolamine
-
?

Organism

EC Number Organism UniProt Comment Textmining
3.5.1.60 Cavia porcellus H0VCJ6
-
-
3.5.1.60 Homo sapiens Q02083
-
-
3.5.1.60 Mus musculus Q9D7V9
-
-
3.5.1.60 Oryctolagus cuniculus G1T7U7
-
-

Posttranslational Modification

EC Number Posttranslational Modification Comment Organism
3.5.1.60 glycoprotein
-
Homo sapiens
3.5.1.60 glycoprotein
-
Mus musculus
3.5.1.60 glycoprotein
-
Oryctolagus cuniculus
3.5.1.60 glycoprotein
-
Cavia porcellus
3.5.1.60 proteolytic modification self-proteolysis exposes the NAAA active site Homo sapiens
3.5.1.60 proteolytic modification self-proteolysis exposes the NAAA active site Mus musculus
3.5.1.60 proteolytic modification self-proteolysis exposes the NAAA active site Oryctolagus cuniculus
3.5.1.60 proteolytic modification self-proteolysis exposes the NAAA active site Cavia porcellus

Purification (Commentary)

EC Number Purification (Comment) Organism
3.5.1.60 recombinant His-tagged enzyme from Spodoptera frugiperda Sf9 insect cells by nickel affinity chromatography, gel filtration, and anion exchange chromatography Oryctolagus cuniculus
3.5.1.60 recombinant His-tagged wild-type and mutant enzymes from Spodoptera frugiperda Sf9 insect cells by nickel affinity chromatography, gel filtration, and anion exchange chromatography Cavia porcellus
3.5.1.60 recombinant His6-tagged wild-type and mutant enzymes from Spodoptera frugiperda Sf9 insect cells by nickel affinity chromatography, gel filtration, and anion exchange chromatography Homo sapiens
3.5.1.60 recombinant His6-tagged wild-type and mutant enzymes from Spodoptera frugiperda Sf9 insect cells by nickel affinity chromatography, gel filtration, and anion exchange chromatography Mus musculus

Source Tissue

EC Number Source Tissue Comment Organism Textmining
3.5.1.60 additional information N-acylethanolamine acid amidase is expressed at high levels in immune cells Homo sapiens
-
3.5.1.60 additional information N-acylethanolamine acid amidase is expressed at high levels in immune cells Mus musculus
-
3.5.1.60 additional information N-acylethanolamine acid amidase is expressed at high levels in immune cells Oryctolagus cuniculus
-
3.5.1.60 additional information N-acylethanolamine acid amidase is expressed at high levels in immune cells Cavia porcellus
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
3.5.1.60 N-palmitoylethanolamide + H2O
-
Homo sapiens palmitate + ethanolamine
-
?
3.5.1.60 N-palmitoylethanolamide + H2O
-
Mus musculus palmitate + ethanolamine
-
?
3.5.1.60 N-palmitoylethanolamide + H2O
-
Oryctolagus cuniculus palmitate + ethanolamine
-
?
3.5.1.60 N-palmitoylethanolamide + H2O
-
Cavia porcellus palmitate + ethanolamine
-
?

Subunits

EC Number Subunits Comment Organism
3.5.1.60 heterotetramer enzyme NAAA adopts an alphabetabetaalpha-fold with a helical alpha-subunit Homo sapiens
3.5.1.60 heterotetramer enzyme NAAA adopts an alphabetabetaalpha-fold with a helical alpha-subunit Mus musculus
3.5.1.60 heterotetramer enzyme NAAA adopts an alphabetabetaalpha-fold with a helical alpha-subunit Oryctolagus cuniculus
3.5.1.60 heterotetramer enzyme NAAA adopts an alphabetabetaalpha-fold with a helical alpha-subunit Cavia porcellus

Synonyms

EC Number Synonyms Comment Organism
3.5.1.60 N-acylethanolamine acid amidase
-
Homo sapiens
3.5.1.60 N-acylethanolamine acid amidase
-
Mus musculus
3.5.1.60 N-acylethanolamine acid amidase
-
Oryctolagus cuniculus
3.5.1.60 NAAA
-
Homo sapiens
3.5.1.60 NAAA
-
Mus musculus
3.5.1.60 NAAA
-
Oryctolagus cuniculus
3.5.1.60 NAAA
-
Cavia porcellus
3.5.1.60 Nacylethanolamine acid amidase
-
Cavia porcellus

Temperature Optimum [°C]

EC Number Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
3.5.1.60 37
-
assay at Homo sapiens
3.5.1.60 37
-
assay at Mus musculus
3.5.1.60 37
-
assay at Oryctolagus cuniculus
3.5.1.60 37
-
assay at Cavia porcellus

pH Optimum

EC Number pH Optimum Minimum pH Optimum Maximum Comment Organism
3.5.1.60 4.5
-
assay at Homo sapiens
3.5.1.60 4.5
-
assay at Mus musculus
3.5.1.60 4.5
-
assay at Oryctolagus cuniculus
3.5.1.60 4.5
-
assay at Cavia porcellus

IC50 Value

EC Number IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
3.5.1.60 0.00023
-
pH 4.5, 37°C, recombinant enzyme Homo sapiens [2-(ethylsulfonyl)phenyl][(2S)-4-(6-fluoro-1,3-benzothiazol-2-yl)-2-methylpiperazin-1-yl]methanone

General Information

EC Number General Information Comment Organism
3.5.1.60 malfunction pharmacological inhibitors of NAAA activity exert profound analgesic and antiinflammatory effects Mus musculus
3.5.1.60 additional information structure analysis of the enzme in complex with myristate, substrate binding structure, overview. The enzyme must disrupt the membrane to reach its embedded substrate, and helices alpha3 and alpha6 are likely candidates for this function Oryctolagus cuniculus
3.5.1.60 additional information the enzyme must disrupt the membrane to reach its embedded substrate, and helices alpha3 and alpha6 are likely candidates for this function Homo sapiens
3.5.1.60 additional information the enzyme must disrupt the membrane to reach its embedded substrate, and helices alpha3 and alpha6 are likely candidates for this function Cavia porcellus
3.5.1.60 additional information the enzyme must disrupt the membrane to reach its embedded substrate, and helices alpha3 and alpha6 are likely candidates for this function. Detergent-induced rearrangement generates the NAAA substrate-binding site Mus musculus