Gene Ontology annotation through association of InterPro records with GO terms
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
Annotation inferences using phylogenetic trees
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
Combined Automated Annotation using Multiple IEA Methods
Targeting proteins to the lumen of endoplasmic reticulum using N-terminal domains of 11beta-hydroxysteroid dehydrogenase and the 50-kDa esterase.
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The 50-kDa esterase N-terminal segment acts as a targeting signal for a type II ER protein with its C terminus in the lumen.
"Both are type II membrane proteins with the C terminus projecting into the lumen of the ER."
Characterization of the rodent genes for arylacetamide deacetylase, a putative microsomal lipase, and evidence for transcriptional regulation.
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Rodent expression and homology data motivated a hypothesis that AADA mobilizes intracellular lipids for VLDL assembly.
"The homology of AADA with hormone-sensitive lipase and the tissue distribution of AADA are consistent with the view that AADA plays a role in promoting the mobilization of lipids from intracellular stores and in the liver for assembling VLDL."
Appropriate function of 11beta-hydroxysteroid dehydrogenase type 1 in the endoplasmic reticulum lumen is dependent on its N-terminal region sharing similar topological determinants with 50-kDa esterase.
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The E3/50-kDa esterase N-terminal membrane segment contains determinants for luminal ER orientation.
"Previous studies revealed that the luminal orientation of 11beta-HSD1 and 50-kDa esterase/arylacetamide deacetylase (E3) is determined by their highly similar N-terminal transmembrane domains."
Human carboxylesterases and their role in xenobiotic and endobiotic metabolism.
An acetylation/deacetylation cycle controls the export of sterols and steroids from S. cerevisiae.
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Human AADAC can hydrolyze cholesterol acetate when expressed heterologously in yeast.
"The observation that expression of the human homologue of SAY1 , AADAC, in yeast rescues the sterol acetate accumulation phenotype of say1 Δ-mutant cells indicates that the human aryl acetamide deacetylase acts on cholesterol acetate and thus has overlapping substrate specificity with Say1 in vivo , even though the enzyme has been identified as an N -deacetylase based on its in vitro activity against aryl acetamide ( Probst et al , 1994 )."
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The study did not establish the corresponding sterol-acetylation pathway in human cells.
"Incubation of HepG2 hepatoma cells with radiolabeled pregnenolone, however, did not reveal any conversion to pregnenolone acetate or export of modified pregnenolone into the culture media, indicating that the substrate specificity of a putative lipid acetylase, if present in mammals, is different from that of yeast cells (data not shown)."
Human arylacetamide deacetylase is a principal enzyme in flutamide hydrolysis.
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Recombinant human AADAC directly hydrolyzes flutamide.
"In the present study, we found that human arylacetamide deacetylase (AADAC) efficiently hydrolyzed flutamide using recombinant AADAC expressed in COS7 cells."
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AADAC is localized to the endoplasmic reticulum.
"AADAC is specifically expressed in the endoplasmic reticulum."
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Human liver microsomal flutamide hydrolysis correlates with AADAC protein abundance.
"In human liver microsomal samples (n = 50), the flutamide hydrolase activities were significantly correlated with the expression levels of AADAC protein (r = 0.66, p < 0.001)."
Arylacetamide deacetylase attenuates fatty-acid-induced triacylglycerol accumulation in rat hepatoma cells.
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The study expressed mouse AADA in rat hepatoma cells.
"We have established McArdle-RH7777 (rat hepatoma) cell lines stably expressing mouse AADA cDNA and performed metabolic labeling as well as lipid mass analyses."
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The ortholog hydrolyzed endogenous diacylglycerol, but did not show direct in-vitro activity toward membrane-associated triacylglycerol or cholesteryl ester.
"Although AADA shares similarity with HSL and like HSL showed hydrolytic activity toward endogenously synthesized DG, we did not observe any in vitro activity of AADA toward membrane-associated TG or CE."
Purification and characterization of a human liver arylacetamide deacetylase.
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AADAC was purified directly from human liver microsomes as an acetylaminofluorene deacetylase.
"An acetylaminofluorene deacetylase was purified 90 fold from human liver microsomes by PEG-fractionation, anion exchange and hydrophobic interaction chromatography."
Arylacetamide deacetylase is a determinant enzyme for the difference in hydrolase activities of phenacetin and acetaminophen.
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Recombinant-human and human-liver-microsome data identify AADAC as the principal phenacetin hydrolase.
"In conclusion, we found that AADAC is the principal enzyme responsible for the phenacetin hydrolysis, and the difference of hydrolase activity between phenacetin and APAP is largely due to the substrate specificity of AADAC."
Human arylacetamide deacetylase is responsible for deacetylation of rifamycins: rifampicin, rifabutin, and rifapentine.
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Recombinant human AADAC directly deacetylates rifamycins, unlike CES1 and CES2.
"In this study, we found that recombinant human arylacetamide deacetylase (AADAC) could efficiently deacetylate rifamycins, whereas human carboxylesterases, which are enzymes responsible for the hydrolysis of many prodrugs, showed no activity."
Species differences in tissue distribution and enzyme activities of arylacetamide deacetylase in human, rat, and mouse.
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Human AADAC transcript is enriched in liver and gastrointestinal tissues.
"In human, AADAC mRNA was highly expressed in liver and the gastrointestinal tract, followed by bladder."
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Rifampicin hydrolysis shows marked human-specific activity.
"High rifampicin hydrolase activity was detected only by recombinant human AADAC and human liver and jejunum microsomes."
Arylacetamide deacetylase: a novel host factor with important roles in the lipolysis of cellular triacylglycerol stores, VLDL assembly and HCV production.
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Knockdown and rescue link AADAC in human hepatoma cells to cellular TG lipolysis and VLDL production.
"The re-introduction of AADAC to infected cells restored cellular TG lipolysis, indicating a role for HCV-mediated downregulation of AADAC in this process."
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Stable AADAC deficiency impairs cellular TG lipolysis and VLDL production.
"Defective lipolysis of cellular TG stores and VLDL production were also observed in HuH7.5 cells stably expressing a short hairpin RNA targeting AADAC expression, proving AADAC deficiency contributes to these defective pathways."
N-Glycosylation during translation is essential for human arylacetamide deacetylase enzyme activity.
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Human AADAC is glycosylated at Asn-78 and Asn-282.
"This result indicated that AADAC was glycosylated at both N78 and N282."
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N282 glycosylation is important for proper folding and enzyme activity.
"Overall, this study found that the translational, but not post-translational, N-glycosylation of AADAC plays a crucial role in regulating AADAC enzyme activity."
Indiplon is hydrolyzed by arylacetamide deacetylase in human liver.
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Human AADAC is the principal microsomal indiplon hydrolase.
"Recombinant AADAC showed a high level of indiplon hydrolase activity, whereas recombinant carboxylesterase 1 (CES1) and 2 (CES2) showed marginal activity."
Comparison of substrate specificity among human arylacetamide deacetylase and carboxylesterases.
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Recombinant AADAC prefers substrates with comparatively small acyl groups.
"Collectively, these results suggest that AADAC prefers compounds with smaller acyl moieties than does CES2."
Human arylacetamide deacetylase hydrolyzes ketoconazole to trigger hepatocellular toxicity.
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Human AADAC catalyzes ketoconazole hydrolysis in recombinant and human-liver microsomal systems.
"Kinetic analysis and inhibition studies using human liver microsomes (HLM) and recombinant enzymes revealed that human arylacetamide deacetylase (AADAC) is responsible for KC hydrolysis to form DAK, and confirmed that FMO3 is the enzyme responsible for DAK N-hydroxylation."
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AADAC-mediated ketoconazole hydrolysis bioactivates toxicity rather than detoxifying the compound.
"In conclusion, the present study demonstrated that human AADAC hydrolyzes KC to trigger hepatocellular toxicity."
A reference map of the human binary protein interactome.
Role of Human Arylacetamide Deacetylase (AADAC) on Hydrolysis of Eslicarbazepine Acetate and Effects of AADAC Genetic Polymorphisms on Hydrolase Activity.
Arylacetamide deacetylase as a determinant of the hydrolysis and activation of abiraterone acetate in mice and humans.
In vitro deacetylation of N-acetylserotonin by arylacetamide deacetylase.
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Recombinant human AADAC directly deacetylates N-acetylserotonin in vitro.
"Both human and rodent recombinant AADAC proteins can deacetylate NAS in vitro, although the human AADAC shows markedly higher activity compared with rodent enzyme."
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Recombinant human AADAC also deacetylates melatonin and N-acetyltryptamine.
"In addition to NAS, recombinant hAADAC can deacetylate melatonin (to form 5-methoxytryptamine) and N-acetyltryptamine (NAT) (to form tryptamine)."
Human Carboxylesterase 2 Reverses Obesity-Induced Diacylglycerol Accumulation and Glucose Intolerance.
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Partial endogenous AADAC knockdown in primary human hepatocytes did not alter fatty-acid oxidation.
"Here, knockdown of endogenous AADAC in PHH did not alter fatty acid oxidation. However, our negative findings may be due to the modest level of AADAC knockdown and do not preclude a role for this enzyme in metabolism."
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Human hepatic AADAC activity did not associate significantly with DAG abundance.
"By contrast, AADAC activity did not significantly associate with HOMA-IR nor with DAG species (Figure S4)."
Impact of miR-222-3p-mediated downregulation of arylacetamide deacetylase on drug hydrolysis and lipid accumulation.
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Reciprocal AADAC rescue and knockdown experiments link reduced AADAC to lipid accumulation in human-derived hepatic cells.
"Overexpression of miR-222-3p resulted in increased lipid accumulation in Huh-1 cells, which was reversed by AADAC overexpression. In contrast, miR-222-3p inhibition decreased lipid accumulation, which was reversed by AADAC knockdown."
Human liver arylacetamide deacetylase. Molecular cloning of a novel esterase involved in the metabolic activation of arylamine carcinogens with high sequence similarity to hormone-sensitive lipase.
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The cloned human cDNA was matched to peptides from purified liver AADAC.
"The cDNA was confirmed to be that for DAC in tryptic peptides from the purified human liver protein."
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The sequence supports classification as an esterase.
"Highest sequence similarity of DAC was found in a series of prokaryotic esterases encompassing the putative active site."
Determination of lumenal orientation of microsomal 50-kDa esterase/N-deacetylase.
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Structural, glycosylation, and protease-protection evidence places most of the microsomal esterase polypeptide in the ER lumen.
"The proposed model of the 50-kDa protein predicts one transmembrane segment at the N-terminus, flanked by positively charged residues on the cytosolic surface and negatively charged residues on the lumenal side of the hydrophobic domain, with most of the polypeptide projecting into the lumen of the ER."
Phase I - Functionalization of compounds
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Phase-I hydrolases act on ester and amide bonds, and functionalization can either promote excretion or produce reactive metabolites.
"Hydrolases hydrolyse esters, amides, epoxides and glucuronides."
AADAC deacetylates PHEN
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Reactome represents human AADAC hydrolysis of phenacetin to p-phenetidine.
"AADAC hydrolyses PHEN to the p-phenetidine metabolite which is a nephrotoxicant (Watanabe et al. 2010, Fukami & Yokoi 2012)."
UniProtKB/Swiss-Prot record for human AADAC (P22760)