Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTMB3JY)

• DOT Name: Bile acid-CoA:amino acid N-acyltransferase (BAAT)
• Synonyms: BACAT; BAT; EC 2.3.1.65; Bile acid-CoA thioesterase; Choloyl-CoA hydrolase; EC 3.1.2.27; Glycine N-choloyltransferase; Long-chain fatty-acyl-CoA hydrolase; EC 3.1.2.2
• Gene Name: BAAT
• Related Disease:
  Hypercholanemia, familial 1
  Bile acid CoA:amino acid N-acyltransferase deficiency
  Obsolete familial hypercholanemia
• UniProt ID: BAAT_HUMAN
• EC Number: 2.3.1.65; 3.1.2.2; 3.1.2.27
• Pfam ID: PF08840 ; PF04775
• Sequence:
  MIQLTATPVSALVDEPVHIRATGLIPFQMVSFQASLEDENGDMFYSQAHYRANEFGEVDL
  NHASSLGGDYMGVHPMGLFWSLKPEKLLTRLLKRDVMNRPFQVQVKLYDLELIVNNKVAS
  APKASLTLERWYVAPGVTRIKVREGRLRGALFLPPGEGLFPGVIDLFGGLGGLLEFRASL
  LASRGFASLALAYHNYEDLPRKPEVTDLEYFEEAANFLLRHPKVFGSGVGVVSVCQGVQI
  GLSMAIYLKQVTATVLINGTNFPFGIPQVYHGQIHQPLPHSAQLISTNALGLLELYRTFE
  TTQVGASQYLFPIEEAQGQFLFIVGEGDKTINSKAHAEQAIGQLKRHGKNNWTLLSYPGA
  GHLIEPPYSPLCCASTTHDLRLHWGGEVIPHAAAQEHAWKEIQRFLRKHLIPDVTSQL
• Function: Catalyzes the amidation of bile acids (BAs) with the amino acids taurine and glycine. More than 95% of the BAs are N-acyl amidates with glycine and taurine. Amidation of BAs in the liver with glycine or taurine prior to their excretion into bile is an important biochemical event in bile acid metabolism. This conjugation (or amidation) plays several important biological roles in that it promotes the secretion of BAs and cholesterol into bile and increases the detergent properties of BAs in the intestine, which facilitates lipid and vitamin absorption. May also act as an acyl-CoA thioesterase that regulates intracellular levels of free fatty acids. In vitro, catalyzes the hydrolysis of long- and very long-chain saturated acyl-CoAs to the free fatty acid and coenzyme A (CoASH), and conjugates glycine to these acyl-CoAs.
• Tissue Specificity: Expressed in the gallbladder mucosa and pancreas . Expressed in hepatocytes (at protein level) .
• KEGG Pathway:
  Primary bile acid biosynthesis (hsa00120)
  Taurine and hypotaurine metabolism (hsa00430)
  Biosynthesis of unsaturated fatty acids (hsa01040)
  Metabolic pathways (hsa01100)
  Peroxisome (hsa04146)
  Bile secretion (hsa04976)
• Reactome Pathway:
  Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol (R-HSA-193368)
  Peroxisomal protein import (R-HSA-9033241)
  Recycling of bile acids and salts (R-HSA-159418)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypercholanemia, familial 1	DISHF4Z3	Strong	Autosomal recessive	[1]
Bile acid CoA:amino acid N-acyltransferase deficiency	DISFVYGL	Moderate	Autosomal recessive	[2]
Obsolete familial hypercholanemia	DISMGYNC	Supportive	Autosomal recessive	[1]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Bile acid-CoA:amino acid N-acyltransferase (BAAT).	[3]

12 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Bile acid-CoA:amino acid N-acyltransferase (BAAT).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Bile acid-CoA:amino acid N-acyltransferase (BAAT).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Bile acid-CoA:amino acid N-acyltransferase (BAAT).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Bile acid-CoA:amino acid N-acyltransferase (BAAT).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Bile acid-CoA:amino acid N-acyltransferase (BAAT).	[4]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Bile acid-CoA:amino acid N-acyltransferase (BAAT).	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Bile acid-CoA:amino acid N-acyltransferase (BAAT).	[9]
Chenodiol	DMQ8JIK	Approved	Chenodiol decreases the expression of Bile acid-CoA:amino acid N-acyltransferase (BAAT).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Bile acid-CoA:amino acid N-acyltransferase (BAAT).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Bile acid-CoA:amino acid N-acyltransferase (BAAT).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Bile acid-CoA:amino acid N-acyltransferase (BAAT).	[13]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Bile acid-CoA:amino acid N-acyltransferase (BAAT).	[14]

References

• [1] Complex inheritance of familial hypercholanemia with associated mutations in TJP2 and BAAT. Nat Genet. 2003 May;34(1):91-6. doi: 10.1038/ng1147.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [4] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [9] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [10] Chenodeoxycholic acid significantly impacts the expression of miRNAs and genes involved in lipid, bile acid and drug metabolism in human hepatocytes. Life Sci. 2016 Jul 1;156:47-56.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Gene expression profiling of A549 cells exposed to Milan PM2.5. Toxicol Lett. 2012 Mar 7;209(2):136-45.
• [13] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [14] Comparison of base-line and chemical-induced transcriptomic responses in HepaRG and RPTEC/TERT1 cells using TempO-Seq. Arch Toxicol. 2018 Aug;92(8):2517-2531.