Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQE88BE)

• DOT Name: Holocytochrome c-type synthase (HCCS)
• Synonyms: EC 4.4.1.17; Cytochrome c-type heme lyase
• Gene Name: HCCS
• Related Disease:
  Linear skin defects with multiple congenital anomalies 1
  Aniridia-cerebellar ataxia-intellectual disability syndrome
  Autism
  Fibrosarcoma
  Focal dermal hypoplasia
  Hyperthyroxinemia, familial dysalbuminemic
  Liposarcoma
  Methicillin-resistant staphylococci infection
  Microphthalmia
  Neoplasm
  Neuralgia
  Non-insulin dependent diabetes
  Sclerocornea
  Recessive X-linked ichthyosis
  Linear skin defects with multiple congenital anomalies
  B-cell neoplasm
  Endocarditis
  Lymphoma
  Melanocytic nevus
  Multiple sclerosis
  Pneumonia
  Type-1 diabetes
• UniProt ID: CCHL_HUMAN
• EC Number: 4.4.1.17
• Pfam ID: PF01265
• Sequence:
  MGLSPSAPAVAVQASNASASPPSGCPMHEGKMKGCPVNTEPSGPTCEKKTYSVPAHQERA
  YEYVECPIRGTAAENKENLDPSNLMPPPNQTPAPDQPFALSTVREESSIPRADSEKKWVY
  PSEQMFWNAMLKKGWKWKDEDISQKDMYNIIRIHNQNNEQAWKEILKWEALHAAECPCGP
  SLIRFGGKAKEYSPRARIRSWMGYELPFDRHDWIINRCGTEVRYVIDYYDGGEVNKDYQF
  TILDVRPALDSLSAVWDRMKVAWWRWTS
• Function: Lyase that catalyzes the covalent linking of the heme group to the cytochrome C apoprotein to produce the mature functional cytochrome.
• KEGG Pathway:
  Porphyrin metabolism (hsa00860)
  Metabolic pathways (hsa01100)
• BioCyc Pathway: MetaCyc:HS00120-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
Linear skin defects with multiple congenital anomalies 1	DISNYKBT	Definitive	X-linked dominant	[1]
Aniridia-cerebellar ataxia-intellectual disability syndrome	DIS4QZ3S	Strong	Genetic Variation	[2]
Autism	DISV4V1Z	Strong	Genetic Variation	[3]
Fibrosarcoma	DISWX7MU	Strong	Genetic Variation	[4]
Focal dermal hypoplasia	DISXBAOL	Strong	Genetic Variation	[5]
Hyperthyroxinemia, familial dysalbuminemic	DIS0BPAW	Strong	Genetic Variation	[5]
Liposarcoma	DIS8IZVM	Strong	Biomarker	[6]
Methicillin-resistant staphylococci infection	DIS6DRDZ	Strong	Biomarker	[7]
Microphthalmia	DISGEBES	Strong	Genetic Variation	[8]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[9]
Neuralgia	DISWO58J	Strong	Biomarker	[10]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[11]
Sclerocornea	DIS7HV8A	Strong	Genetic Variation	[12]
Recessive X-linked ichthyosis	DISZY56W	moderate	Biomarker	[6]
Linear skin defects with multiple congenital anomalies	DIS5BT4L	Supportive	X-linked	[1]
B-cell neoplasm	DISVY326	Limited	Biomarker	[13]
Endocarditis	DISBU610	Limited	Genetic Variation	[14]
Lymphoma	DISN6V4S	Limited	Biomarker	[13]
Melanocytic nevus	DISYS32D	Limited	Biomarker	[15]
Multiple sclerosis	DISB2WZI	Limited	Genetic Variation	[16]
Pneumonia	DIS8EF3M	Limited	Biomarker	[14]
Type-1 diabetes	DIS7HLUB	Limited	Biomarker	[17]

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 Holocytochrome c-type synthase (HCCS).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Holocytochrome c-type synthase (HCCS).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Holocytochrome c-type synthase (HCCS).	[19]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Holocytochrome c-type synthase (HCCS).	[20]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Holocytochrome c-type synthase (HCCS).	[21]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Holocytochrome c-type synthase (HCCS).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Holocytochrome c-type synthase (HCCS).	[23]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE decreases the expression of Holocytochrome c-type synthase (HCCS).	[24]

References

• [1] Mutations of the mitochondrial holocytochrome c-type synthase in X-linked dominant microphthalmia with linear skin defects syndrome. Am J Hum Genet. 2006 Nov;79(5):878-89. doi: 10.1086/508474. Epub 2006 Sep 6.
• [2] Genetic Analysis of 'PAX6-Negative' Individuals with Aniridia or Gillespie Syndrome.PLoS One. 2016 Apr 28;11(4):e0153757. doi: 10.1371/journal.pone.0153757. eCollection 2016.
• [3] Microphthalmia with Linear Skin Defects (MLS) associated with Autism Spectrum Disorder (ASD) in a patient with Familial 12.9Mb Terminal Xp deletion.BMC Pediatr. 2014 Sep 2;14:220. doi: 10.1186/1471-2431-14-220.
• [4] Curcumin and Viscum album Extract Decrease Proliferation and Cell Viability of Soft-Tissue Sarcoma Cells: An In Vitro Analysis of Eight Cell Lines Using Real-Time Monitoring and Colorimetric Assays.Nutr Cancer. 2017 Feb-Mar;69(2):340-351. doi: 10.1080/01635581.2017.1263349. Epub 2017 Jan 3.
• [5] Goltz-Gorlin (focal dermal hypoplasia) and the microphthalmia with linear skin defects (MLS) syndrome: no evidence of genetic overlap.Eur J Hum Genet. 2009 Oct;17(10):1207-15. doi: 10.1038/ejhg.2009.40. Epub 2009 Mar 11.
• [6] Antiproliferative activity of epigallocatechin?gallate and silibinin on soft tissue sarcoma cells.Mol Med Rep. 2017 Jan;15(1):103-110. doi: 10.3892/mmr.2016.5969. Epub 2016 Nov 28.
• [7] Diversity in the antimicrobial susceptibility patterns of methicillin-resistant Staphylococcus aureus clones.Eur J Clin Microbiol Infect Dis. 2012 Dec;31(12):3317-21. doi: 10.1007/s10096-012-1698-3. Epub 2012 Jul 25.
• [8] A mosaic form of microphthalmia with linear skin defects.BMC Pediatr. 2018 Aug 1;18(1):254. doi: 10.1186/s12887-018-1234-4.
• [9] Normal and functional TP53 in genetically stable myxoid/round cell liposarcoma.PLoS One. 2014 Nov 13;9(11):e113110. doi: 10.1371/journal.pone.0113110. eCollection 2014.
• [10] Effect of NIR laser therapy by MLS-MiS source against neuropathic pain in rats: in vivo and ex vivo analysis.Sci Rep. 2019 Jun 26;9(1):9297. doi: 10.1038/s41598-019-45469-5.
• [11] Subsets of Finns with high HDL to total cholesterol ratio show evidence for linkage to type 2 diabetes on chromosome 6q.Hum Hered. 2007;63(1):17-25. doi: 10.1159/000097927. Epub 2006 Dec 14.
• [12] HCCS loss-of-function missense mutation in a female with bilateral microphthalmia and sclerocornea: a novel gene for severe ocular malformations?.Mol Vis. 2007 Aug 27;13:1475-82.
• [13] Newcastle Disease Virus: Potential Therapeutic Application for Human and Canine Lymphoma.Viruses. 2015 Dec 23;8(1):3. doi: 10.3390/v8010003.
• [14] Macrolide-resistant pneumococcal endocarditis and epidural abscess that develop during erythromycin therapy.Clin Infect Dis. 2003 Jan 15;36(2):e19-25. doi: 10.1086/344965. Epub 2003 Jan 7.
• [15] Isolation by flow cytometry of a human ovarian tumor cell subpopulation exhibiting a high glutathione content phenotype and increased resistance to adriamycin.Int J Radiat Oncol Biol Phys. 1989 May;16(5):1315-9. doi: 10.1016/0360-3016(89)90306-4.
• [16] Rapid increase in macrolide resistance among penicillin non-susceptible pneumococci in Finland, 1996-2000.J Antimicrob Chemother. 2002 May;49(5):785-92. doi: 10.1093/jac/dkf033.
• [17] High-density single nucleotide polymorphism genome-wide linkage scan for susceptibility genes for diabetic nephropathy in type 1 diabetes: discordant sibpair approach.Diabetes. 2008 Sep;57(9):2519-26. doi: 10.2337/db07-1086. Epub 2008 Jun 16.
• [18] 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.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [22] 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.
• [23] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [24] Preferential induction of the AhR gene battery in HepaRG cells after a single or repeated exposure to heterocyclic aromatic amines. Toxicol Appl Pharmacol. 2010 Nov 15;249(1):91-100.