Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3NHO99)

• DOT Name: Phosphatidylcholine:ceramide cholinephosphotransferase 2 (SGMS2)
• Synonyms: EC 2.7.8.27; Sphingomyelin synthase 2
• Gene Name: SGMS2
• Related Disease:
  Alzheimer disease
  Arteriosclerosis
  Atherosclerosis
  Bone cancer
  Bone osteosarcoma
  Calvarial doughnut lesions-bone fragility syndrome
  Colitis
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Depression
  Fatty liver disease
  Glioma
  Hyperinsulinemia
  Neoplasm
  Obesity
  Osteochondrodysplasia
  Skeletal dysplasia
  Osteoporosis
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Non-insulin dependent diabetes
  Pulmonary emphysema
  Type-1/2 diabetes
• UniProt ID: SMS2_HUMAN
• EC Number: 2.7.8.27
• Pfam ID: PF14360
• Sequence:
  MDIIETAKLEEHLENQPSDPTNTYARPAEPVEEENKNGNGKPKSLSSGLRKGTKKYPDYI
  QIAMPTESRNKFPLEWWKTGIAFIYAVFNLVLTTVMITVVHERVPPKELSPPLPDKFFDY
  IDRVKWAFSVSEINGIILVGLWITQWLFLRYKSIVGRRFCFIIGTLYLYRCITMYVTTLP
  VPGMHFQCAPKLNGDSQAKVQRILRLISGGGLSITGSHILCGDFLFSGHTVTLTLTYLFI
  KEYSPRHFWWYHLICWLLSAAGIICILVAHEHYTIDVIIAYYITTRLFWWYHSMANEKNL
  KVSSQTNFLSRAWWFPIFYFFEKNVQGSIPCCFSWPLSWPPGCFKSSCKKYSRVQKIGED
  NEKST
• Function: Sphingomyelin synthase that primarily contributes to sphingomyelin synthesis and homeostasis at the plasma membrane. Catalyzes the reversible transfer of phosphocholine moiety in sphingomyelin biosynthesis: in the forward reaction transfers phosphocholine head group of phosphatidylcholine (PC) on to ceramide (CER) to form ceramide phosphocholine (sphingomyelin, SM) and diacylglycerol (DAG) as by-product, and in the reverse reaction transfers phosphocholine from SM to DAG to form PC and CER. The direction of the reaction appears to depend on the levels of CER and DAG in the plasma membrane. Does not use free phosphorylcholine or CDP-choline as donors. Can also transfer phosphoethanolamine head group of phosphatidylethanolamine (PE) on to ceramide (CER) to form ceramide phosphoethanolamine (CPE). Regulates receptor-mediated signal transduction via mitogenic DAG and proapoptotic CER, as well as via SM, a structural component of membrane rafts that serve as platforms for signal transduction and protein sorting. To a lesser extent, plays a role in secretory transport via regulation of DAG pool at the Golgi apparatus and its downstream effects on PRKD1. Required for normal bone matrix mineralization.
• Tissue Specificity: Brain, heart, kidney, liver, muscle and stomach. Also expressed in a number of cell lines such as carcinoma HeLa cells, hepatoma Hep-G2 cells, and colon carcinoma Caco-2 cells.
• KEGG Pathway:
  Sphingolipid metabolism (hsa00600)
  Metabolic pathways (hsa01100)
  Sphingolipid sig.ling pathway (hsa04071)
• Reactome Pathway: Sphingolipid de novo biosynthesis (R-HSA-1660661)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Altered Expression	[1]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[2]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[2]
Bone cancer	DIS38NA0	Strong	Biomarker	[3]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[3]
Calvarial doughnut lesions-bone fragility syndrome	DIS1Z0LO	Strong	Autosomal dominant	[4]
Colitis	DISAF7DD	Strong	Biomarker	[5]
Colon cancer	DISVC52G	Strong	Biomarker	[5]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Depression	DIS3XJ69	Strong	Biomarker	[6]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[7]
Glioma	DIS5RPEH	Strong	Biomarker	[8]
Hyperinsulinemia	DISIDWT6	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Obesity	DIS47Y1K	Strong	Biomarker	[9]
Osteochondrodysplasia	DIS9SPWW	Strong	Genetic Variation	[4]
Skeletal dysplasia	DIS5Z8U6	Strong	Genetic Variation	[4]
Osteoporosis	DISF2JE0	moderate	Genetic Variation	[4]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[10]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[10]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[10]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[11]
Pulmonary emphysema	DIS5M7HZ	Limited	Altered Expression	[12]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[13]

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 Phosphatidylcholine:ceramide cholinephosphotransferase 2 (SGMS2).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Phosphatidylcholine:ceramide cholinephosphotransferase 2 (SGMS2).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Phosphatidylcholine:ceramide cholinephosphotransferase 2 (SGMS2).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate affects the expression of Phosphatidylcholine:ceramide cholinephosphotransferase 2 (SGMS2).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Phosphatidylcholine:ceramide cholinephosphotransferase 2 (SGMS2).	[18]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Phosphatidylcholine:ceramide cholinephosphotransferase 2 (SGMS2).	[19]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Phosphatidylcholine:ceramide cholinephosphotransferase 2 (SGMS2).	[20]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Phosphatidylcholine:ceramide cholinephosphotransferase 2 (SGMS2).	[21]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Phosphatidylcholine:ceramide cholinephosphotransferase 2 (SGMS2).	[22]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Phosphatidylcholine:ceramide cholinephosphotransferase 2 (SGMS2).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Phosphatidylcholine:ceramide cholinephosphotransferase 2 (SGMS2).	[25]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Phosphatidylcholine:ceramide cholinephosphotransferase 2 (SGMS2).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Phosphatidylcholine:ceramide cholinephosphotransferase 2 (SGMS2).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Phosphatidylcholine:ceramide cholinephosphotransferase 2 (SGMS2).	[28]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Phosphatidylcholine:ceramide cholinephosphotransferase 2 (SGMS2).	[29]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Phosphatidylcholine:ceramide cholinephosphotransferase 2 (SGMS2).	[30]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Phosphatidylcholine:ceramide cholinephosphotransferase 2 (SGMS2).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Phosphatidylcholine:ceramide cholinephosphotransferase 2 (SGMS2).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Phosphatidylcholine:ceramide cholinephosphotransferase 2 (SGMS2).	[27]

References

• [1] Inhibition of sphingomyelin synthase 1 ameliorates alzheimer-like pathology in APP/PS1 transgenic mice through promoting lysosomal degradation of BACE1.Exp Neurol. 2019 Jan;311:67-79. doi: 10.1016/j.expneurol.2018.09.012. Epub 2018 Sep 20.
• [2] Discovery, synthesis and anti-atherosclerotic activities of a novel selective sphingomyelin synthase 2 inhibitor.Eur J Med Chem. 2019 Feb 1;163:864-882. doi: 10.1016/j.ejmech.2018.12.028. Epub 2018 Dec 13.
• [3] Simultaneous inhibition of NMDA and mGlu1/5 receptors by levo-corydalmine in rat spinal cord attenuates bone cancer pain.Int J Cancer. 2017 Aug 15;141(4):805-815. doi: 10.1002/ijc.30780. Epub 2017 May 29.
• [4] Osteoporosis and skeletal dysplasia caused by pathogenic variants in SGMS2. JCI Insight. 2019 Apr 4;4(7):e126180. doi: 10.1172/jci.insight.126180. eCollection 2019 Apr 4.
• [5] Sphingomyelin synthase 2 deficiency inhibits the induction of murine colitis-associated colon cancer.FASEB J. 2017 Sep;31(9):3816-3830. doi: 10.1096/fj.201601225RR. Epub 2017 May 18.
• [6] Stressful learning paradigm precludes manifestation of cognitive ability in sphingomyelin synthase-2 knockout mice.Behav Brain Res. 2017 Feb 15;319:25-30. doi: 10.1016/j.bbr.2016.11.010. Epub 2016 Nov 10.
• [7] Sphingomyelin synthase 2 activity and liver steatosis: an effect of ceramide-mediated peroxisome proliferator-activated receptor 2 suppression.Arterioscler Thromb Vasc Biol. 2013 Jul;33(7):1513-20. doi: 10.1161/ATVBAHA.113.301498. Epub 2013 May 2.
• [8] The Opposing Contribution of SMS1 and SMS2 to Glioma Progression and Their Value in the Therapeutic Response to 2OHOA.Cancers (Basel). 2019 Jan 14;11(1):88. doi: 10.3390/cancers11010088.
• [9] Reducing plasma membrane sphingomyelin increases insulin sensitivity.Mol Cell Biol. 2011 Oct;31(20):4205-18. doi: 10.1128/MCB.05893-11. Epub 2011 Aug 15.
• [10] Sphingomyelin synthase 2 promotes an aggressive breast cancer phenotype by disrupting the homoeostasis of ceramide and sphingomyelin.Cell Death Dis. 2019 Feb 15;10(3):157. doi: 10.1038/s41419-019-1303-0.
• [11] Dynamic modification of sphingomyelin in lipid microdomains controls development of obesity, fatty liver, and type 2 diabetes.J Biol Chem. 2011 Aug 12;286(32):28544-55. doi: 10.1074/jbc.M111.255646. Epub 2011 Jun 13.
• [12] Airway Resistance Caused by Sphingomyelin Synthase 2 Insufficiency in Response to Cigarette Smoke.Am J Respir Cell Mol Biol. 2020 Mar;62(3):342-353. doi: 10.1165/rcmb.2019-0133OC.
• [13] The sphingomyelin synthase family: proteins, diseases, and inhibitors.Biol Chem. 2017 Nov 27;398(12):1319-1325. doi: 10.1515/hsz-2017-0148.
• [14] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [15] 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.
• [16] 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.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [19] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [20] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [21] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [22] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [27] 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.
• [28] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [29] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [30] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [31] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.