Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0MTVGF)

• DOT Name: CDGSH iron-sulfur domain-containing protein 1 (CISD1)
• Synonyms: Cysteine transaminase CISD1; EC 2.6.1.3; MitoNEET
• Gene Name: CISD1
• Related Disease:
  Arteriosclerosis
  Atherosclerosis
  Cardiovascular disease
  Cystic fibrosis
  Non-insulin dependent diabetes
  Obesity
  Parkinson disease
  Type-1/2 diabetes
  Wolfram syndrome 2
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Neoplasm
  Neuroblastoma
• UniProt ID: CISD1_HUMAN
• PDB ID: 2QD0; 2QH7; 2R13; 3EW0; 3LPQ; 3REE; 4EZF; 4F1E; 4F28; 4F2C; 6DE9; 7P0O
• EC Number: 2.6.1.3
• Pfam ID: PF10660 ; PF09360
• Sequence:
  MSLTSSSSVRVEWIAAVTIAAGTAAIGYLAYKRFYVKDHRNKAMINLHIQKDNPKIVHAF
  DMEDLGDKAVYCRCWRSKKFPFCDGAHTKHNEETGDNVGPLIIKKKET
• Function: L-cysteine transaminase that catalyzes the reversible transfer of the amino group from L-cysteine to the alpha-keto acid 2-oxoglutarate to respectively form 2-oxo-3-sulfanylpropanoate and L-glutamate. The catalytic cycle occurs in the presence of pyridoxal 5'-phosphate (PLP) cofactor that facilitates transamination by initially forming an internal aldimine with the epsilon-amino group of active site Lys-55 residue on the enzyme (PLP-enzyme aldimine), subsequently displaced by formation of an external aldimine with the substrate amino group (PLP-L-cysteine aldimine). The external aldimine is further deprotonated to form a carbanion intermediate, which in the presence of 2-oxoglutarate regenerates PLP yielding final products 2-oxo-3-sulfanylpropanoate and L-glutamate. The proton transfer in carbanion intermediate is suggested to be controlled by the active site lysine residue, whereas PLP stabilizes carbanion structure through electron delocalization, also known as the electron sink effect. Plays a key role in regulating maximal capacity for electron transport and oxidative phosphorylation. May be involved in iron-sulfur cluster shuttling and/or in redox reactions. Can transfer the [2Fe-2S] cluster to an apo-acceptor protein only when in the oxidation state, likely serving as a redox sensor that regulates mitochondrial iron-sulfur cluster assembly and iron trafficking upon oxidative stress.
• Tissue Specificity: Expression is reduced in cells derived from cystic fibrosis patients.
• BioCyc Pathway: MetaCyc:ENSG00000122873-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[1]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[1]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[2]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[3]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[4]
Obesity	DIS47Y1K	Strong	Altered Expression	[5]
Parkinson disease	DISQVHKL	Strong	Biomarker	[4]
Type-1/2 diabetes	DISIUHAP	moderate	Biomarker	[2]
Wolfram syndrome 2	DISEO4HZ	moderate	Biomarker	[6]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[3]
Breast cancer	DIS7DPX1	Limited	Biomarker	[7]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[7]
Neoplasm	DISZKGEW	Limited	Biomarker	[7]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[8]

16 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 CDGSH iron-sulfur domain-containing protein 1 (CISD1).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of CDGSH iron-sulfur domain-containing protein 1 (CISD1).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of CDGSH iron-sulfur domain-containing protein 1 (CISD1).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of CDGSH iron-sulfur domain-containing protein 1 (CISD1).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of CDGSH iron-sulfur domain-containing protein 1 (CISD1).	[13]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of CDGSH iron-sulfur domain-containing protein 1 (CISD1).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of CDGSH iron-sulfur domain-containing protein 1 (CISD1).	[15]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of CDGSH iron-sulfur domain-containing protein 1 (CISD1).	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of CDGSH iron-sulfur domain-containing protein 1 (CISD1).	[17]
DNCB	DMDTVYC	Phase 2	DNCB decreases the expression of CDGSH iron-sulfur domain-containing protein 1 (CISD1).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of CDGSH iron-sulfur domain-containing protein 1 (CISD1).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of CDGSH iron-sulfur domain-containing protein 1 (CISD1).	[21]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of CDGSH iron-sulfur domain-containing protein 1 (CISD1).	[14]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of CDGSH iron-sulfur domain-containing protein 1 (CISD1).	[22]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of CDGSH iron-sulfur domain-containing protein 1 (CISD1).	[23]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of CDGSH iron-sulfur domain-containing protein 1 (CISD1).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of CDGSH iron-sulfur domain-containing protein 1 (CISD1).	[19]

References

• [1] MitoNEET in Perivascular Adipose Tissue Blunts Atherosclerosis under Mild Cold Condition in Mice.Front Physiol. 2017 Dec 19;8:1032. doi: 10.3389/fphys.2017.01032. eCollection 2017.
• [2] Interactions between mitoNEET and NAF-1 in cells.PLoS One. 2017 Apr 20;12(4):e0175796. doi: 10.1371/journal.pone.0175796. eCollection 2017.
• [3] Isoliquiritigenin Induces Mitochondrial Dysfunction and Apoptosis by Inhibiting mitoNEET in a Reactive Oxygen Species-Dependent Manner in A375 Human Melanoma Cells.Oxid Med Cell Longev. 2019 Jan 21;2019:9817576. doi: 10.1155/2019/9817576. eCollection 2019.
• [4] 4-Hydroxynonenal and 4-Oxononenal Differentially Bind to the Redox Sensor MitoNEET.Chem Res Toxicol. 2019 Jun 17;32(6):977-981. doi: 10.1021/acs.chemrestox.9b00166. Epub 2019 May 29.
• [5] CISD1 in association with obesity-associated dysfunctional adipogenesis in human visceral adipose tissue.Obesity (Silver Spring). 2016 Jan;24(1):139-47. doi: 10.1002/oby.21334.
• [6] Binding of Nitric Oxide in CDGSH-type [2Fe-2S] Clusters of the Human Mitochondrial Protein Miner2.J Biol Chem. 2017 Feb 24;292(8):3146-3153. doi: 10.1074/jbc.M116.766774. Epub 2017 Jan 12.
• [7] NAF-1 and mitoNEET are central to human breast cancer proliferation by maintaining mitochondrial homeostasis and promoting tumor growth.Proc Natl Acad Sci U S A. 2013 Sep 3;110(36):14676-81. doi: 10.1073/pnas.1313198110. Epub 2013 Aug 19.
• [8] Quantitative Proteomics of Presynaptic Mitochondria Reveal an Overexpression and Biological Relevance of Neuronal MitoNEET in Postnatal Brain Development.Dev Neurobiol. 2019 Apr;79(4):370-386. doi: 10.1002/dneu.22684. Epub 2019 May 9.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [11] 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.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [15] 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.
• [16] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Microarray analyses in dendritic cells reveal potential biomarkers for chemical-induced skin sensitization. Mol Immunol. 2007 May;44(12):3222-33.
• [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] 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.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [22] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [23] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [24] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.