Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIVQBG5)

• DOT Name: Alkaline ceramidase 3 (ACER3)
• Synonyms: AlkCDase 3; Alkaline CDase 3; EC 3.5.1.-; EC 3.5.1.23; Alkaline dihydroceramidase SB89; Alkaline phytoceramidase; aPHC
• Gene Name: ACER3
• Related Disease:
  Acute myelogenous leukaemia
  Alkaline ceramidase 3 deficiency
  Cerebellar ataxia
  Melanoma
  Leukodystrophy
  Hepatocellular carcinoma
  Lentivirus infection
• UniProt ID: ACER3_HUMAN
• PDB ID: 6G7O; 6YXH
• EC Number: 3.5.1.-; 3.5.1.23
• Pfam ID: PF05875
• Sequence:
  MAPAADREGYWGPTTSTLDWCEENYSVTWYIAEFWNTVSNLIMIIPPMFGAVQSVRDGLE
  KRYIASYLALTVVGMGSWCFHMTLKYEMQLLDELPMIYSCCIFVYCMFECFKIKNSVNYH
  LLFTLVLFSLIVTTVYLKVKEPIFHQVMYGMLVFTLVLRSIYIVTWVYPWLRGLGYTSLG
  IFLLGFLFWNIDNIFCESLRNFRKKVPPIIGITTQFHAWWHILTGLGSYLHILFSLYTRT
  LYLRYRPKVKFLFGIWPVILFEPLRKH
• Function: Endoplasmic reticulum and Golgi ceramidase that catalyzes the hydrolysis of unsaturated long-chain C18:1-, C20:1- and C20:4-ceramides, dihydroceramides and phytoceramides into sphingoid bases like sphingosine and free fatty acids at alkaline pH. Ceramides, sphingosine, and its phosphorylated form sphingosine-1-phosphate are bioactive lipids that mediate cellular signaling pathways regulating several biological processes including cell proliferation, apoptosis and differentiation. Controls the generation of sphingosine in erythrocytes, and thereby sphingosine-1-phosphate in plasma. Through the regulation of ceramides and sphingosine-1-phosphate homeostasis in the brain may play a role in neurons survival and function. By regulating the levels of pro-inflammatory ceramides in immune cells and tissues, may modulate the inflammatory response.
• Tissue Specificity: Ubiquitously expressed. Highly expressed in placenta . Expressed in erythrocytes .
• KEGG Pathway:
  Sphingolipid metabolism (hsa00600)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Sphingolipid metabolism (R-HSA-428157)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Alkaline ceramidase 3 deficiency	DISMHFVM	Strong	Autosomal recessive	[2]
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[3]
Melanoma	DIS1RRCY	Strong	Biomarker	[4]
Leukodystrophy	DISVY1TT	moderate	Genetic Variation	[5]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[6]
Lentivirus infection	DISX17PY	Limited	Biomarker	[6]

3 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 Alkaline ceramidase 3 (ACER3).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Alkaline ceramidase 3 (ACER3).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Alkaline ceramidase 3 (ACER3).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Alkaline ceramidase 3 (ACER3).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Alkaline ceramidase 3 (ACER3).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Alkaline ceramidase 3 (ACER3).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Alkaline ceramidase 3 (ACER3).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Alkaline ceramidase 3 (ACER3).	[12]
Quercetin	DM3NC4M	Approved	Quercetin affects the expression of Alkaline ceramidase 3 (ACER3).	[13]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Alkaline ceramidase 3 (ACER3).	[14]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Alkaline ceramidase 3 (ACER3).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Alkaline ceramidase 3 (ACER3).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Alkaline ceramidase 3 (ACER3).	[19]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of Alkaline ceramidase 3 (ACER3).	[20]

References

• [1] ACER3 supports development of acute myeloid leukemia.Biochem Biophys Res Commun. 2016 Sep 9;478(1):33-38. doi: 10.1016/j.bbrc.2016.07.099. Epub 2016 Jul 25.
• [2] Deficiency of alkaline ceramidase 3 with infancy-onset progressive leukoencephalopathy: a second case report. Acta Neurol Belg. 2021 Dec;121(6):1867-1870. doi: 10.1007/s13760-020-01474-4. Epub 2020 Aug 20.
• [3] Alkaline Ceramidase 3 Deficiency Results in Purkinje Cell Degeneration and Cerebellar Ataxia Due to Dyshomeostasis of Sphingolipids in the Brain.PLoS Genet. 2015 Oct 16;11(10):e1005591. doi: 10.1371/journal.pgen.1005591. eCollection 2015 Oct.
• [4] Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation.Oncotarget. 2012 Apr;3(4):399-413. doi: 10.18632/oncotarget.473.
• [5] Deficiency of the alkaline ceramidase ACER3 manifests in early childhood by progressive leukodystrophy. J Med Genet. 2016 Jun;53(6):389-96. doi: 10.1136/jmedgenet-2015-103457. Epub 2016 Jan 20.
• [6] Alkaline ceramidase 3 promotes growth of hepatocellular carcinoma cells via regulating S1P/S1PR2/PI3K/AKT signaling.Pathol Res Pract. 2018 Sep;214(9):1381-1387. doi: 10.1016/j.prp.2018.07.029. Epub 2018 Jul 27.
• [7] 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.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [10] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [11] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [12] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [13] 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.
• [14] 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.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [17] 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.
• [18] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [19] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [20] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.