Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRFFAL4)

• DOT Name: Bone morphogenetic protein 1 (BMP1)
• Synonyms: BMP-1; EC 3.4.24.19; Mammalian tolloid protein; mTld; Procollagen C-proteinase; PCP
• Gene Name: BMP1
• Related Disease:
  Osteogenesis imperfecta type 13
  High bone mass osteogenesis imperfecta
  Osteogenesis imperfecta type 3
• UniProt ID: BMP1_HUMAN
• PDB ID: 3EDG; 3EDH; 6BSL; 6BSM; 6BTN; 6BTO; 6BTP; 6BTQ
• EC Number: 3.4.24.19
• Pfam ID: PF01400 ; PF00431 ; PF07645 ; PF14670
• Sequence:
  MPGVARLPLLLGLLLLPRPGRPLDLADYTYDLAEEDDSEPLNYKDPCKAAAFLGDIALDE
  EDLRAFQVQQAVDLRRHTARKSSIKAAVPGNTSTPSCQSTNGQPQRGACGRWRGRSRSRR
  AATSRPERVWPDGVIPFVIGGNFTGSQRAVFRQAMRHWEKHTCVTFLERTDEDSYIVFTY
  RPCGCCSYVGRRGGGPQAISIGKNCDKFGIVVHELGHVVGFWHEHTRPDRDRHVSIVREN
  IQPGQEYNFLKMEPQEVESLGETYDFDSIMHYARNTFSRGIFLDTIVPKYEVNGVKPPIG
  QRTRLSKGDIAQARKLYKCPACGETLQDSTGNFSSPEYPNGYSAHMHCVWRISVTPGEKI
  ILNFTSLDLYRSRLCWYDYVEVRDGFWRKAPLRGRFCGSKLPEPIVSTDSRLWVEFRSSS
  NWVGKGFFAVYEAICGGDVKKDYGHIQSPNYPDDYRPSKVCIWRIQVSEGFHVGLTFQSF
  EIERHDSCAYDYLEVRDGHSESSTLIGRYCGYEKPDDIKSTSSRLWLKFVSDGSINKAGF
  AVNFFKEVDECSRPNRGGCEQRCLNTLGSYKCSCDPGYELAPDKRRCEAACGGFLTKLNG
  SITSPGWPKEYPPNKNCIWQLVAPTQYRISLQFDFFETEGNDVCKYDFVEVRSGLTADSK
  LHGKFCGSEKPEVITSQYNNMRVEFKSDNTVSKKGFKAHFFSDKDECSKDNGGCQQDCVN
  TFGSYECQCRSGFVLHDNKHDCKEAGCDHKVTSTSGTITSPNWPDKYPSKKECTWAISST
  PGHRVKLTFMEMDIESQPECAYDHLEVFDGRDAKAPVLGRFCGSKKPEPVLATGSRMFLR
  FYSDNSVQRKGFQASHATECGGQVRADVKTKDLYSHAQFGDNNYPGGVDCEWVIVAEEGY
  GVELVFQTFEVEEETDCGYDYMELFDGYDSTAPRLGRYCGSGPPEEVYSAGDSVLVKFHS
  DDTITKKGFHLRYTSTKFQDTLHSRK
• Function: Metalloprotease that plays key roles in regulating the formation of the extracellular matrix (ECM) via processing of various precursor proteins into mature functional enzymes or structural proteins. Thereby participates in several developmental and physiological processes such as cartilage and bone formation, muscle growth and homeostasis, wound healing and tissue repair. Roles in ECM formation include cleavage of the C-terminal propeptides from procollagens such as procollagen I, II and III or the proteolytic activation of the enzyme lysyl oxidase LOX, necessary to formation of covalent cross-links in collagen and elastic fibers. Additional substrates include matricellular thrombospondin-1/THBS1 whose cleavage leads to cell adhesion disruption and TGF-beta activation ; [Isoform BMP1-3]: Plays an important role in bone repair by acting as a coactivator of BMP7.
• Tissue Specificity: Ubiquitous.
• Reactome Pathway:
  (Name not found)
  Collagen biosynthesis and modifying enzymes (R-HSA-1650814)
  Anchoring fibril formation (R-HSA-2214320)
  Crosslinking of collagen fibrils (R-HSA-2243919)
  Degradation of the extracellular matrix (R-HSA-1474228)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Osteogenesis imperfecta type 13	DISVQZCR	Strong	Autosomal recessive	[1]
High bone mass osteogenesis imperfecta	DIS9U2CU	Supportive	Autosomal dominant	[2]
Osteogenesis imperfecta type 3	DISFJVSJ	Supportive	Autosomal dominant	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Bone morphogenetic protein 1 (BMP1).	[4]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Bone morphogenetic protein 1 (BMP1).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Bone morphogenetic protein 1 (BMP1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Bone morphogenetic protein 1 (BMP1).	[6]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Bone morphogenetic protein 1 (BMP1).	[7]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Bone morphogenetic protein 1 (BMP1).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Bone morphogenetic protein 1 (BMP1).	[9]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Bone morphogenetic protein 1 (BMP1).	[10]
Phenytoin	DMNOKBV	Approved	Phenytoin decreases the expression of Bone morphogenetic protein 1 (BMP1).	[11]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol increases the expression of Bone morphogenetic protein 1 (BMP1).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Bone morphogenetic protein 1 (BMP1).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Bone morphogenetic protein 1 (BMP1).	[14]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Bone morphogenetic protein 1 (BMP1).	[16]
Hydroxydimethylarsine Oxide	DMPS2B1	Investigative	Hydroxydimethylarsine Oxide decreases the expression of Bone morphogenetic protein 1 (BMP1).	[17]

References

• [1] Induced ablation of Bmp1 and Tll1 produces osteogenesis imperfecta in mice. Hum Mol Genet. 2014 Jun 15;23(12):3085-101. doi: 10.1093/hmg/ddu013. Epub 2014 Jan 12.
• [2] Distinctive skeletal phenotype in high bone mass osteogenesis imperfecta due to a COL1A2 cleavage site mutation. Am J Med Genet A. 2016 Aug;170(8):2212-4. doi: 10.1002/ajmg.a.37744. Epub 2016 Jun 5.
• [3] Identification of a mutation causing deficient BMP1/mTLD proteolytic activity in autosomal recessive osteogenesis imperfecta. Hum Mutat. 2012 Feb;33(2):343-50. doi: 10.1002/humu.21647. Epub 2011 Nov 30.
• [4] 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.
• [5] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [6] 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.
• [7] Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [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] Role of phenytoin in wound healing: microarray analysis of early transcriptional responses in human dermal fibroblasts. Biochem Biophys Res Commun. 2004 Feb 13;314(3):661-6. doi: 10.1016/j.bbrc.2003.12.146.
• [12] Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
• [13] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [14] 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.
• [15] 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.
• [16] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [17] Identification of interspecies concordance of mechanisms of arsenic-induced bladder cancer. Toxicol In Vitro. 2007 Dec;21(8):1513-29. doi: 10.1016/j.tiv.2007.06.021. Epub 2007 Jul 21.