Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8F1MBF)

• DOT Name: Palmitoyl thioesterase CPT1C (CPT1C)
• Synonyms: EC 3.1.2.22; Carnitine O-palmitoyltransferase 1, brain isoform; CPTI-B; Carnitine palmitoyltransferase 1C; Carnitine palmitoyltransferase I; CPT I-C
• Gene Name: CPT1C
• Related Disease:
  Adult glioblastoma
  Autoimmune disease
  Autoimmune disease, susceptibility to, 6
  Breast cancer
  Breast carcinoma
  Glioblastoma multiforme
  Hereditary spastic paraplegia 10
  Hereditary spastic paraplegia 73
  Hypothyroidism
  Lung neoplasm
  Melanoma
  Non-alcoholic fatty liver disease
  STAT3-related early-onset multisystem autoimmune disease
  Vascular purpura
  Hypoglycemia
  Obesity
  Advanced cancer
  Hereditary spastic paraplegia
  Neoplasm
  Peripheral neuropathy
  Plasma cell myeloma
  Thyroid gland papillary carcinoma
• UniProt ID: CPT1C_HUMAN
• PDB ID: 2M76
• EC Number: 3.1.2.22
• Pfam ID: PF00755 ; PF16484
• Sequence:
  MAEAHQAVGFRPSLTSDGAEVELSAPVLQEIYLSGLRSWKRHLSRFWNDFLTGVFPASPL
  SWLFLFSAIQLAWFLQLDPSLGLMEKIKELLPDWGGQHHGLRGVLAAALFASCLWGALIF
  TLHVALRLLLSYHGWLLEPHGAMSSPTKTWLALVRIFSGRHPMLFSYQRSLPRQPVPSVQ
  DTVRKYLESVRPILSDEDFDWTAVLAQEFLRLQASLLQWYLRLKSWWASNYVSDWWEEFV
  YLRSRNPLMVNSNYYMMDFLYVTPTPLQAARAGNAVHALLLYRHRLNRQEIPPTLLMGMR
  PLCSAQYEKIFNTTRIPGVQKDYIRHLHDSQHVAVFHRGRFFRMGTHSRNSLLSPRALEQ
  QFQRILDDPSPACPHEEHLAALTAAPRGTWAQVRTSLKTQAAEALEAVEGAAFFVSLDAE
  PAGLTREDPAASLDAYAHALLAGRGHDRWFDKSFTLIVFSNGKLGLSVEHSWADCPISGH
  MWEFTLATECFQLGYSTDGHCKGHPDPTLPQPQRLQWDLPDQIHSSISLALRGAKILSEN
  VDCHVVPFSLFGKSFIRRCHLSSDSFIQIALQLAHFRDRGQFCLTYESAMTRLFLEGRTE
  TVRSCTREACNFVRAMEDKEKTDPQCLALFRVAVDKHQALLKAAMSGQGVDRHLFALYIV
  SRFLHLQSPFLTQVHSEQWQLSTSQIPVQQMHLFDVHNYPDYVSSGGGFGPADDHGYGVS
  YIFMGDGMITFHISSKKSSTKTDSHRLGQHIEDALLDVASLFQAGQHFKRRFRGSGKENS
  RHRCGFLSRQTGASKASMTSTDF
• Function: Palmitoyl thioesterase specifically expressed in the endoplasmic reticulum of neurons. Modulates the trafficking of the glutamate receptor, AMPAR, to plasma membrane through depalmitoylation of GRIA1. Also regulates AMPR trafficking through the regulation of SACM1L phosphatidylinositol-3-phosphatase activity by interaction in a malonyl-CoA dependent manner. Binds malonyl-CoA and couples malonyl-CoA to ceramide levels, necessary for proper spine maturation and contributing to systemic energy homeostasis and appetite control. Binds to palmitoyl-CoA, but does not have carnitine palmitoyltransferase 1 catalytic activity or at very low levels.
• Tissue Specificity: Expressed predominantly in brain and testis. Expressed in motor neurons.
• KEGG Pathway:
  Fatty acid degradation (hsa00071)
  Fatty acid metabolism (hsa01212)
  PPAR sig.ling pathway (hsa03320)
  Efferocytosis (hsa04148)
  AMPK sig.ling pathway (hsa04152)
  Thermogenesis (hsa04714)
  Adipocytokine sig.ling pathway (hsa04920)
  Glucagon sig.ling pathway (hsa04922)
  Alcoholic liver disease (hsa04936)
• BioCyc Pathway: MetaCyc:HS09892-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[1]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[2]
Autoimmune disease, susceptibility to, 6	DISHNUXI	Strong	Genetic Variation	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[1]
Hereditary spastic paraplegia 10	DISYFO3L	Strong	Genetic Variation	[4]
Hereditary spastic paraplegia 73	DIS9ZMRP	Strong	Autosomal dominant	[5]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[2]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[6]
Melanoma	DIS1RRCY	Strong	Biomarker	[7]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[8]
STAT3-related early-onset multisystem autoimmune disease	DISAXTN7	Strong	Genetic Variation	[2]
Vascular purpura	DIS6ZZMF	Strong	Biomarker	[9]
Hypoglycemia	DISRCKR7	moderate	Biomarker	[10]
Obesity	DIS47Y1K	moderate	Altered Expression	[11]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[12]
Hereditary spastic paraplegia	DISGZQV1	Limited	Autosomal dominant	[13]
Neoplasm	DISZKGEW	Limited	Biomarker	[12]
Peripheral neuropathy	DIS7KN5G	Limited	Biomarker	[14]
Plasma cell myeloma	DIS0DFZ0	Limited	Biomarker	[14]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Altered Expression	[15]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Bortezomib	DMNO38U	Approved	Palmitoyl thioesterase CPT1C (CPT1C) increases the response to substance of Bortezomib.	[14]

2 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 Palmitoyl thioesterase CPT1C (CPT1C).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Palmitoyl thioesterase CPT1C (CPT1C).	[19]

5 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 Palmitoyl thioesterase CPT1C (CPT1C).	[17]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Palmitoyl thioesterase CPT1C (CPT1C).	[18]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Palmitoyl thioesterase CPT1C (CPT1C).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Palmitoyl thioesterase CPT1C (CPT1C).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Palmitoyl thioesterase CPT1C (CPT1C).	[22]

References

• [1] High grade glioblastoma is associated with aberrant expression of ZFP57, a protein involved in gene imprinting, and of CPT1A and CPT1C that regulate fatty acid metabolism.Cancer Biol Ther. 2014 Jun 1;15(6):735-41. doi: 10.4161/cbt.28408. Epub 2014 Mar 11.
• [2] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [3] Molecular characterization, genomic structure and expression analysis of a gene (CATL1/CPT1C) encoding a third member of the human carnitine acyltransferase family.Genomics. 2019 May 22:S0888-7543(18)30715-8. doi: 10.1016/j.ygeno.2019.05.019. Online ahead of print.
• [4] Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia. JAMA Neurol. 2015 May;72(5):561-70. doi: 10.1001/jamaneurol.2014.4769.
• [5] Carnitine palmitoyltransferase 1C deficiency causes motor impairment and hypoactivity. Behav Brain Res. 2013 Nov 1;256:291-7. doi: 10.1016/j.bbr.2013.08.004. Epub 2013 Aug 21.
• [6] Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress.Genes Dev. 2011 May 15;25(10):1041-51. doi: 10.1101/gad.1987211.
• [7] Silencing of Peroxiredoxin 2 and aberrant methylation of 33 CpG islands in putative promoter regions in human malignant melanomas.Cancer Res. 2006 Jun 15;66(12):6080-6. doi: 10.1158/0008-5472.CAN-06-0157.
• [8] Genome-wide analysis of DNA methylation in human peripheral leukocytes identifies potential biomarkers of nonalcoholic fatty liver disease.Int J Mol Med. 2018 Jul;42(1):443-452. doi: 10.3892/ijmm.2018.3583. Epub 2018 Mar 22.
• [9] Hereditary ataxias and paraparesias: clinical and genetic update. Curr Opin Neurol. 2018 Aug;31(4):462-471. doi: 10.1097/WCO.0000000000000585.
• [10] Hypothalamic Regulation of Liver and Muscle Nutrient Partitioning by Brain-Specific Carnitine Palmitoyltransferase 1C in Male Mice.Endocrinology. 2017 Jul 1;158(7):2226-2238. doi: 10.1210/en.2017-00151.
• [11] CPT1C in the ventromedial nucleus of the hypothalamus is necessary for brown fat thermogenesis activation in obesity.Mol Metab. 2019 Jan;19:75-85. doi: 10.1016/j.molmet.2018.10.010. Epub 2018 Nov 2.
• [12] Effects of carnitine palmitoyltransferases on cancer cellular senescence.J Cell Physiol. 2019 Feb;234(2):1707-1719. doi: 10.1002/jcp.27042. Epub 2018 Aug 2.
• [13] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [14] Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial. Lancet Oncol. 2010 Nov;11(11):1057-65. doi: 10.1016/S1470-2045(10)70206-0. Epub 2010 Sep 21.
• [15] Cpt1c regulated by AMPK promotes papillary thyroid carcinomas cells survival under metabolic stress conditions.J Cancer. 2017 Oct 12;8(18):3675-3681. doi: 10.7150/jca.21148. eCollection 2017.
• [16] 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.
• [17] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [18] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [19] 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.
• [20] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [21] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [22] 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.
• [23] Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial. Lancet Oncol. 2010 Nov;11(11):1057-65. doi: 10.1016/S1470-2045(10)70206-0. Epub 2010 Sep 21.