Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT96UIP1)

• DOT Name: Acetyl-CoA carboxylase 2 (ACACB)
• Synonyms: EC 6.4.1.2; ACC-beta
• Gene Name: ACACB
• Related Disease: Isolated cleft palate
• UniProt ID: ACACB_HUMAN
• PDB ID: 2DN8; 2HJW; 2KCC; 3FF6; 3GID; 3GLK; 3JRW; 3JRX; 3TDC; 4HQ6; 5KKN
• EC Number: 6.4.1.2
• Pfam ID: PF08326 ; PF21385 ; PF02785 ; PF00289 ; PF00364 ; PF01039 ; PF02786
• Sequence:
  MVLLLCLSCLIFSCLTFSWLKIWGKMTDSKPITKSKSEANLIPSQEPFPASDNSGETPQR
  NGEGHTLPKTPSQAEPASHKGPKDAGRRRNSLPPSHQKPPRNPLSSSDAAPSPELQANGT
  GTQGLEATDTNGLSSSARPQGQQAGSPSKEDKKQANIKRQLMTNFILGSFDDYSSDEDSV
  AGSSRESTRKGSRASLGALSLEAYLTTGEAETRVPTMRPSMSGLHLVKRGREHKKLDLHR
  DFTVASPAEFVTRFGGDRVIEKVLIANNGIAAVKCMRSIRRWAYEMFRNERAIRFVVMVT
  PEDLKANAEYIKMADHYVPVPGGPNNNNYANVELIVDIAKRIPVQAVWAGWGHASENPKL
  PELLCKNGVAFLGPPSEAMWALGDKIASTVVAQTLQVPTLPWSGSGLTVEWTEDDLQQGK
  RISVPEDVYDKGCVKDVDEGLEAAERIGFPLMIKASEGGGGKGIRKAESAEDFPILFRQV
  QSEIPGSPIFLMKLAQHARHLEVQILADQYGNAVSLFGRDCSIQRRHQKIVEEAPATIAP
  LAIFEFMEQCAIRLAKTVGYVSAGTVEYLYSQDGSFHFLELNPRLQVEHPCTEMIADVNL
  PAAQLQIAMGVPLHRLKDIRLLYGESPWGVTPISFETPSNPPLARGHVIAARITSENPDE
  GFKPSSGTVQELNFRSSKNVWGYFSVAATGGLHEFADSQFGHCFSWGENREEAISNMVVA
  LKELSIRGDFRTTVEYLINLLETESFQNNDIDTGWLDYLIAEKVQAEKPDIMLGVVCGAL
  NVADAMFRTCMTDFLHSLERGQVLPADSLLNLVDVELIYGGVKYILKVARQSLTMFVLIM
  NGCHIEIDAHRLNDGGLLLSYNGNSYTTYMKEEVDSYRITIGNKTCVFEKENDPTVLRSP
  SAGKLTQYTVEDGGHVEAGSSYAEMEVMKMIMTLNVQERGRVKYIKRPGAVLEAGCVVAR
  LELDDPSKVHPAEPFTGELPAQQTLPILGEKLHQVFHSVLENLTNVMSGFCLPEPVFSIK
  LKEWVQKLMMTLRHPSLPLLELQEIMTSVAGRIPAPVEKSVRRVMAQYASNITSVLCQFP
  SQQIATILDCHAATLQRKADREVFFINTQSIVQLVQRYRSGIRGYMKTVVLDLLRRYLRV
  EHHFQQAHYDKCVINLREQFKPDMSQVLDCIFSHAQVAKKNQLVIMLIDELCGPDPSLSD
  ELISILNELTQLSKSEHCKVALRARQILIASHLPSYELRHNQVESIFLSAIDMYGHQFCP
  ENLKKLILSETTIFDVLPTFFYHANKVVCMASLEVYVRRGYIAYELNSLQHRQLPDGTCV
  VEFQFMLPSSHPNRMTVPISITNPDLLRHSTELFMDSGFSPLCQRMGAMVAFRRFEDFTR
  NFDEVISCFANVPKDTPLFSEARTSLYSEDDCKSLREEPIHILNVSIQCADHLEDEALVP
  ILRTFVQSKKNILVDYGLRRITFLIAQEKEFPKFFTFRARDEFAEDRIYRHLEPALAFQL
  ELNRMRNFDLTAVPCANHKMHLYLGAAKVKEGVEVTDHRFFIRAIIRHSDLITKEASFEY
  LQNEGERLLLEAMDELEVAFNNTSVRTDCNHIFLNFVPTVIMDPFKIEESVRYMVMRYGS
  RLWKLRVLQAEVKINIRQTTTGSAVPIRLFITNESGYYLDISLYKEVTDSRSGNIMFHSF
  GNKQGPQHGMLINTPYVTKDLLQAKRFQAQTLGTTYIYDFPEMFRQALFKLWGSPDKYPK
  DILTYTELVLDSQGQLVEMNRLPGGNEVGMVAFKMRFKTQEYPEGRDVIVIGNDITFRIG
  SFGPGEDLLYLRASEMARAEGIPKIYVAANSGARIGMAEEIKHMFHVAWVDPEDPHKGFK
  YLYLTPQDYTRISSLNSVHCKHIEEGGESRYMITDIIGKDDGLGVENLRGSGMIAGESSL
  AYEEIVTISLVTCRAIGIGAYLVRLGQRVIQVENSHIILTGASALNKVLGREVYTSNNQL
  GGVQIMHYNGVSHITVPDDFEGVYTILEWLSYMPKDNHSPVPIITPTDPIDREIEFLPSR
  APYDPRWMLAGRPHPTLKGTWQSGFFDHGSFKEIMAPWAQTVVTGRARLGGIPVGVIAVE
  TRTVEVAVPADPANLDSEAKIIQQAGQVWFPDSAYKTAQAVKDFNREKLPLMIFANWRGF
  SGGMKDMYDQVLKFGAYIVDGLRQYKQPILIYIPPYAELRGGSWVVIDATINPLCIEMYA
  DKESRGGVLEPEGTVEIKFRKKDLIKSMRRIDPAYKKLMEQLGEPDLSDKDRKDLEGRLK
  AREDLLLPIYHQVAVQFADFHDTPGRMLEKGVISDILEWKTARTFLYWRLRRLLLEDQVK
  QEILQASGELSHVHIQSMLRRWFVETEGAVKAYLWDNNQVVVQWLEQHWQAGDGPRSTIR
  ENITYLKHDSVLKTIRGLVEENPEVAVDCVIYLSQHISPAERAQVVHLLSTMDSPAST
• Function: Mitochondrial enzyme that catalyzes the carboxylation of acetyl-CoA to malonyl-CoA and plays a central role in fatty acid metabolism. Catalyzes a 2 steps reaction starting with the ATP-dependent carboxylation of the biotin carried by the biotin carboxyl carrier (BCC) domain followed by the transfer of the carboxyl group from carboxylated biotin to acetyl-CoA. Through the production of malonyl-CoA that allosterically inhibits carnitine palmitoyltransferase 1 at the mitochondria, negatively regulates fatty acid oxidation. Together with its cytosolic isozyme ACACA, which is involved in de novo fatty acid biosynthesis, promotes lipid storage.
• Tissue Specificity: Widely expressed with highest levels in heart, skeletal muscle, liver, adipose tissue, mammary gland, adrenal gland and colon . Isoform 3 is expressed in skeletal muscle, adipose tissue and liver (at protein level) . Isoform 3 is detected at high levels in adipose tissue with lower levels in heart, liver, skeletal muscle and testis .
• KEGG Pathway:
  Fatty acid biosynthesis (hsa00061)
  Pyruvate metabolism (hsa00620)
  Propanoate metabolism (hsa00640)
  Metabolic pathways (hsa01100)
  AMPK sig.ling pathway (hsa04152)
  Insulin sig.ling pathway (hsa04910)
  Adipocytokine sig.ling pathway (hsa04920)
  Glucagon sig.ling pathway (hsa04922)
  Insulin resistance (hsa04931)
  Alcoholic liver disease (hsa04936)
• Reactome Pathway:
  Biotin transport and metabolism (R-HSA-196780)
  Carnitine metabolism (R-HSA-200425)
  Activation of gene expression by SREBF (SREBP) (R-HSA-2426168)
  ChREBP activates metabolic gene expression (R-HSA-163765)
• BioCyc Pathway: MetaCyc:HS01211-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Isolated cleft palate	DISV80CD	Limited	Unknown	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Sodium lauryl sulfate	DMLJ634	Approved	Acetyl-CoA carboxylase 2 (ACACB) affects the response to substance of Sodium lauryl sulfate.	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Acetyl-CoA carboxylase 2 (ACACB).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Acetyl-CoA carboxylase 2 (ACACB).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Acetyl-CoA carboxylase 2 (ACACB).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Acetyl-CoA carboxylase 2 (ACACB).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Acetyl-CoA carboxylase 2 (ACACB).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Acetyl-CoA carboxylase 2 (ACACB).	[8]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Acetyl-CoA carboxylase 2 (ACACB).	[9]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Acetyl-CoA carboxylase 2 (ACACB).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Acetyl-CoA carboxylase 2 (ACACB).	[11]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Acetyl-CoA carboxylase 2 (ACACB).	[12]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Acetyl-CoA carboxylase 2 (ACACB).	[13]
Zidovudine	DM4KI7O	Approved	Zidovudine affects the expression of Acetyl-CoA carboxylase 2 (ACACB).	[14]
Fructose	DM43AN2	Approved	Fructose decreases the expression of Acetyl-CoA carboxylase 2 (ACACB).	[15]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Acetyl-CoA carboxylase 2 (ACACB).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Acetyl-CoA carboxylase 2 (ACACB).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Acetyl-CoA carboxylase 2 (ACACB).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Acetyl-CoA carboxylase 2 (ACACB).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Acetyl-CoA carboxylase 2 (ACACB).	[7]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the phosphorylation of Acetyl-CoA carboxylase 2 (ACACB).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Acetyl-CoA carboxylase 2 (ACACB).	[20]
D-glucose	DMMG2TO	Investigative	D-glucose decreases the phosphorylation of Acetyl-CoA carboxylase 2 (ACACB).	[22]

References

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• [2] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [3] 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.
• [4] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] Mechanism of cisplatin proximal tubule toxicity revealed by integrating transcriptomics, proteomics, metabolomics and biokinetics. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):117-27.
• [7] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [8] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [9] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [12] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [13] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [14] Adipocyte differentiation, mitochondrial gene expression and fat distribution: differences between zidovudine and tenofovir after 6 months. Antivir Ther. 2009;14(8):1089-100. doi: 10.3851/IMP1457.
• [15] Effects of four-week high-fructose diet on gene expression in skeletal muscle of healthy men. Diabetes Metab. 2008 Feb;34(1):82-5. doi: 10.1016/j.diabet.2007.08.004. Epub 2007 Dec 11.
• [16] Acute exposure to resveratrol inhibits AMPK activity in human skeletal muscle cells. Diabetologia. 2012 Nov;55(11):3051-60. doi: 10.1007/s00125-012-2691-1. Epub 2012 Aug 17.
• [17] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [18] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [19] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [20] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [21] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [22] Faster lipid -oxidation rate by acetyl-CoA carboxylase 2 inhibition alleviates high-glucose-induced insulin resistance via SIRT1/PGC-1 in human podocytes. J Biochem Mol Toxicol. 2021 Jul;35(7):e22797. doi: 10.1002/jbt.22797. Epub 2021 May 6.
• [23] Genetic Basis of Irritant Susceptibility in Health Care Workers. J Occup Environ Med. 2016 Aug;58(8):753-9. doi: 10.1097/JOM.0000000000000784.