Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7XNL0K)

• DOT Name: Cardiolipin synthase (CRLS1)
• Synonyms: CMP-forming; CLS; EC 2.7.8.41; Protein GCD10 homolog
• Gene Name: CRLS1
• Related Disease:
  Breast cancer
  Breast carcinoma
  Breast fibrocystic disease
  Coffin-Lowry syndrome
  Colitis
  Colorectal carcinoma
  Combined oxidative phosphorylation deficiency 57
  Depression
  Ductal carcinoma
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Paroxysmal nocturnal haemoglobinuria
  Schizophrenia
  Sexually transmitted infection
  Vascular dementia
  Pneumonia
  Wilms tumor
• UniProt ID: CRLS1_HUMAN
• EC Number: 2.7.8.41
• Pfam ID: PF01066
• Sequence:
  MLALRVARGSWGALRGAAWAPGTRPSKRRACWALLPPVPCCLGCLAERWRLRPAALGLRL
  PGIGQRNHCSGAGKAAPRPAAGAGAAAEAPGGQWGPASTPSLYENPWTIPNMLSMTRIGL
  APVLGYLIIEEDFNIALGVFALAGLTDLLDGFIARNWANQRSALGSALDPLADKILISIL
  YVSLTYADLIPVPLTYMIISRDVMLIAAVFYVRYRTLPTPRTLAKYFNPCYATARLKPTF
  ISKVNTAVQLILVAASLAAPVFNYADSIYLQILWCFTAFTTAASAYSYYHYGRKTVQVIK
  D
• Function: Catalyzes the synthesis of cardiolipin (CL) (diphosphatidylglycerol) by specifically transferring a phosphatidyl group from CDP-diacylglycerol to phosphatidylglycerol (PG). CL is a key phospholipid in mitochondrial membranes and plays important roles in maintaining the functional integrity and dynamics of mitochondria under both optimal and stress conditions.
• Tissue Specificity: Highly expressed in tissues such as heart, skeletal muscle and liver.
• KEGG Pathway:
  Glycerophospholipid metabolism (hsa00564)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Synthesis of CL (R-HSA-1483076)
  Acyl chain remodelling of PG (R-HSA-1482925)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[1]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[1]
Breast fibrocystic disease	DISUM7ID	Strong	Biomarker	[1]
Coffin-Lowry syndrome	DISMTBDA	Strong	Biomarker	[2]
Colitis	DISAF7DD	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Combined oxidative phosphorylation deficiency 57	DISXH312	Strong	Autosomal recessive	[5]
Depression	DIS3XJ69	Strong	Biomarker	[6]
Ductal carcinoma	DIS15EA5	Strong	Biomarker	[4]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[8]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[9]
Lung cancer	DISCM4YA	Strong	Altered Expression	[9]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[9]
Neoplasm	DISZKGEW	Strong	Altered Expression	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[9]
Paroxysmal nocturnal haemoglobinuria	DISBHMYH	Strong	Biomarker	[10]
Schizophrenia	DISSRV2N	Strong	Biomarker	[11]
Sexually transmitted infection	DISIVIAL	Strong	Biomarker	[7]
Vascular dementia	DISVO82H	Strong	Altered Expression	[12]
Pneumonia	DIS8EF3M	Limited	Biomarker	[13]
Wilms tumor	DISB6T16	Limited	Altered Expression	[14]

2 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 Cardiolipin synthase (CRLS1).	[15]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Cardiolipin synthase (CRLS1).	[25]

15 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 Cardiolipin synthase (CRLS1).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cardiolipin synthase (CRLS1).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cardiolipin synthase (CRLS1).	[18]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Cardiolipin synthase (CRLS1).	[19]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Cardiolipin synthase (CRLS1).	[20]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Cardiolipin synthase (CRLS1).	[21]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Cardiolipin synthase (CRLS1).	[22]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Cardiolipin synthase (CRLS1).	[23]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Cardiolipin synthase (CRLS1).	[24]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Cardiolipin synthase (CRLS1).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Cardiolipin synthase (CRLS1).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Cardiolipin synthase (CRLS1).	[28]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Cardiolipin synthase (CRLS1).	[29]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Cardiolipin synthase (CRLS1).	[30]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Cardiolipin synthase (CRLS1).	[30]

References

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• [2] Adult with an interstitial deletion of chromosome 10 [del(10)(q25. 1q25.3)]: overlap with Coffin-Lowry syndrome.Am J Med Genet. 2000 Nov 13;95(2):93-8. doi: 10.1002/1096-8628(20001113)95:2<93::aid-ajmg1>3.0.co;2-b.
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• [4] Mutational Profiling Can Establish Clonal or Independent Origin in Synchronous Bilateral Breast and Other Tumors.PLoS One. 2015 Nov 10;10(11):e0142487. doi: 10.1371/journal.pone.0142487. eCollection 2015.
• [5] Deleterious variants in CRLS1 lead to cardiolipin deficiency and cause an autosomal recessive multi-system mitochondrial disease. Hum Mol Genet. 2022 Oct 28;31(21):3597-3612. doi: 10.1093/hmg/ddac040.
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• [9] Expression and potential mechanism of metabolism-related genes and CRLS1 in non-small cell lung cancer.Oncol Lett. 2018 Feb;15(2):2661-2668. doi: 10.3892/ol.2017.7591. Epub 2017 Dec 12.
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• [13] E3 ligase subunit Fbxo15 and PINK1 kinase regulate cardiolipin synthase 1 stability and mitochondrial function in pneumonia.Cell Rep. 2014 Apr 24;7(2):476-487. doi: 10.1016/j.celrep.2014.02.048. Epub 2014 Apr 3.
• [14] miR-140-5p could suppress tumor proliferation and progression by targeting TGFBRI/SMAD2/3 and IGF-1R/AKT signaling pathways in Wilms' tumor.BMC Cancer. 2019 Apr 29;19(1):405. doi: 10.1186/s12885-019-5609-1.
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• [21] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [22] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [23] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
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• [25] 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.
• [26] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
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