Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZQE7PW)

• DOT Name: Phosphatidylcholine:ceramide cholinephosphotransferase 1 (SGMS1)
• Synonyms: EC 2.7.8.27; Medulla oblongata-derived protein; Protein Mob; Sphingomyelin synthase 1; Transmembrane protein 23
• Gene Name: SGMS1
• Related Disease:
  Advanced cancer
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Non-insulin dependent diabetes
  Non-small-cell lung cancer
  Alzheimer disease
  Arteriosclerosis
  Atherosclerosis
  Autoimmune disease
  Glioma
  Hepatitis
  Hepatitis A virus infection
  Intrahepatic cholangiocarcinoma
  Lupus
  Melanoma
  Obesity
  Pulmonary edema
  Renal fibrosis
  Systemic lupus erythematosus
  Pancreatic cancer
  Colorectal carcinoma
  Neoplasm
• UniProt ID: SMS1_HUMAN
• EC Number: 2.7.8.27
• Pfam ID: PF14360
• Sequence:
  MKEVVYWSPKKVADWLLENAMPEYCEPLEHFTGQDLINLTQEDFKKPPLCRVSSDNGQRL
  LDMIETLKMEHHLEAHKNGHANGHLNIGVDIPTPDGSFSIKIKPNGMPNGYRKEMIKIPM
  PELERSQYPMEWGKTFLAFLYALSCFVLTTVMISVVHERVPPKEVQPPLPDTFFDHFNRV
  QWAFSICEINGMILVGLWLIQWLLLKYKSIISRRFFCIVGTLYLYRCITMYVTTLPVPGM
  HFNCSPKLFGDWEAQLRRIMKLIAGGGLSITGSHNMCGDYLYSGHTVMLTLTYLFIKEYS
  PRRLWWYHWICWLLSVVGIFCILLAHDHYTVDVVVAYYITTRLFWWYHTMANQQVLKEAS
  QMNLLARVWWYRPFQYFEKNVQGIVPRSYHWPFPWPVVHLSRQVKYSRLVNDT
• Function: Major sphingomyelin synthase at the Golgi apparatus. 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 depends on the levels of CER and DAG in Golgi membranes. Does not use free phosphorylcholine or CDP-choline as donor. 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. Plays a role in secretory transport via regulation of DAG pool at the Golgi apparatus and its downstream effects on PRKD1.
• Tissue Specificity: Brain, heart, kidney, liver, muscle and stomach.
• 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

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Altered Expression	[1]
Lung cancer	DISCM4YA	Definitive	Altered Expression	[1]
Lung carcinoma	DISTR26C	Definitive	Altered Expression	[1]
Lung neoplasm	DISVARNB	Definitive	Altered Expression	[1]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Biomarker	[2]
Non-small-cell lung cancer	DIS5Y6R9	Definitive	Altered Expression	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[4]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[4]
Autoimmune disease	DISORMTM	Strong	Biomarker	[4]
Glioma	DIS5RPEH	Strong	Biomarker	[5]
Hepatitis	DISXXX35	Strong	Biomarker	[4]
Hepatitis A virus infection	DISUMFQV	Strong	Biomarker	[4]
Intrahepatic cholangiocarcinoma	DIS6GOC8	Strong	Biomarker	[6]
Lupus	DISOKJWA	Strong	Biomarker	[4]
Melanoma	DIS1RRCY	Strong	Altered Expression	[7]
Obesity	DIS47Y1K	Strong	Biomarker	[8]
Pulmonary edema	DISNPHO6	Strong	Biomarker	[9]
Renal fibrosis	DISMHI3I	Strong	Altered Expression	[10]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[4]
Pancreatic cancer	DISJC981	moderate	Biomarker	[11]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[12]
Neoplasm	DISZKGEW	Limited	Biomarker	[7]

4 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 Phosphatidylcholine:ceramide cholinephosphotransferase 1 (SGMS1).	[13]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Phosphatidylcholine:ceramide cholinephosphotransferase 1 (SGMS1).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Phosphatidylcholine:ceramide cholinephosphotransferase 1 (SGMS1).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Phosphatidylcholine:ceramide cholinephosphotransferase 1 (SGMS1).	[26]

10 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 Phosphatidylcholine:ceramide cholinephosphotransferase 1 (SGMS1).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Phosphatidylcholine:ceramide cholinephosphotransferase 1 (SGMS1).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phosphatidylcholine:ceramide cholinephosphotransferase 1 (SGMS1).	[16]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Phosphatidylcholine:ceramide cholinephosphotransferase 1 (SGMS1).	[18]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Phosphatidylcholine:ceramide cholinephosphotransferase 1 (SGMS1).	[19]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Phosphatidylcholine:ceramide cholinephosphotransferase 1 (SGMS1).	[20]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Phosphatidylcholine:ceramide cholinephosphotransferase 1 (SGMS1).	[21]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Phosphatidylcholine:ceramide cholinephosphotransferase 1 (SGMS1).	[22]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Phosphatidylcholine:ceramide cholinephosphotransferase 1 (SGMS1).	[24]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Phosphatidylcholine:ceramide cholinephosphotransferase 1 (SGMS1).	[25]

References

• [1] Human MOB1 expression in non-small-cell lung cancer.Clin Lung Cancer. 2007 Jan;8(4):273-6. doi: 10.3816/CLC.2007.n.006.
• [2] Lipid environment induces ER stress, TXNIP expression and inflammation in immune cells of individuals with type 2 diabetes.Diabetologia. 2018 Feb;61(2):399-412. doi: 10.1007/s00125-017-4462-5. Epub 2017 Oct 7.
• [3] 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.
• [4] Sphingomyelin synthase 1 enhances BCR signaling to promote lupus-like autoimmune response.EBioMedicine. 2019 Jul;45:578-587. doi: 10.1016/j.ebiom.2019.06.038. Epub 2019 Jun 28.
• [5] 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.
• [6] Altered Expression of Hippo Signaling Pathway Molecules in Intrahepatic Cholangiocarcinoma.Oncology. 2017;93(1):67-74. doi: 10.1159/000463390. Epub 2017 Apr 28.
• [7] Sphingomyelin Synthase 1 (SMS1) Downregulation Is Associated With Sphingolipid Reprogramming and a Worse Prognosis in Melanoma.Front Pharmacol. 2019 Apr 30;10:443. doi: 10.3389/fphar.2019.00443. eCollection 2019.
• [8] Genetic modifiers of Leprfa associated with variability in insulin production and susceptibility to NIDDM.Genomics. 1997 May 1;41(3):332-44. doi: 10.1006/geno.1997.4672.
• [9] MOB-1 and TNF-alpha interact to induce microvascular lung injury.Shock. 2002 Sep;18(3):261-4. doi: 10.1097/00024382-200209000-00010.
• [10] Kindlin-2 Inhibits the Hippo Signaling Pathway by Promoting Degradation of MOB1.Cell Rep. 2019 Dec 10;29(11):3664-3677.e5. doi: 10.1016/j.celrep.2019.11.035.
• [11] The MST4-MOB4 complex disrupts the MST1-MOB1 complex in the Hippo-YAP pathway and plays a pro-oncogenic role in pancreatic cancer.J Biol Chem. 2018 Sep 14;293(37):14455-14469. doi: 10.1074/jbc.RA118.003279. Epub 2018 Aug 2.
• [12] Mob-1, a Ras target gene, is overexpressed in colorectal cancer.Oncogene. 1997 Apr 3;14(13):1607-10. doi: 10.1038/sj.onc.1200957.
• [13] 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.
• [14] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [19] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [20] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [21] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [22] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [23] 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.
• [24] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [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] 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.