Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6EYRM3)

• DOT Name: Ceramide synthase 1 (CERS1)
• Synonyms: CerS1; LAG1 longevity assurance homolog 1; Longevity assurance gene 1 protein homolog 1; Protein UOG-1; Sphingoid base N-stearoyltransferase CERS1; EC 2.3.1.299
• Gene Name: CERS1
• Related Disease:
  Malaria
  Advanced cancer
  Congestive heart failure
  Crohn disease
  Dengue
  Fatty liver disease
  Glioma
  Hand, foot and mouth disease
  Head-neck squamous cell carcinoma
  Huntington disease
  Inflammatory bowel disease
  Neoplasm
  Neuroblastoma
  Progressive myoclonic epilepsy type 8
  Sleep disorder
  Visceral heterotaxy
  Dementia
  Myocardial ischemia
  Nervous system disease
  Thyroid gland papillary carcinoma
  Familial spontaneous pneumothorax
• UniProt ID: CERS1_HUMAN
• EC Number: 2.3.1.299
• Pfam ID: PF03798
• Sequence:
  MAAAGPAAGPTGPEPMPSYAQLVQRGWGSALAAARGCTDCGWGLARRGLAEHAHLAPPEL
  LLLALGALGWTALRSAATARLFRPLAKRCCLQPRDAAKMPESAWKFLFYLGSWSYSAYLL
  FGTDYPFFHDPPSVFYDWTPGMAVPRDIAAAYLLQGSFYGHSIYATLYMDTWRKDSVVML
  LHHVVTLILIVSSYAFRYHNVGILVLFLHDISDVQLEFTKLNIYFKSRGGSYHRLHALAA
  DLGCLSFGFSWFWFRLYWFPLKVLYATSHCSLRTVPDIPFYFFFNALLLLLTLMNLYWFL
  YIVAFAAKVLTGQVHELKDLREYDTAEAQSLKPSKAEKPLRNGLVKDKRF
• Function: Ceramide synthase that catalyzes the transfer of the acyl chain from acyl-CoA to a sphingoid base, with high selectivity toward stearoyl-CoA (octadecanoyl-CoA; C18:0-CoA). N-acylates sphinganine and sphingosine bases to form dihydroceramides and ceramides in de novo synthesis and salvage pathways, respectively. Plays a predominant role in skeletal muscle in regulating C18 ceramide and dihydroceramide levels with an impact on whole-body glucose metabolism and insulin sensitivity. Protects from diet-induced obesity by suppressing the uptake of glucose in multiple organs in a FGF21-dependent way. Generates C18 ceramides in the brain, playing a critical role in cerebellar development and Purkinje cell function. In response to cellular stress mediates mitophagy, a known defense mechanism against cell transformation and aging. Upon mitochondria fission, generates C18 ceramides that anchor lipidated MAP1LC3B/LC3B-II autophagolysosomes to outer mitochondrial membranes to eliminate damaged mitochondria.
• KEGG Pathway:
  Sphingolipid metabolism (hsa00600)
  Metabolic pathways (hsa01100)
  Sphingolipid sig.ling pathway (hsa04071)
• Reactome Pathway: Sphingolipid de novo biosynthesis (R-HSA-1660661)
• BioCyc Pathway: MetaCyc:MONOMER66-34367

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Malaria	DISQ9Y50	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[3]
Crohn disease	DIS2C5Q8	Strong	Altered Expression	[4]
Dengue	DISKH221	Strong	Biomarker	[5]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[6]
Glioma	DIS5RPEH	Strong	Biomarker	[7]
Hand, foot and mouth disease	DISKJHLL	Strong	Biomarker	[8]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[9]
Huntington disease	DISQPLA4	Strong	Altered Expression	[10]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[11]
Progressive myoclonic epilepsy type 8	DIS8S849	Strong	Autosomal recessive	[12]
Sleep disorder	DIS3JP1U	Strong	Biomarker	[13]
Visceral heterotaxy	DIS1DV90	Strong	Genetic Variation	[14]
Dementia	DISXL1WY	moderate	Genetic Variation	[15]
Myocardial ischemia	DISFTVXF	moderate	Genetic Variation	[16]
Nervous system disease	DISJ7GGT	Disputed	Biomarker	[17]
Thyroid gland papillary carcinoma	DIS48YMM	Disputed	Biomarker	[18]
Familial spontaneous pneumothorax	DISNM7SU	Limited	Genetic Variation	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Ceramide synthase 1 (CERS1).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Ceramide synthase 1 (CERS1).	[23]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Ceramide synthase 1 (CERS1).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Marinol	DM70IK5	Approved	Marinol increases the expression of Ceramide synthase 1 (CERS1).	[21]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Ceramide synthase 1 (CERS1).	[22]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Ceramide synthase 1 (CERS1).	[25]

References

• [1] A Time Series Analysis: Weather Factors, Human Migration and Malaria Cases in Endemic Area of Purworejo, Indonesia, 2005-2014.Iran J Public Health. 2018 Apr;47(4):499-509.
• [2] Concerted functions of HDAC1 and microRNA-574-5p repress alternatively spliced ceramide synthase 1 expression in human cancer cells.EMBO Mol Med. 2012 Feb;4(2):78-92. doi: 10.1002/emmm.201100189. Epub 2011 Dec 19.
• [3] A tissue-specific screen of ceramide expression in aged mice identifies ceramide synthase-1 and ceramide synthase-5 as potential regulators of fiber size and strength in skeletal muscle.Aging Cell. 2020 Jan;19(1):e13049. doi: 10.1111/acel.13049. Epub 2019 Nov 6.
• [4] mTNF reverse signalling induced by TNF antagonists involves a GDF-1 dependent pathway: implications for Crohn's disease.Gut. 2013 Mar;62(3):376-86. doi: 10.1136/gutjnl-2011-300384. Epub 2012 Apr 25.
• [5] Influence of meteorological variables on dengue incidence in the municipality of Arapiraca, Alagoas, Brazil.Rev Soc Bras Med Trop. 2017 May-Jun;50(3):309-314. doi: 10.1590/0037-8682-0432-2016.
• [6] Hepatocyte-specific deletion of LASS2 protects against diet-induced hepatic steatosis and insulin resistance.Free Radic Biol Med. 2018 May 20;120:330-341. doi: 10.1016/j.freeradbiomed.2018.04.003. Epub 2018 Apr 4.
• [7] Overexpression of ceramide synthase 1 increases C18-ceramide and leads to lethal autophagy in human glioma.Oncotarget. 2017 Oct 23;8(61):104022-104036. doi: 10.18632/oncotarget.21955. eCollection 2017 Nov 28.
• [8] Short-term exposure to sulfur dioxide and the risk of childhood hand, foot, and mouth disease during different seasons in Hefei, China.Sci Total Environ. 2019 Mar 25;658:116-121. doi: 10.1016/j.scitotenv.2018.11.481. Epub 2018 Dec 2.
• [9] Role of human longevity assurance gene 1 and C18-ceramide in chemotherapy-induced cell death in human head and neck squamous cell carcinomas.Mol Cancer Ther. 2007 Feb;6(2):712-22. doi: 10.1158/1535-7163.MCT-06-0558.
• [10] De novo Synthesis of Sphingolipids Is Defective in Experimental Models of Huntington's Disease.Front Neurosci. 2017 Dec 19;11:698. doi: 10.3389/fnins.2017.00698. eCollection 2017.
• [11] Autosomal recessive progressive myoclonus epilepsy due to impaired ceramide synthesis.Epileptic Disord. 2016 Sep 1;18(S2):120-127. doi: 10.1684/epd.2016.0857.
• [12] Ablation of neuronal ceramide synthase 1 in mice decreases ganglioside levels and expression of myelin-associated glycoprotein in oligodendrocytes. J Biol Chem. 2012 Dec 7;287(50):41888-902. doi: 10.1074/jbc.M112.413500. Epub 2012 Oct 16.
• [13] Search trends preceding increases in suicide: A cross-correlation study of monthly Google search volume and suicide rate using transfer function models.J Affect Disord. 2020 Feb 1;262:155-164. doi: 10.1016/j.jad.2019.11.014. Epub 2019 Nov 4.
• [14] Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. Nat Genet. 2017 Nov;49(11):1593-1601. doi: 10.1038/ng.3970. Epub 2017 Oct 9.
• [15] Impairment of ceramide synthesis causes a novel progressive myoclonus epilepsy. Ann Neurol. 2014 Aug;76(2):206-12. doi: 10.1002/ana.24170. Epub 2014 May 20.
• [16] Exposure to air pollution and risk of hospitalization for cardiovascular diseases amongst Vietnamese adults: Case-crossover study.Sci Total Environ. 2020 Feb 10;703:134637. doi: 10.1016/j.scitotenv.2019.134637. Epub 2019 Nov 3.
• [17] Whole Genome Expression Analysis in a Mouse Model of Tauopathy Identifies MECP2 as a Possible Regulator of Tau Pathology.Front Mol Neurosci. 2017 Mar 17;10:69. doi: 10.3389/fnmol.2017.00069. eCollection 2017.
• [18] Overexpression of LASS2 inhibits proliferation and causes G0/G1 cell cycle arrest in papillary thyroid cancer.Cancer Cell Int. 2018 Oct 1;18:151. doi: 10.1186/s12935-018-0649-1. eCollection 2018.
• [19] Air pollutants and atmospheric pressure increased risk of ED visit for spontaneous pneumothorax.Am J Emerg Med. 2018 Dec;36(12):2249-2253. doi: 10.1016/j.ajem.2018.04.020. Epub 2018 Apr 14.
• [20] 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.
• [21] 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.
• [22] The roles of bioactive sphingolipids in resveratrol-induced apoptosis in HL60: acute myeloid leukemia cells. J Cancer Res Clin Oncol. 2011 Feb;137(2):279-86. doi: 10.1007/s00432-010-0884-x. Epub 2010 Apr 18.
• [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] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [25] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.