Literature summary for 3.3.2.6 extracted from

Lu, W.; Yao, X.; Ouyang, P.; Dong, N.; Wu, D.; Jiang, X.; Wu, Z.; Zhang, C.; Xu, Z.; Tang, Y.; Zou, S.; Liu, M.; Li, J.; Zeng, M.; Lin, P.; Cheng, F.; Huang, J.
Drug repurposing of histone deacetylase inhibitors that alleviate neutrophilic inflammation in acute lung injury and idiopathic pulmonary fibrosis via inhibiting leukotriene A4 hydrolase and blocking LTB4 biosynthesis (2017), J. Med. Chem., 60, 1817-1828 .

Application

Application	Comment	Organism
drug development	Drug repurposing of histone deacetylase inhibitors that alleviate neutrophilic inflammation in acute lung injury and idiopathic pulmonary fibrosis via inhibiting leukotriene A4 hydrolase and blocking LTB4 biosynthesis	Mus musculus
drug development	drug repurposing of histone deacetylase inhibitors that alleviate neutrophilic inflammation in acute lung injury and idiopathic pulmonary fibrosis via inhibiting leukotriene A4 hydrolase and blocking LTB4 biosynthesis. Inhibiting LTB4 biosynthesis and subsequently neutrophilic inflammation may provide a potential strategy for the treatment of acute lung injury (ALI) and idiopathic pulmonary fibrosis (IPF)	Homo sapiens

Crystallization (Commentary)

Crystallization (Comment)	Organism
enzyme in complex with inhibitors SAHA or M344, X-ray diffraction structure determination and analysis	Homo sapiens
enzyme in complex with inhibitors SAHA or M344, X-ray diffraction structure determination and analysis	Mus musculus

Inhibitors

Inhibitors	Comment	Organism
(S)-2-((2S,3R)-3-amino-2-hydroxy-4-phenylbutanamido)-4-methylpentanoic acid	-	Homo sapiens
(S)-2-((2S,3R)-3-amino-2-hydroxy-4-phenylbutanamido)-4-methylpentanoic acid	-	Mus musculus
3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]-propanoic acid	-	Homo sapiens
3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]-propanoic acid	-	Mus musculus
4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide	enzyme binding structure, overview	Homo sapiens
4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide	markedly diminishes early neutrophilic inflammation in mouse models of ALI and IPF under a clinical safety dose, enzyme binding structure, overview	Mus musculus
abexinostat	-	Homo sapiens
abexinostat	-	Mus musculus
belinostat	-	Homo sapiens
belinostat	-	Mus musculus
CUDC-101	-	Homo sapiens
CUDC-101	-	Mus musculus
entinostat	-	Homo sapiens
entinostat	-	Mus musculus
givinostat	-	Homo sapiens
givinostat	-	Mus musculus
JNJ-26481585	-	Homo sapiens
JNJ-26481585	-	Mus musculus
mocetinostat	-	Homo sapiens
mocetinostat	-	Mus musculus
additional information	drug repurposing of histone deacetylase (HDAC) inhibitors that alleviate neutrophilic inflammation in acute lung injury and idiopathic pulmonary fibrosis via inhibiting leukotriene A4 hydrolase and blocking LTB4 biosynthesis, overview. Analysis of potential inhibitors of LTA4H across a panel of 18 HDAC inhibitors, using enzymatic assay, thermofluor assay, and X-ray crystallographic investigation. Detailed mechanisms of down-regulation of proinflammatory cytokines by SAHA or M344 are determined in vivo. Cotreatment of N-(6-(2-aminophenylamino)-6-oxyhexyl)-4-methylbenzamide and (S)-2-((2S,3R)-3-amino-2-hydroxy-4-phenylbutanamido)-4-methylpentanoic acid synergistically represses the migration of neutrophil and LTB4-induced neutrophil migration is not affected by these treatments. Molecular modelling of HDAC inhibitors against LTA4H hydrolase and aminopeptidase	Homo sapiens
additional information	drug repurposing of histone deacetylase (HDAC) inhibitors that alleviate neutrophilic inflammation in acute lung injury and idiopathic pulmonary fibrosis via inhibiting leukotriene A4 hydrolase and blocking LTB4 biosynthesis, overview. Analysis of potential inhibitors of LTA4H across a panel of 18 HDAC inhibitors, using enzymatic assay, thermofluor assay, and X-ray crystallographic investigation. Detailed mechanisms of down-regulation of proinflammatory cytokines by SAHA or M344 are determined in vivo. Cotreatment of N-(6-(2-aminophenylamino)-6-oxyhexyl)-4-methylbenzamide and (S)-2-((2S,3R)-3-amino-2-hydroxy-4-phenylbutanamido)-4-methylpentanoic acid synergistically represses the migration of neutrophil and LTB4-induced neutrophil migration is not affected by these treatments. Molecular modeling of HDAC inhibitors against LTA4H hydrolase and aminopeptidase	Mus musculus
N-(6-(2-aminophenylamino)-6-oxyhexyl)-4-methylbenzamide	-	Homo sapiens
N-(6-(2-aminophenylamino)-6-oxyhexyl)-4-methylbenzamide	-	Mus musculus
panobinostat	-	Homo sapiens
panobinostat	-	Mus musculus
pracinostat	-	Homo sapiens
pracinostat	-	Mus musculus
resminostat	-	Homo sapiens
resminostat	-	Mus musculus
rocilinostat	-	Homo sapiens
rocilinostat	-	Mus musculus
scriptaid	-	Homo sapiens
scriptaid	-	Mus musculus
suberanilohydroxamic acid	enzyme binding structure, overview	Homo sapiens
suberanilohydroxamic acid	markedly diminishes early neutrophilic inflammation in mouse models of ALI and IPF under a clinical safety dose, enzyme binding structure, overview	Mus musculus
trichostatin A	-	Homo sapiens
trichostatin A	-	Mus musculus
tubacin	-	Homo sapiens
tubacin	-	Mus musculus
Valproate	-	Homo sapiens
Valproate	-	Mus musculus

Metals/Ions

Metals/Ions	Comment	Organism	Structure
Zn2+	zinc metalloenzyme, enzyme LTA4H folds into three domains and creates a deep cleft harboring the catalytic Zn2+ site, forming the active site with an L-shaped hydrophobic pocket deep into the protein	Homo sapiens
Zn2+	zinc metalloenzyme, enzyme LTA4H folds into three domains and creates a deep cleft harboring the catalytic Zn2+ site, forming the active site with an L-shaped hydrophobic pocket deep into the protein	Mus musculus

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
leukotriene A4 + H2O	Homo sapiens	-	leukotriene B4	-	?
leukotriene A4 + H2O	Mus musculus	-	leukotriene B4	-	?

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	P09960	-	-
Mus musculus	P24527	-	-

Source Tissue

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

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.
leukotriene A4 + H2O	-	Homo sapiens	leukotriene B4	-	?
leukotriene A4 + H2O	-	Mus musculus	leukotriene B4	-	?
additional information	the aminopeptidase binding site shares a similar structure to LTA4H at its ligand binding sites	Homo sapiens	?	-	?
additional information	the aminopeptidase binding site shares a similar structure to LTA4H at its ligand binding sites	Mus musculus	?	-	?

Subunits

Subunits	Comment	Organism
More	LTA4H folds into three domains and creates a deep cleft harboring the catalytic Zn2+ site, forming the active site with an L-shaped hydrophobic pocket deep into the protein	Homo sapiens
More	LTA4H folds into three domains and creates a deep cleft harboring the catalytic Zn2+ site, forming the active site with an L-shaped hydrophobic pocket deep into the protein	Mus musculus

Synonyms

Synonyms	Comment	Organism
leukotriene A4 hydrolase	-	Homo sapiens
leukotriene A4 hydrolase	-	Mus musculus
LTA4H	-	Homo sapiens
LTA4H	-	Mus musculus
More	see also EC 3.4.11.6	Homo sapiens

IC50 Value

IC50 Value	IC50 Value Maximum	Comment	Organism	Inhibitor
0.00068	-	pH and temperature not specified in the publication	Homo sapiens	4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide
0.00068	-	pH and temperature not specified in the publication	Mus musculus	4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide
0.00765	-	pH and temperature not specified in the publication	Homo sapiens	suberanilohydroxamic acid
0.00765	-	pH and temperature not specified in the publication	Mus musculus	suberanilohydroxamic acid
0.01	-	above, pH and temperature not specified in the publication	Homo sapiens	trichostatin A
0.01	-	above, pH and temperature not specified in the publication	Mus musculus	trichostatin A
0.01	-	above, pH and temperature not specified in the publication	Homo sapiens	Valproate
0.01	-	above, pH and temperature not specified in the publication	Mus musculus	Valproate
0.01	-	above, pH and temperature not specified in the publication	Homo sapiens	tubacin
0.01	-	above, pH and temperature not specified in the publication	Mus musculus	tubacin
0.01	-	above, pH and temperature not specified in the publication	Homo sapiens	JNJ-26481585
0.01	-	above, pH and temperature not specified in the publication	Mus musculus	JNJ-26481585
0.01	-	above, pH and temperature not specified in the publication	Homo sapiens	belinostat
0.01	-	above, pH and temperature not specified in the publication	Mus musculus	belinostat
0.01	-	above, pH and temperature not specified in the publication	Homo sapiens	entinostat
0.01	-	above, pH and temperature not specified in the publication	Mus musculus	entinostat
0.01	-	above, pH and temperature not specified in the publication	Homo sapiens	scriptaid
0.01	-	above, pH and temperature not specified in the publication	Mus musculus	scriptaid
0.01	-	above, pH and temperature not specified in the publication	Homo sapiens	panobinostat
0.01	-	above, pH and temperature not specified in the publication	Mus musculus	panobinostat
0.01	-	above, pH and temperature not specified in the publication	Homo sapiens	mocetinostat
0.01	-	above, pH and temperature not specified in the publication	Mus musculus	mocetinostat
0.01	-	above, pH and temperature not specified in the publication	Homo sapiens	resminostat
0.01	-	above, pH and temperature not specified in the publication	Mus musculus	resminostat
0.01	-	above, pH and temperature not specified in the publication	Homo sapiens	abexinostat
0.01	-	above, pH and temperature not specified in the publication	Mus musculus	abexinostat
0.01	-	above, pH and temperature not specified in the publication	Homo sapiens	CUDC-101
0.01	-	above, pH and temperature not specified in the publication	Mus musculus	CUDC-101
0.01	-	above, pH and temperature not specified in the publication	Homo sapiens	givinostat
0.01	-	above, pH and temperature not specified in the publication	Mus musculus	givinostat
0.01	-	above, pH and temperature not specified in the publication	Homo sapiens	N-(6-(2-aminophenylamino)-6-oxyhexyl)-4-methylbenzamide
0.01	-	above, pH and temperature not specified in the publication	Mus musculus	N-(6-(2-aminophenylamino)-6-oxyhexyl)-4-methylbenzamide
0.01	-	above, pH and temperature not specified in the publication	Homo sapiens	pracinostat
0.01	-	above, pH and temperature not specified in the publication	Mus musculus	pracinostat
0.01	-	above, pH and temperature not specified in the publication	Homo sapiens	rocilinostat
0.01	-	above, pH and temperature not specified in the publication	Mus musculus	rocilinostat

General Information

General Information	Comment	Organism
malfunction	LTB4 levels are persistently elevated in bronchoalveolar lavage fluid (BALF) of lipopolysaccharide (LPS)-induced ALI, and the leukotriene levels in pulmonary edema fluid are significantly higher in ALI patients compared to control patients with hydrostatic pulmonary edema. In addition, LTB4 level is increased in lung homogenates, and BALF of patients with IPF and the level of LTB4 correlate with the extent of fibrosis in histological sections	Homo sapiens
additional information	LTA4H folds into three domains and creates a deep cleft harboring the catalytic Zn2+ site, forming the active site with an L-shaped hydrophobic pocket deep into the protein	Homo sapiens
additional information	LTA4H folds into three domains and creates a deep cleft harboring the catalytic Zn2+ site, forming the active site with an L-shaped hydrophobic pocket deep into the protein	Mus musculus
physiological function	leukotriene A4 hydrolase (LTA4H) is a bifunctional enzyme that exhibits LTA4H and aminopeptidase activities, it is a key enzyme in the biosynthesis of leukotriene B4 (LTB4). LTA4H is well-known to regulate chemotactic activity of human neutrophils. LTB4 is secreted by neutrophils at inflammation sites in response to formyl peptides, playing an important role in neutrophil activation and migration to formyl peptides	Homo sapiens
physiological function	leukotriene A4 hydrolase (LTA4H) is a key enzyme in the biosynthesis of leukotriene B4 (LTB4)	Mus musculus