Details of Drug Off-Target (DOT)

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

• DOT Name: Succinate--CoA ligase subunit alpha, mitochondrial (SUCLG1)
• Synonyms: EC 6.2.1.4; EC 6.2.1.5; Succinyl-CoA synthetase subunit alpha; SCS-alpha
• Gene Name: SUCLG1
• Related Disease:
  Mitochondrial DNA depletion syndrome
  Mitochondrial DNA depletion syndrome 9
  Gastric cancer
  Gastric neoplasm
  Glioblastoma multiforme
  Glioma
  Hereditary diffuse gastric adenocarcinoma
  Hypertrophic cardiomyopathy
  McCune-Albright syndrome
  Methylmalonic acidemia
  Mitochondrial encephalomyopathy
  Leigh syndrome
• UniProt ID: SUCA_HUMAN
• PDB ID: 6G4Q; 6WCV; 7MSR; 7MSS; 7MST
• EC Number: 6.2.1.4; 6.2.1.5
• Pfam ID: PF02629 ; PF00549
• Sequence:
  MTATLAAAADIATMVSGSSGLAAARLLSRSFLLPQNGIRHCSYTASRQHLYVDKNTKIIC
  QGFTGKQGTFHSQQALEYGTKLVGGTTPGKGGQTHLGLPVFNTVKEAKEQTGATASVIYV
  PPPFAAAAINEAIEAEIPLVVCITEGIPQQDMVRVKHKLLRQEKTRLIGPNCPGVINPGE
  CKIGIMPGHIHKKGRIGIVSRSGTLTYEAVHQTTQVGLGQSLCVGIGGDPFNGTDFIDCL
  EIFLNDSATEGIILIGEIGGNAEENAAEFLKQHNSGPNSKPVVSFIAGLTAPPGRRMGHA
  GAIIAGGKGGAKEKISALQSAGVVVSMSPAQLGTTIYKEFEKRKML
• Function: Succinyl-CoA synthetase functions in the citric acid cycle (TCA), coupling the hydrolysis of succinyl-CoA to the synthesis of either ATP or GTP and thus represents the only step of substrate-level phosphorylation in the TCA. The alpha subunit of the enzyme binds the substrates coenzyme A and phosphate, while succinate binding and specificity for either ATP or GTP is provided by different beta subunits.
• KEGG Pathway:
  Citrate cycle (TCA cycle) (hsa00020)
  Propanoate metabolism (hsa00640)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
• Reactome Pathway: Citric acid cycle (TCA cycle) (R-HSA-71403)
• BioCyc Pathway: MetaCyc:HS08877-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial DNA depletion syndrome	DISIGZSM	Definitive	Genetic Variation	[1]
Mitochondrial DNA depletion syndrome 9	DIS89YWA	Definitive	Autosomal recessive	[2]
Gastric cancer	DISXGOUK	Strong	Biomarker	[3]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[3]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[4]
Glioma	DIS5RPEH	Strong	Biomarker	[4]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[3]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Biomarker	[5]
McCune-Albright syndrome	DISCO2QT	Strong	Genetic Variation	[6]
Methylmalonic acidemia	DISHY8VB	Strong	Genetic Variation	[7]
Mitochondrial encephalomyopathy	DISA6PTN	Strong	Genetic Variation	[8]
Leigh syndrome	DISWQU45	Moderate	Autosomal recessive	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Succinate--CoA ligase subunit alpha, mitochondrial (SUCLG1) affects the response to substance of Doxorubicin.	[21]
Vinblastine	DM5TVS3	Approved	Succinate--CoA ligase subunit alpha, mitochondrial (SUCLG1) affects the response to substance of Vinblastine.	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Succinate--CoA ligase subunit alpha, mitochondrial (SUCLG1).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Succinate--CoA ligase subunit alpha, mitochondrial (SUCLG1).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Succinate--CoA ligase subunit alpha, mitochondrial (SUCLG1).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Succinate--CoA ligase subunit alpha, mitochondrial (SUCLG1).	[13]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Succinate--CoA ligase subunit alpha, mitochondrial (SUCLG1).	[15]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Succinate--CoA ligase subunit alpha, mitochondrial (SUCLG1).	[16]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Succinate--CoA ligase subunit alpha, mitochondrial (SUCLG1).	[17]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of Succinate--CoA ligase subunit alpha, mitochondrial (SUCLG1).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Succinate--CoA ligase subunit alpha, mitochondrial (SUCLG1).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Succinate--CoA ligase subunit alpha, mitochondrial (SUCLG1).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Succinate--CoA ligase subunit alpha, mitochondrial (SUCLG1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Succinate--CoA ligase subunit alpha, mitochondrial (SUCLG1).	[14]

References

• [1] Fatal infantile lactic acidosis and a novel homozygous mutation in the SUCLG1 gene: a mitochondrial DNA depletion disorder.Mol Genet Metab. 2011 Feb;102(2):149-52. doi: 10.1016/j.ymgme.2010.10.014. Epub 2010 Oct 30.
• [2] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [3] A gene expression signature of acquired chemoresistance to cisplatin and fluorouracil combination chemotherapy in gastric cancer patients.PLoS One. 2011 Feb 18;6(2):e16694. doi: 10.1371/journal.pone.0016694.
• [4] Elucidation of the genetic and epigenetic landscape alterations in RNA binding proteins in glioblastoma.Oncotarget. 2017 Mar 7;8(10):16650-16668. doi: 10.18632/oncotarget.14287.
• [5] Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients.J Inherit Metab Dis. 2016 Mar;39(2):243-52. doi: 10.1007/s10545-015-9894-9. Epub 2015 Oct 16.
• [6] Identification of a second-site suppressor mutation of the GTPase defect associated with McCune-Albright syndrome: a model using the yeast heterotrimeric G protein, GPA1.Arch Physiol Biochem. 2006 Jul;112(3):166-73. doi: 10.1080/13813450600935271.
• [7] Five novel SUCLG1 mutations in three Chinese patients with succinate-CoA ligase deficiency noticed by mild methylmalonic aciduria.Brain Dev. 2016 Jan;38(1):61-7. doi: 10.1016/j.braindev.2015.05.002. Epub 2015 May 28.
• [8] Clinical, Molecular, and Computational Analysis in two cases with mitochondrial encephalomyopathy associated with SUCLG1 mutation in a consanguineous family.Biochem Biophys Res Commun. 2018 Jan 8;495(2):1730-1737. doi: 10.1016/j.bbrc.2017.12.011. Epub 2017 Dec 5.
• [9] 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.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] 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.
• [14] 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.
• [15] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [16] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [17] Linalool is a PPARalpha ligand that reduces plasma TG levels and rewires the hepatic transcriptome and plasma metabolome. J Lipid Res. 2014 Jun;55(6):1098-110.
• [18] 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.
• [19] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [21] 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.