Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMH0YLN)

• DOT Name: Choline-phosphate cytidylyltransferase A (PCYT1A)
• Synonyms: EC 2.7.7.15; CCT-alpha; CTP:phosphocholine cytidylyltransferase A; CCT A; CT A; Phosphorylcholine transferase A
• Gene Name: PCYT1A
• Related Disease:
  Spondylometaphyseal dysplasia-cone-rod dystrophy syndrome
  Leber congenital amaurosis
• UniProt ID: PCY1A_HUMAN
• EC Number: 2.7.7.15
• Pfam ID: PF01467
• Sequence:
  MDAQCSAKVNARKRRKEAPGPNGATEEDGVPSKVQRCAVGLRQPAPFSDEIEVDFSKPYV
  RVTMEEASRGTPCERPVRVYADGIFDLFHSGHARALMQAKNLFPNTYLIVGVCSDELTHN
  FKGFTVMNENERYDAVQHCRYVDEVVRNAPWTLTPEFLAEHRIDFVAHDDIPYSSAGSDD
  VYKHIKEAGMFAPTQRTEGISTSDIITRIVRDYDVYARRNLQRGYTAKELNVSFINEKKY
  HLQERVDKVKKKVKDVEEKSKEFVQKVEEKSIDLIQKWEEKSREFIGSFLEMFGPEGALK
  HMLKEGKGRMLQAISPKQSPSSSPTRERSPSPSFRWPFSGKTSPPCSPANLSRHKAAAYD
  ISEDEED
• Function: Catalyzes the key rate-limiting step in the CDP-choline pathway for phosphatidylcholine biosynthesis.
• Tissue Specificity: Brain, placenta, liver, fetal and adult lung.
• KEGG Pathway:
  Phospho.te and phosphi.te metabolism (hsa00440)
  Glycerophospholipid metabolism (hsa00564)
  Metabolic pathways (hsa01100)
  Choline metabolism in cancer (hsa05231)
• Reactome Pathway: Synthesis of PC (R-HSA-1483191)
• BioCyc Pathway: MetaCyc:HS08577-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Spondylometaphyseal dysplasia-cone-rod dystrophy syndrome	DISXRSJE	Definitive	Autosomal recessive	[1]
Leber congenital amaurosis	DISMGH8F	Supportive	Autosomal dominant	[2]

9 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 Choline-phosphate cytidylyltransferase A (PCYT1A).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Choline-phosphate cytidylyltransferase A (PCYT1A).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Choline-phosphate cytidylyltransferase A (PCYT1A).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Choline-phosphate cytidylyltransferase A (PCYT1A).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Choline-phosphate cytidylyltransferase A (PCYT1A).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Choline-phosphate cytidylyltransferase A (PCYT1A).	[8]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Choline-phosphate cytidylyltransferase A (PCYT1A).	[10]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Choline-phosphate cytidylyltransferase A (PCYT1A).	[11]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Choline-phosphate cytidylyltransferase A (PCYT1A).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of Choline-phosphate cytidylyltransferase A (PCYT1A).	[9]
G1	DMTV42K	Phase 1/2	G1 decreases the phosphorylation of Choline-phosphate cytidylyltransferase A (PCYT1A).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Choline-phosphate cytidylyltransferase A (PCYT1A).	[13]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Choline-phosphate cytidylyltransferase A (PCYT1A).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Choline-phosphate cytidylyltransferase A (PCYT1A).	[9]

References

• [1] 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.
• [2] Mutations in the PCYT1A gene are responsible for isolated forms of retinal dystrophy. Eur J Hum Genet. 2017 May;25(5):651-655. doi: 10.1038/ejhg.2017.23. Epub 2017 Mar 8.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [8] 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.
• [9] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [10] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [11] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [12] The G Protein-Coupled Estrogen Receptor Agonist G-1 Inhibits Nuclear Estrogen Receptor Activity and Stimulates Novel Phosphoproteomic Signatures. Toxicol Sci. 2016 Jun;151(2):434-46. doi: 10.1093/toxsci/kfw057. Epub 2016 Mar 29.
• [13] 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.
• [14] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [15] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.