Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT43A0JA)

• DOT Name: Phosphoethanolamine/phosphocholine phosphatase (PHOSPHO1)
• Synonyms: EC 3.1.3.75
• Gene Name: PHOSPHO1
• Related Disease:
  Metabolic bone disease
  Non-insulin dependent diabetes
• UniProt ID: PHOP1_HUMAN
• EC Number: 3.1.3.75
• Pfam ID: PF06888
• Sequence:
  MSGCFPVSGLRCLSRDGRMAAQGAPRFLLTFDFDETIVDENSDDSIVRAAPGQRLPESLR
  ATYREGFYNEYMQRVFKYLGEQGVRPRDLSAIYEAIPLSPGMSDLLQFVAKQGACFEVIL
  ISDANTFGVESSLRAAGHHSLFRRILSNPSGPDARGLLALRPFHTHSCARCPANMCKHKV
  LSDYLRERAHDGVHFERLFYVGDGANDFCPMGLLAGGDVAFPRRGYPMHRLIQEAQKAEP
  SSFRASVVPWETAADVRLHLQQVLKSC
• Function: Phosphatase that has a high activity toward phosphoethanolamine (PEA) and phosphocholine (PCho). Involved in the generation of inorganic phosphate for bone mineralization. Acts in a non-redundant manner with PHOSPHO1 in skeletal mineralization: while PHOSPHO1 mediates the initiation of hydroxyapatite crystallization in the matrix vesicles (MVs), ALPL/TNAP catalyzes the spread of hydroxyapatite crystallization in the extracellular matrix.
• Tissue Specificity: Expressed at sites of mineralization in bone and cartilage. Highly expressed in osteoblast cell line SaOS-2 which produces a mineralized matrix, but not in MG-63 cell line, which do not mineralize.
• KEGG Pathway:
  Glycerophospholipid metabolism (hsa00564)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Synthesis of PE (R-HSA-1483213)
  Synthesis of PC (R-HSA-1483191)
• BioCyc Pathway: MetaCyc:HS16266-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
Metabolic bone disease	DISO7RI8	Strong	Biomarker	[1]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Phosphoethanolamine/phosphocholine phosphatase (PHOSPHO1).	[3]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Phosphoethanolamine/phosphocholine phosphatase (PHOSPHO1).	[4]
Lansoprazole	DMXYLQ3	Approved	Lansoprazole decreases the activity of Phosphoethanolamine/phosphocholine phosphatase (PHOSPHO1).	[5]
SPI-1005	DM6XFHS	Phase 2 Trial	SPI-1005 decreases the activity of Phosphoethanolamine/phosphocholine phosphatase (PHOSPHO1).	[5]
Mivebresib	DMCPF90	Phase 1	Mivebresib increases the expression of Phosphoethanolamine/phosphocholine phosphatase (PHOSPHO1).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Phosphoethanolamine/phosphocholine phosphatase (PHOSPHO1).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Phosphoethanolamine/phosphocholine phosphatase (PHOSPHO1).	[9]

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 increases the methylation of Phosphoethanolamine/phosphocholine phosphatase (PHOSPHO1).	[6]

References

• [1] Skeletal Mineralization Deficits and Impaired Biogenesis and Function of Chondrocyte-Derived Matrix Vesicles in Phospho1(-/-) and Phospho1/Pi t1 Double-Knockout Mice.J Bone Miner Res. 2016 Jun;31(6):1275-86. doi: 10.1002/jbmr.2790. Epub 2016 May 17.
• [2] Blood-Based DNA Methylation Biomarkers for Type 2 Diabetes: Potential for Clinical Applications.Front Endocrinol (Lausanne). 2018 Dec 4;9:744. doi: 10.3389/fendo.2018.00744. eCollection 2018.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [5] Functional involvement of PHOSPHO1 in matrix vesicle-mediated skeletal mineralization. J Bone Miner Res. 2007 Apr;22(4):617-27. doi: 10.1359/jbmr.070108.
• [6] 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.
• [7] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [8] 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.
• [9] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.