Literature summary for 2.3.1.67 extracted from

Tarui, M.; Shindou, H.; Kumagai, K.; Morimoto, R.; Harayama, T.; Hashidate, T.; Kojima, H.; Okabe, T.; Nagano, T.; Nagase, T.; Shimizu, T.
Selective inhibitors of a PAF biosynthetic enzyme lysophosphatidylcholine acyltransferase 2 (2014), J. Lipid Res., 55, 1386-1396.

Application

Application	Comment	Organism
analysis	procedure for identification of LPCAT2-specific inhibitors via high-throughput screening	Mus musculus
analysis	procedure for identification of LPCAT2-specific inhibitors via high-throughput screening	Homo sapiens
drug development	identification of LPCAT2-specific inhibitors in order to ameliorate PAF-related inflammatory diseases, fluorescence-based high-throughput library screening	Mus musculus
drug development	identification of LPCAT2-specific inhibitors in order to ameliorate PAF-related inflammatory diseases, fluorescence-based high-throughput library screening	Homo sapiens

Cloned(Commentary)

Cloned (Comment)	Organism
expression in CHO-S and CHO-S-PAFR cells	Homo sapiens
gene LPCAT2, recombinant expression of FLAG-tagged human LPCAT2 in CHO cells	Homo sapiens
gene LPCAT2, recombinant expression of FLAG-tagged mouse LPCAT2 in CHO cells, stable recombinant enzyme expression in RAW264.7 cells	Mus musculus

Inhibitors

Inhibitors	Comment	Organism
3,4-dichloro-1-(4,5-dichloro-2-methoxyphenyl)-1H-pyrrole-2,5-dione	-	Homo sapiens
3,4-dichloro-1-(4,5-dichloro-2-methoxyphenyl)-1H-pyrrole-2,5-dione	-	Mus musculus
3-chloro-1-(3-chloro-4-methoxyphenyl)-4-(2-methoxyphenoxy)-1H-pyrrole-2,5-dione	-	Homo sapiens
3-chloro-1-(3-chloro-4-methoxyphenyl)-4-(2-methoxyphenoxy)-1H-pyrrole-2,5-dione	-	Mus musculus
3-chloro-1-(4,5-dichloro-2-methoxyphenyl)-4-(2-hydroxyanilino)-1H-pyrrole-2,5-dione	-	Homo sapiens
3-chloro-1-(4,5-dichloro-2-methoxyphenyl)-4-(2-hydroxyanilino)-1H-pyrrole-2,5-dione	-	Mus musculus
3-chloro-4-(morpholin-4-yl)-1-(4-phenoxyphenyl)-1H-pyrrole-2,5-dione	-	Homo sapiens
3-chloro-4-(morpholin-4-yl)-1-(4-phenoxyphenyl)-1H-pyrrole-2,5-dione	-	Mus musculus
butyl 4-(3,4-dichloro-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoate	80.4% inhibition at 0.02 mM	Homo sapiens
butyl 4-(3,4-dichloro-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoate	83.0% inhibition at 0.02 mM	Mus musculus
methyl 4-(3,4-dichloro-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoate	-	Homo sapiens
methyl 4-(3,4-dichloro-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoate	-	Mus musculus
methyl 4-[3-chloro-2,5-dioxo-4-(4-sulfamoylanilino)-2,5-dihydro-1H-pyrrol-1-yl]benzoate	-	Homo sapiens
methyl 4-[3-chloro-2,5-dioxo-4-(4-sulfamoylanilino)-2,5-dihydro-1H-pyrrol-1-yl]benzoate	-	Mus musculus
additional information	identification of LPCAT2-specific inhibitors in order to ameliorate platelet-activating factor-related inflammatory diseases: N-phenylmaleimide derivatives are selected from a 174000-compound library using fluorescence-based high-throughput screening followed by the evaluation of the effects on LPCAT1 and LPCAT2 activities, cell viability, and cellular platelet-activating factor production. The selected compounds have low inhibitory effects on enzyme LPCAT1 activity which is mostly expressed in the lungs where it produces platelet-activating factor, indicating that adverse effects on respiratory functions may be avoided. Structure-activity relationship, overview	Homo sapiens
additional information	identification of LPCAT2-specific inhibitors in order to ameliorate platelet-activating factor-related infl ammatory diseases: N-phenylmaleimide derivatives are selected from a 174000-compound library using fluorescence-based high-throughput screening followed by the evaluation of the effects on LPCAT1 and LPCAT2 activities, cell viability, and cellular platelet-activating factor production. The selected compounds have low inhibitory effects on enzyme LPCAT1 activity which is mostly expressed in the lungs where it produces platelet-activating factor, indicating that adverse effects on respiratory functions may be avoided. Structure-activity relationship, overview	Mus musculus
propan-2-yl 4-(3,4-dichloro-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoate	95.2% inhibition at 0.02 mM	Homo sapiens
propan-2-yl 4-(3,4-dichloro-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoate	95.5% inhibition at 0.02 mM	Mus musculus
propan-2-yl 4-(3-chloro-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoate	competitively inhibits the lyso-PAFAT activity with acetyl-CoA	Homo sapiens
propan-2-yl 4-(3-chloro-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoate	compound competes with acetyl-CoA for the inhibition of isoform LPCAT2 lyso-PAFAT activity and suppresses platelet-activating factor biosynthesis in mouse peritoneal macrophages stimulated with a calcium ionophore. The compound has low inhibitory effects on isoform LPCAT1 activity	Mus musculus
propan-2-yl 4-[3-chloro-4-(2-hydroxyanilino)-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl]benzoate	83.1% inhibition at 0.02 mM	Homo sapiens
propan-2-yl 4-[3-chloro-4-(2-hydroxyanilino)-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl]benzoate	82.4% inhibition at 0.02 mM	Mus musculus
propan-2-yl 4-[3-chloro-4-(morpholin-4-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl]benzoate	-	Homo sapiens
propan-2-yl 4-[3-chloro-4-(morpholin-4-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl]benzoate	-	Mus musculus
propyl 4-(3,4-dichloro-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoate	85.4% inhibition at 0.02 mM	Homo sapiens
propyl 4-(3,4-dichloro-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoate	86.7% inhibition at 0.02 mM	Mus musculus

Localization

Localization	Comment	Organism	GeneOntology No.	Textmining
microsome	-	Homo sapiens	-	-

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
acetyl-CoA + 1-alkyl-sn-glycero-3-phosphocholine	Mus musculus	-	CoA + 2-acetyl-1-alkyl-sn-glycero-3-phosphocholine	-	?
acetyl-CoA + 1-alkyl-sn-glycero-3-phosphocholine	Homo sapiens	-	CoA + 2-acetyl-1-alkyl-sn-glycero-3-phosphocholine	-	?

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	Q7L5N7	-	-
Homo sapiens	Q7L5N7	gene Lpcat2	-
Mus musculus	Q8BYI6	-	-
Mus musculus	Q8BYI6	gene Lpcat2	-

Source Tissue

Source Tissue	Comment	Organism	Textmining
macrophage	-	Mus musculus	-
macrophage	-	Homo sapiens	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.
acetyl-CoA + 1-alkyl-sn-glycero-3-phosphocholine	-	Mus musculus	CoA + 2-acetyl-1-alkyl-sn-glycero-3-phosphocholine	-	?
acetyl-CoA + 1-alkyl-sn-glycero-3-phosphocholine	-	Homo sapiens	CoA + 2-acetyl-1-alkyl-sn-glycero-3-phosphocholine	-	?
acetyl-CoA + 1-alkyl-sn-glycero-3-phosphocholine	substrates are d31-16:0 LPC or d4-lyso-PAF	Mus musculus	CoA + 2-acetyl-1-alkyl-sn-glycero-3-phosphocholine	-	?
acetyl-CoA + 1-alkyl-sn-glycero-3-phosphocholine	substrates are d31-16:0 LPC or d4-lyso-PAF	Homo sapiens	CoA + 2-acetyl-1-alkyl-sn-glycero-3-phosphocholine	-	?

Synonyms

Synonyms	Comment	Organism
acetyl-CoA:lyso-PAF acetyltransferase	-	Mus musculus
acetyl-CoA:lyso-PAF acetyltransferase	-	Homo sapiens
LPCAT2	-	Mus musculus
LPCAT2	-	Homo sapiens
lyso-PAFAT	-	Mus musculus
lyso-PAFAT	-	Homo sapiens

Temperature Optimum [°C]

Temperature Optimum [°C]	Temperature Optimum Maximum [°C]	Comment	Organism
37	-	assay at	Mus musculus
37	-	assay at	Homo sapiens

pH Optimum

pH Optimum Minimum	pH Optimum Maximum	Comment	Organism
7.4	-	assay at	Mus musculus
7.4	-	assay at	Homo sapiens

Cofactor

Cofactor	Comment	Organism	Structure
acetyl-CoA	-	Mus musculus
acetyl-CoA	-	Homo sapiens

IC50 Value

IC50 Value	IC50 Value Maximum	Comment	Organism	Inhibitor
0.0003	-	pH 7.4, 37°C	Homo sapiens	propyl 4-(3,4-dichloro-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoate
0.00033	-	pH 7.4, 37°C	Homo sapiens	butyl 4-(3,4-dichloro-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoate
0.00047	-	pH 7.4, 37°C	Homo sapiens	propan-2-yl 4-(3-chloro-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoate
0.00116	-	pH 7.4, 37°C	Homo sapiens	3-chloro-4-(morpholin-4-yl)-1-(4-phenoxyphenyl)-1H-pyrrole-2,5-dione
0.00127	-	pH 7.4, 37°C	Homo sapiens	propan-2-yl 4-(3,4-dichloro-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoate
0.00758	-	pH 7.4, 37°C	Homo sapiens	3-chloro-1-(3-chloro-4-methoxyphenyl)-4-(2-methoxyphenoxy)-1H-pyrrole-2,5-dione
0.0116	-	pH 7.4, 37°C	Homo sapiens	methyl 4-(3,4-dichloro-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoate
0.0133	-	pH 7.4, 37°C	Homo sapiens	propan-2-yl 4-[3-chloro-4-(2-hydroxyanilino)-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl]benzoate
0.0171	-	pH 7.4, 37°C	Homo sapiens	3,4-dichloro-1-(4,5-dichloro-2-methoxyphenyl)-1H-pyrrole-2,5-dione
0.02	-	pH 7.4, 37°C	Homo sapiens	3-chloro-1-(4,5-dichloro-2-methoxyphenyl)-4-(2-hydroxyanilino)-1H-pyrrole-2,5-dione
0.02	-	pH 7.4, 37°C	Homo sapiens	propan-2-yl 4-[3-chloro-4-(morpholin-4-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl]benzoate
0.02	-	pH 7.4, 37°C	Homo sapiens	methyl 4-[3-chloro-2,5-dioxo-4-(4-sulfamoylanilino)-2,5-dihydro-1H-pyrrol-1-yl]benzoate

Expression

Organism	Comment	Expression
Mus musculus	under inflammatory conditions, LPCAT2, but not LPCAT1, is activated and upregulated to produce the platelet-activating factor	up
Homo sapiens	under inflammatory conditions, LPCAT2, but not LPCAT1, is activated and upregulated to produce the platelet-activating factor	up

General Information

General Information	Comment	Organism
evolution	two entities of lyso-PAFAT belonging to the 1-acylglycerol-3-phosphate O-acyltransferase (AGPAT) family: a constitutively expressed lyso-PAFAT, LPCAT1,and an inducible lyso-PAFAT, LPCAT2. LPCAT1 is mainly expressed in the lungs and produces PAF and dipalmitoyl-phosphatidylcholine, which is a main component of a pulmonary surfactant essential for respiration. LPCAT2 is mainly expressed in inflammatory cells and also possesses biosynthetic activities for PAF and cellular membrane phosphatidylcholine	Mus musculus
evolution	two entities of lyso-PAFAT belonging to the 1-acylglycerol-3-phosphate O-acyltransferase (AGPAT) family: a constitutively expressed lyso-PAFAT, LPCAT1,and an inducible lyso-PAFAT, LPCAT2. LPCAT1 is mainly expressed in the lungs and produces PAF and dipalmitoyl-phosphatidylcholine, which is a main component of a pulmonary surfactant essential for respiration. LPCAT2 is mainly expressed in inflammatory cells and also possesses biosynthetic activities for PAF and cellular membrane phosphatidylcholine	Homo sapiens
metabolism	following extracellular stimulation, platelet-activating factor is rapidly biosynthesized via a remodeling pathway in inflammatory cells such as macrophages and neutrophils. In the remodeling pathway, one of the membrane phospholipids, 1-O-alkyl-2-acyl-sn-glycero-3-phosphocholine is hydrolyzed by phospholipase A2 to produce free fatty acids and lyso-PAF (1-O-alkyl-2-hydroxy-sn-glycero-3-phosphocholine). Acetyl-CoA:lyso-PAF acetyltransferase (lyso-PAFAT) subsequently converts lyso-PAF to PAF, which is rapidly degraded to lyso-PAF and acetic acid by PAF acetylhydrolases, terminating its effects	Mus musculus
metabolism	following extracellular stimulation, platelet-activating factor is rapidly biosynthesized via a remodeling pathway in inflammatory cells such as macrophages and neutrophils. In the remodeling pathway, one of the membrane phospholipids, 1-O-alkyl-2-acyl-sn-glycero-3-phosphocholine is hydrolyzed by phospholipase A2 to produce free fatty acids and lyso-PAF (1-O-alkyl-2-hydroxy-sn-glycero-3-phosphocholine). Acetyl-CoA:lyso-PAF acetyltransferase (lyso-PAFAT) subsequently converts lyso-PAF to PAF, which is rapidly degraded to lyso-PAF and acetic acid by PAF acetylhydrolases, terminating its effects	Homo sapiens
physiological function	platelet-activating factor (PAF) is a potent pro-inflammatory phospholipid mediator. In response to extracellular stimuli, PAF is rapidly biosynthesized by lyso-PAF acetyltransferase. Under inflammatory conditions, LPCAT2, but not LPCAT1, is activated and upregulated to produce the platelet-activating factor	Mus musculus
physiological function	platelet-activating factor (PAF) is a potent pro-inflammatory phospholipid mediator. In response to extracellular stimuli, PAF is rapidly biosynthesized by lyso-PAF acetyltransferase. Under inflammatory conditions, LPCAT2, but not LPCAT1, is activated and upregulated to produce the platelet-activating factor	Homo sapiens