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Information on EC 3.1.4.54 - N-acetylphosphatidylethanolamine-hydrolysing phospholipase D and Organism(s) Homo sapiens
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3.1.4.54 N-acetylphosphatidylethanolamine-hydrolysing phospholipase DIUBMB Comments
This enzyme is involved in the biosynthesis of anandamide. It does not hydrolyse phosphatidylcholine and phosphatidylethanolamine . No transphosphatidation . The enzyme contains Zn2+ and is activated by Mg2+ or Ca2+ .
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The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
Reaction Schemes
Synonyms
napepld, n-acyl phosphatidylethanolamine phospholipase d, n-acyl-phosphatidylethanolamine-specific phospholipase d, n-acylphosphatidylethanolamine-specific phospholipase d, nape-hydrolysing phospholipase d, 
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topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
NAPE-PLD
PATHWAY SOURCE
PATHWAYS
-
-, -, -
SYSTEMATIC NAME
IUBMB Comments
N-acetylphosphatidylethanolamine phosphatidohydrolase
This enzyme is involved in the biosynthesis of anandamide. It does not hydrolyse phosphatidylcholine and phosphatidylethanolamine [1]. No transphosphatidation [1]. The enzyme contains Zn2+ and is activated by Mg2+ or Ca2+ [2].
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
1,2-dihexadecyl-sn-glycerol-3-phospho-(N-palmitoyl)ethanolamine + H2O
N-palmitoylethanolamine + 1,2-dihexadecyl-sn-glycerol-3-phosphate
-
-
-
?
N-acylphosphatidylethanolamine + H2O
N-acylethanolamine + phosphatidate
N-acylethanolamines constitute a family of endogenous bioactive lipids that includes arachidonoylethanolamide, i.e. anandamide, palmitoylethanolamide, and oleoylethanolamide. These lipids are formed from their respective N-acylated ethanolamine phospholipid precursor by the action of a phospholipase D enzyme, NAPE-PLD. The bioactive lipids may influence, amongst others: neuroinflammation, food intake, and oocyte implantation
-
-
?
N-arachidonoylphosphatidylethanolamine + H2O
N-arachidonoylethanolamine + phosphatidic acid
N-palmitoyl-1,2-dilauroylphosphatidylethanolamine + H2O
N-palmitoylethanolamine + 1,2-dilauroyl-sn-glycerol 3-phosphate
-
-
-
?
N-palmitoyl-1,2-dioleoyl-phosphatidylethanolamine + H2O
N-palmitoylethanolamine + 1,2-dioleoyl-sn-glycerol 3-phosphate
-
-
-
?
N-arachidonoylphosphatidylethanolamine + H2O
N-arachidonoylethanolamine + phosphatidic acid
-
-
-
?
N-arachidonoylphosphatidylethanolamine + H2O
N-arachidonoylethanolamine + phosphatidic acid
the enzyme is involved in the biosynthesis of anandamide (N-arachidonoylethanolamine). NAPE-PLD is responsible for the conversion of N-acylphosphatidylethanolamines to N-acylethanolamines in vivo, but other enzyme(s) or pathway(s) are also involved in it, especially in the formation of polyunsaturated N-acylethanolamines, including anandamide. Unlike classical neurotransmitters and neuropeptides, endocannabinoids are not stored in vesicles in the cell, rather they are produced on demand from membrane phospholipids by a series of intracellular enzymes and released from cells, followed by immediate action as signaling molecules. Binding of endocannabinoids as well as cannabinoids to cannabinoid receptors results in the decrease in intracellular cyclic AMP level and the activation of mitogen-activated protein kinase through the coupled Gi/o proteins. The activation of cannabinoid receptors modulates ion channels through Gi/o proteins, leading to the activation of A-type and inwardly rectifying potassium channels and the inhibition of N-type and P/Q-type calcium channels. The endocannabinoid system is involved in a broad range of physiological functions, such as emotion, cardiovascular regulation, energy metabolism, and reproduction, and in a growing number of pathophysiological conditions
N-arachidonoylethanolamine i.e. anandamide
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
N-acylphosphatidylethanolamine + H2O
N-acylethanolamine + phosphatidate
N-acylethanolamines constitute a family of endogenous bioactive lipids that includes arachidonoylethanolamide, i.e. anandamide, palmitoylethanolamide, and oleoylethanolamide. These lipids are formed from their respective N-acylated ethanolamine phospholipid precursor by the action of a phospholipase D enzyme, NAPE-PLD. The bioactive lipids may influence, amongst others: neuroinflammation, food intake, and oocyte implantation
-
-
?
N-arachidonoylphosphatidylethanolamine + H2O
N-arachidonoylethanolamine + phosphatidic acid
the enzyme is involved in the biosynthesis of anandamide (N-arachidonoylethanolamine). NAPE-PLD is responsible for the conversion of N-acylphosphatidylethanolamines to N-acylethanolamines in vivo, but other enzyme(s) or pathway(s) are also involved in it, especially in the formation of polyunsaturated N-acylethanolamines, including anandamide. Unlike classical neurotransmitters and neuropeptides, endocannabinoids are not stored in vesicles in the cell, rather they are produced on demand from membrane phospholipids by a series of intracellular enzymes and released from cells, followed by immediate action as signaling molecules. Binding of endocannabinoids as well as cannabinoids to cannabinoid receptors results in the decrease in intracellular cyclic AMP level and the activation of mitogen-activated protein kinase through the coupled Gi/o proteins. The activation of cannabinoid receptors modulates ion channels through Gi/o proteins, leading to the activation of A-type and inwardly rectifying potassium channels and the inhibition of N-type and P/Q-type calcium channels. The endocannabinoid system is involved in a broad range of physiological functions, such as emotion, cardiovascular regulation, energy metabolism, and reproduction, and in a growing number of pathophysiological conditions
N-arachidonoylethanolamine i.e. anandamide
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Zn2+
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
1,2-dihexanoyl-glycero-N-(3-(tetradecanoylamino)propyl)phosphoramidate
i.e. AHP-71B, 96.6% inhibition at 1 mM
2,4-dioxo-N-[4-(4-pyridyl)phenyl]-1H-quinazoline-6-sulfonamide
reversible uncompetitive inhibitor, compound binds via a reversible mechanism to the enzyme's zinc center. Compound is not inhibitory to carbonic anhydrase II, neutral endopeptidase and angiotensin-converting enzyme
4-(4-(2-(3-methoxyphenyl)benzo[b]thiophen-3-yl)phenoxy)-N,N-dimethylethan-1-amine
-
compound additionally inhibits human phospholipases Pld1 and Pld2 and Pseudomonas aeruginosa PldA
N-(2,4-dinitrophenyl)-1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine
1 mM, 35.6% inhibition
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
1,2-dihexanoyl-glycero-3-(hexanoylamino)propylphosphonate
i.e. AHP-57, a phosphonic acid, activates 1.9fold at 1 mM
deoxycholate
presence of deoxycholate stabilizes the enzyme dimer and increases the catalytic activity with EC50 value of 0.186 mM. Binding is rapid and reversible
methyl-1,2-dihexanoyl-glycero-3-(hexanoylamino)propylphosphonate
i.e. AHP-38, a methylphosphonate, activates 68% at 1 mM
methyl-1,2-dihexanoyl-glycero-3-(tetradecanoylamino)propylphosphonate
i.e. AHP-36, a methylphosphonate, activates 2fold at 1 mM
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0029
N-palmitoyl-1,2-dioleoyl-phosphatidylethanolamine
37°C, pH 7.4, mutant enzyme D389N
0.0037
N-palmitoyl-1,2-dioleoyl-phosphatidylethanolamine
37°C, pH 7.4, mutant enzyme S152A
0.0046
N-palmitoyl-1,2-dioleoyl-phosphatidylethanolamine
37°C, pH 7.4, wild-type enzyme
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.01
1,2-dihexanoyl-glycero-N-(3-(tetradecanoylamino)propyl)phosphoramidate
Homo sapiens
pH 8.0, 37°C
0.067
4-(4-(2-(3-methoxyphenyl)benzo[b]thiophen-3-yl)phenoxy)-N,N-dimethylethan-1-amine
Homo sapiens
-
pH 7.5, 37°C
0.0367
2,4-dioxo-N-[4-(4-pyridyl)phenyl]-1H-quinazoline-6-sulfonamide
Homo sapiens
mutant Q320S, pH not specified in the publication, temperature not specified in the publication
0.0462
2,4-dioxo-N-[4-(4-pyridyl)phenyl]-1H-quinazoline-6-sulfonamide
Homo sapiens
wild-type, pH not specified in the publication, temperature not specified in the publication
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
associated to membrane. At the membrane interface, the NAPE-PLD dimer forms a hydrophobic nook that contains two molecules of phosphatidylethanolamine, one bound to each monomer
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
metabolism
the enzyme catalyzes a step in the biosynthesis of N-acylethanolamines, the biosynthetic route of N-acylethanolamines seems to involve at least three alternative pathways, overview
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). NAPEP_HUMAN
393
0
45596
Swiss-Prot
other Location (Reliability: 2)
A0A024R737_HUMAN
393
0
45595
TrEMBL
other Location (Reliability: 2)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
the enzyme is not a subject to posttranslational modification
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
to 2.65 A resolution. NAPE-PLD forms homodimers partly separated by an internal about 9 A wide channel and adapted to associate with phospholipids. A hydrophobic cavity provides an entryway for N-acylphosphatidylethanolamine into the active site, where a binuclear Zn2+ center is involved in hydrolysis. Bile acids bind with high affinity to selective pockets in this cavity, enhancing dimer assembly and enabling catalysis
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
D389N
Vmax is about 87% of wild-type activity, single nucleotide polymorphism mutant
L207F
complete loss of activity, single nucleotide polymorphism mutant of
Q158S/Y159S
mutant is unable to form stable dimers and shows a decreased melting temperature
S152A
Vmax is about 84% of wild-type activity, single nucleotide polymorphism mutant
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Wang, J.; Okamoto, Y.; Morishita, J.; Tsuboi, K.; Miyatake, A.; Ueda, N.
Functional analysis of the purified anandamide-generating phospholipase D as a member of the metallo-beta-lactamase family
J. Biol. Chem.
281
12325-12335
2006
Homo sapiens (Q6IQ20), Rattus norvegicus (Q769K2)
Okamoto, Y.; Wang, J.; Morishita, J.; Ueda, N.
Biosynthetic pathways of the endocannabinoid anandamide
Chem. Biodivers.
4
1842-1857
2007
Homo sapiens (Q6IQ20), Mus musculus (Q8BH82), Rattus norvegicus (Q769K2)
Petersen, G.; Pedersen, A.H.; Pickering, D.S.; Begtrup, M.; Hansen, H.S.
Effect of synthetic and natural phospholipids on N-acylphosphatidylethanolamine-hydrolyzing phospholipase D activity
Chem. Phys. Lipids
162
53-61
2009
Homo sapiens (Q6IQ20)
Wang, J.; Zhao, L.Y.; Uyama, T.; Tsuboi, K.; Wu, X.X., Kakehi, Y.; Ueda, N.
Expression and secretion of N-acylethanolamine-hydrolysing acid amidase in human prostate cancer cells
J. Biochem.
144
685-690
2008
Homo sapiens
Wang, J.; Ueda, N.
Biology of endocannabinoid synthesis system
Prostaglandins Other Lipid Mediat.
89
112-119
2009
Canis lupus familiaris, Homo sapiens (Q6IQ20), Mus musculus (Q8BH82), Rattus norvegicus (Q769K2)
Scott, S.; Spencer, C.; OReilly, M.; Brown, K.; Lavieri, R.; Cho, C.; Jung, D.; Larock, R.; Brown, H.; Lindsley, C.
Discovery of desketoraloxifene analogues as inhibitors of mammalian, Pseudomonas aeruginosa, and NAPE phospholipase D enzymes
ACS Chem. Biol.
10
421-432
2015
Homo sapiens
Castellani, B.; Diamanti, E.; Pizzirani, D.; Tardia, P.; Maccesi, M.; Realini, N.; Magotti, P.; Garau, G.; Bakkum, T.; Rivara, S.; Mor, M.; Piomelli, D.
Synthesis and characterization of the first inhibitor of N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD)
Chem. Commun. (Camb.)
53
12814-12817
2017
Homo sapiens (Q6IQ20)
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