Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT536PE7)

• DOT Name: Succinyl-CoA:3-ketoacid coenzyme A transferase 1, mitochondrial (OXCT1)
• Synonyms: SCOT; EC 2.8.3.5; 3-oxoacid CoA-transferase 1; Somatic-type succinyl-CoA:3-oxoacid CoA-transferase; SCOT-s; Succinyl-CoA:3-oxoacid CoA transferase
• Gene Name: OXCT1
• Related Disease:
  Glioma
  Succinyl-CoA:3-ketoacid CoA transferase deficiency
  Beta-ketothiolase deficiency
  Coronary atherosclerosis
  Hepatocellular carcinoma
  Non-insulin dependent diabetes
  Osteoporosis
  Scleroderma
  Systemic sclerosis
  Myocardial ischemia
  Coronary heart disease
  Advanced cancer
  Classic phenylketonuria
  Neoplasm
  Obesity
  Phenylketonuria
  Sickle-cell anaemia
• UniProt ID: SCOT1_HUMAN
• PDB ID: 3DLX
• EC Number: 2.8.3.5
• Pfam ID: PF01144
• Sequence:
  MAALKLLSSGLRLCASARGSGATWYKGCVCSFSTSAHRHTKFYTDPVEAVKDIPDGATVL
  VGGFGLCGIPENLIDALLKTGVKGLTAVSNNAGVDNFGLGLLLRSKQIKRMVSSYVGENA
  EFERQYLSGELEVELTPQGTLAERIRAGGAGVPAFYTPTGYGTLVQEGGSPIKYNKDGSV
  AIASKPREVREFNGQHFILEEAITGDFALVKAWKADRAGNVIFRKSARNFNLPMCKAAET
  TVVEVEEIVDIGAFAPEDIHIPQIYVHRLIKGEKYEKRIERLSIRKEGDGEAKSAKPGDD
  VRERIIKRAALEFEDGMYANLGIGIPLLASNFISPNITVHLQSENGVLGLGPYPRQHEAD
  ADLINAGKETVTILPGASFFSSDESFAMIRGGHVDLTMLGAMQVSKYGDLANWMIPGKMV
  KGMGGAMDLVSSAKTKVVVTMEHSAKGNAHKIMEKCTLPLTGKQCVNRIITEKAVFDVDK
  KKGLTLIELWEGLTVDDVQKSTGCDFAVSPKLMPMQQIAN
• Function: Key enzyme for ketone body catabolism. Catalyzes the first, rate-limiting step of ketone body utilization in extrahepatic tissues, by transferring coenzyme A (CoA) from a donor thiolester species (succinyl-CoA) to an acceptor carboxylate (acetoacetate), and produces acetoacetyl-CoA. Acetoacetyl-CoA is further metabolized by acetoacetyl-CoA thiolase into two acetyl-CoA molecules which enter the citric acid cycle for energy production. Forms a dimeric enzyme where both of the subunits are able to form enzyme-CoA thiolester intermediates, but only one subunit is competent to transfer the CoA moiety to the acceptor carboxylate (3-oxo acid) and produce a new acyl-CoA. Formation of the enzyme-CoA intermediate proceeds via an unstable anhydride species formed between the carboxylate groups of the enzyme and substrate.
• Tissue Specificity: Abundant in heart, followed in order by brain, kidney, skeletal muscle, and lung, whereas in liver it is undetectable. Expressed (at protein level) in all tissues (except in liver), most abundant in myocardium, then brain, kidney, adrenal glands, skeletal muscle and lung; also detectable in leukocytes and fibroblasts.
• KEGG Pathway:
  Valine, leucine and isoleucine degradation (hsa00280)
  Butanoate metabolism (hsa00650)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Utilization of Ketone Bodies (R-HSA-77108)
• BioCyc Pathway: MetaCyc:HS01447-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glioma	DIS5RPEH	Definitive	Altered Expression	[1]
Succinyl-CoA:3-ketoacid CoA transferase deficiency	DIS0YEM9	Definitive	Autosomal recessive	[2]
Beta-ketothiolase deficiency	DIS7NWEJ	Strong	Biomarker	[3]
Coronary atherosclerosis	DISKNDYU	Strong	Genetic Variation	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[5]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[6]
Osteoporosis	DISF2JE0	Strong	Biomarker	[7]
Scleroderma	DISVQ342	Strong	Biomarker	[8]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[8]
Myocardial ischemia	DISFTVXF	moderate	Genetic Variation	[9]
Coronary heart disease	DIS5OIP1	Disputed	Genetic Variation	[4]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[10]
Classic phenylketonuria	DISLU64N	Limited	Genetic Variation	[11]
Neoplasm	DISZKGEW	Limited	Biomarker	[10]
Obesity	DIS47Y1K	Limited	Biomarker	[12]
Phenylketonuria	DISCU56J	Limited	Genetic Variation	[11]
Sickle-cell anaemia	DIS5YNZB	Limited	Genetic Variation	[13]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Succinyl-CoA:3-ketoacid coenzyme A transferase 1, mitochondrial (OXCT1) affects the response to substance of Fluorouracil.	[30]
Mitoxantrone	DMM39BF	Approved	Succinyl-CoA:3-ketoacid coenzyme A transferase 1, mitochondrial (OXCT1) affects the response to substance of Mitoxantrone.	[30]

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 Succinyl-CoA:3-ketoacid coenzyme A transferase 1, mitochondrial (OXCT1).	[14]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Succinyl-CoA:3-ketoacid coenzyme A transferase 1, mitochondrial (OXCT1).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Succinyl-CoA:3-ketoacid coenzyme A transferase 1, mitochondrial (OXCT1).	[26]

13 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 Succinyl-CoA:3-ketoacid coenzyme A transferase 1, mitochondrial (OXCT1).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Succinyl-CoA:3-ketoacid coenzyme A transferase 1, mitochondrial (OXCT1).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Succinyl-CoA:3-ketoacid coenzyme A transferase 1, mitochondrial (OXCT1).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Succinyl-CoA:3-ketoacid coenzyme A transferase 1, mitochondrial (OXCT1).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Succinyl-CoA:3-ketoacid coenzyme A transferase 1, mitochondrial (OXCT1).	[19]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Succinyl-CoA:3-ketoacid coenzyme A transferase 1, mitochondrial (OXCT1).	[20]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Succinyl-CoA:3-ketoacid coenzyme A transferase 1, mitochondrial (OXCT1).	[22]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Succinyl-CoA:3-ketoacid coenzyme A transferase 1, mitochondrial (OXCT1).	[23]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Succinyl-CoA:3-ketoacid coenzyme A transferase 1, mitochondrial (OXCT1).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Succinyl-CoA:3-ketoacid coenzyme A transferase 1, mitochondrial (OXCT1).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Succinyl-CoA:3-ketoacid coenzyme A transferase 1, mitochondrial (OXCT1).	[27]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Succinyl-CoA:3-ketoacid coenzyme A transferase 1, mitochondrial (OXCT1).	[28]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Succinyl-CoA:3-ketoacid coenzyme A transferase 1, mitochondrial (OXCT1).	[29]

References

• [1] Differential utilization of ketone bodies by neurons and glioma cell lines: a rationale for ketogenic diet as experimental glioma therapy.BMC Cancer. 2011 Jul 26;11:315. doi: 10.1186/1471-2407-11-315.
• [2] Outcome for children with relapsed acute myeloid leukemia in the Netherlands following initial treatment between 1980 and 1998: survival after chemotherapy only?. Haematologica. 2008 Sep;93(9):1418-20. doi: 10.3324/haematol.12807.
• [3] Ketone body metabolism and its defects.J Inherit Metab Dis. 2014 Jul;37(4):541-51. doi: 10.1007/s10545-014-9704-9. Epub 2014 Apr 8.
• [4] Breast arterial calcification on mammography and risk of coronary artery disease: a SCOT-HEART sub-study.Clin Radiol. 2019 Jun;74(6):421-428. doi: 10.1016/j.crad.2019.01.014. Epub 2019 Feb 22.
• [5] Hepatocellular carcinoma redirects to ketolysis for progression under nutrition deprivation stress.Cell Res. 2016 Oct;26(10):1112-1130. doi: 10.1038/cr.2016.109. Epub 2016 Sep 20.
• [6] Lower succinyl-CoA:3-ketoacid-CoA transferase (SCOT) and ATP citrate lyase in pancreatic islets of a rat model of type 2 diabetes: knockdown of SCOT inhibits insulin release in rat insulinoma cells.Arch Biochem Biophys. 2010 Jul;499(1-2):62-8. doi: 10.1016/j.abb.2010.05.007. Epub 2010 May 9.
• [7] Proteomic analysis of circulating monocytes in Chinese premenopausal females with extremely discordant bone mineral density.Proteomics. 2008 Oct;8(20):4259-72. doi: 10.1002/pmic.200700480.
• [8] Myeloablation followed by autologous stem cell transplantation normalises systemic sclerosis molecular signatures.Ann Rheum Dis. 2019 Oct;78(10):1371-1378. doi: 10.1136/annrheumdis-2019-215770. Epub 2019 Aug 7.
• [9] SCOT-HEART trial: reshuffling our approach to stable ischemic heart disease.Br J Radiol. 2020 Sep 1;93(1113):20190763. doi: 10.1259/bjr.20190763. Epub 2019 Oct 31.
• [10] The role of OXCT1 in the pathogenesis of cancer as a rate-limiting enzyme of ketone body metabolism.Life Sci. 2017 Aug 15;183:110-115. doi: 10.1016/j.lfs.2017.07.003. Epub 2017 Jul 4.
• [11] When one disease is not enough: succinyl-CoA: 3-oxoacid coenzyme A transferase (SCOT) deficiency due to a novel mutation in OXCT1 in an infant with known phenylketonuria.J Pediatr Endocrinol Metab. 2017 Oct 26;30(10):1121-1124. doi: 10.1515/jpem-2017-0177.
• [12] Genetic obesity affects neural ketone body utilization in the rat brain.Obesity (Silver Spring). 2009 Mar;17(3):611-5. doi: 10.1038/oby.2008.566. Epub 2008 Dec 11.
• [13] Double-blind, randomized, multicenter phase 2 study of SC411 in children with sickle cell disease (SCOT trial).Blood Adv. 2018 Aug 14;2(15):1969-1979. doi: 10.1182/bloodadvances.2018021444.
• [14] 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.
• [15] 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.
• [16] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [17] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [18] 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.
• [19] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [20] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [21] 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.
• [22] 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.
• [23] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [24] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [25] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [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.
• [27] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [28] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [29] 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.
• [30] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.