Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS3DDE5)

• DOT Name: Alkaline ceramidase 2 (ACER2)
• Synonyms: AlkCDase 2; Alkaline CDase 2; haCER2; EC 3.5.1.-; EC 3.5.1.23; Acylsphingosine deacylase 3-like; N-acylsphingosine amidohydrolase 3-like
• Gene Name: ACER2
• Related Disease:
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
• UniProt ID: ACER2_HUMAN
• EC Number: 3.5.1.-; 3.5.1.23
• Pfam ID: PF05875
• Sequence:
  MGAPHWWDQLQAGSSEVDWCEDNYTIVPAIAEFYNTISNVLFFILPPICMCLFRQYATCF
  NSGIYLIWTLLVVVGIGSVYFHATLSFLGQMLDELAVLWVLMCALAMWFPRRYLPKIFRN
  DRGRFKVVVSVLSAVTTCLAFVKPAINNISLMTLGVPCTALLIAELKRCDNMRVFKLGLF
  SGLWWTLALFCWISDRAFCELLSSFNFPYLHCMWHILICLAAYLGCVCFAYFDAASEIPE
  QGPVIKFWPNEKWAFIGVPYVSLLCANKKSSVKIT
• Function: Golgi ceramidase that catalyzes the hydrolysis of ceramides 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. Has a better catalytic efficiency towards unsaturated long-chain ceramides, including C18:1-, C20:1- and C24:1-ceramides. Saturated long-chain ceramides and unsaturated very long-chain ceramides are also good substrates, whereas saturated very long-chain ceramides and short-chain ceramides are poor substrates. Also hydrolyzes dihydroceramides to produce dihydrosphingosine. It is the ceramidase that controls the levels of circulating sphingosine-1-phosphate and dihydrosphingosine-1-phosphate in plasma through their production by hematopoietic cells. Regulates cell proliferation, autophagy and apoptosis by the production of sphingosine and sphingosine-1-phosphate. As part of a p53/TP53-dependent pathway, promotes for instance autophagy and apoptosis in response to DNA damage. Through the production of sphingosine, may also regulate the function of the Golgi complex and regulate the glycosylation of proteins.
• Tissue Specificity: Highly expressed in placenta.
• KEGG Pathway:
  Sphingolipid metabolism (hsa00600)
  Metabolic pathways (hsa01100)
  Sphingolipid sig.ling pathway (hsa04071)
• Reactome Pathway: Sphingolipid metabolism (R-HSA-428157)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Arteriosclerosis	DISK5QGC	Strong	Altered Expression	[2]
Atherosclerosis	DISMN9J3	Strong	Altered Expression	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Alkaline ceramidase 2 (ACER2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Alkaline ceramidase 2 (ACER2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Alkaline ceramidase 2 (ACER2).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Alkaline ceramidase 2 (ACER2).	[6]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Alkaline ceramidase 2 (ACER2).	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Alkaline ceramidase 2 (ACER2).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Alkaline ceramidase 2 (ACER2).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Alkaline ceramidase 2 (ACER2).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Alkaline ceramidase 2 (ACER2).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Alkaline ceramidase 2 (ACER2).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Alkaline ceramidase 2 (ACER2).	[12]

References

• [1] Tumor suppressor p53 links ceramide metabolism to DNA damage response through alkaline ceramidase 2.Cell Death Differ. 2018 May;25(5):841-856. doi: 10.1038/s41418-017-0018-y. Epub 2017 Dec 11.
• [2] Adipocyte Hypoxia-Inducible Factor 2 Suppresses Atherosclerosis by Promoting Adipose Ceramide Catabolism.Cell Metab. 2019 Nov 5;30(5):937-951.e5. doi: 10.1016/j.cmet.2019.09.016. Epub 2019 Oct 24.
• [3] 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.
• [4] 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.
• [5] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Methotrexate modulates folate phenotype and inflammatory profile in EA.hy 926 cells. Eur J Pharmacol. 2014 Jun 5;732:60-7.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] 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.
• [10] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [11] 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.
• [12] 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.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.