Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2LOUQ1)

• DOT Name: Transforming growth factor beta-3 proprotein (TGFB3)
• Gene Name: TGFB3
• Related Disease:
  Rienhoff syndrome
  Familial thoracic aortic aneurysm and aortic dissection
  Arrhythmogenic right ventricular cardiomyopathy
  Arrhythmogenic right ventricular dysplasia 1
  Loeys-Dietz syndrome
• UniProt ID: TGFB3_HUMAN
• PDB ID: 1KTZ; 1TGJ; 1TGK; 2PJY; 3EO1; 4UM9
• Pfam ID: PF00019 ; PF00688
• Sequence:
  MKMHLQRALVVLALLNFATVSLSLSTCTTLDFGHIKKKRVEAIRGQILSKLRLTSPPEPT
  VMTHVPYQVLALYNSTRELLEEMHGEREEGCTQENTESEYYAKEIHKFDMIQGLAEHNEL
  AVCPKGITSKVFRFNVSSVEKNRTNLFRAEFRVLRVPNPSSKRNEQRIELFQILRPDEHI
  AKQRYIGGKNLPTRGTAEWLSFDVTDTVREWLLRRESNLGLEISIHCPCHTFQPNGDILE
  NIHEVMEIKFKGVDNEDDHGRGDLGRLKKQKDHHNPHLILMMIPPHRLDNPGQGGQRKKR
  ALDTNYCFRNLEENCCVRPLYIDFRQDLGWKWVHEPKGYYANFCSGPCPYLRSADTTHST
  VLGLYNTLNPEASASPCCVPQDLEPLTILYYVGRTPKVEQLSNMVVKSCKCS
• Function: Transforming growth factor beta-3 proprotein: Precursor of the Latency-associated peptide (LAP) and Transforming growth factor beta-3 (TGF-beta-3) chains, which constitute the regulatory and active subunit of TGF-beta-3, respectively; [Latency-associated peptide]: Required to maintain the Transforming growth factor beta-3 (TGF-beta-3) chain in a latent state during storage in extracellular matrix. Associates non-covalently with TGF-beta-3 and regulates its activation via interaction with 'milieu molecules', such as LTBP1 and LRRC32/GARP, that control activation of TGF-beta-3. Interaction with integrins results in distortion of the Latency-associated peptide chain and subsequent release of the active TGF-beta-3; Transforming growth factor beta-3: Multifunctional protein that regulates embryogenesis and cell differentiation and is required in various processes such as secondary palate development. Activation into mature form follows different steps: following cleavage of the proprotein in the Golgi apparatus, Latency-associated peptide (LAP) and Transforming growth factor beta-3 (TGF-beta-3) chains remain non-covalently linked rendering TGF-beta-3 inactive during storage in extracellular matrix. At the same time, LAP chain interacts with 'milieu molecules', such as LTBP1 and LRRC32/GARP that control activation of TGF-beta-3 and maintain it in a latent state during storage in extracellular milieus. TGF-beta-3 is released from LAP by integrins: integrin-binding results in distortion of the LAP chain and subsequent release of the active TGF-beta-3. Once activated following release of LAP, TGF-beta-3 acts by binding to TGF-beta receptors (TGFBR1 and TGFBR2), which transduce signal.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Cytokine-cytokine receptor interaction (hsa04060)
  FoxO sig.ling pathway (hsa04068)
  Cell cycle (hsa04110)
  Cellular senescence (hsa04218)
  TGF-beta sig.ling pathway (hsa04350)
  Hippo sig.ling pathway (hsa04390)
  AGE-RAGE sig.ling pathway in diabetic complications (hsa04933)
  Leishmaniasis (hsa05140)
  Chagas disease (hsa05142)
  Malaria (hsa05144)
  Toxoplasmosis (hsa05145)
  Amoebiasis (hsa05146)
  Tuberculosis (hsa05152)
  Hepatitis B (hsa05161)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Pathways in cancer (hsa05200)
  Colorectal cancer (hsa05210)
  Re.l cell carcinoma (hsa05211)
  Pancreatic cancer (hsa05212)
  Chronic myeloid leukemia (hsa05220)
  Hepatocellular carcinoma (hsa05225)
  Gastric cancer (hsa05226)
  Inflammatory bowel disease (hsa05321)
  Rheumatoid arthritis (hsa05323)
  Hypertrophic cardiomyopathy (hsa05410)
  Dilated cardiomyopathy (hsa05414)
  Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway:
  Molecules associated with elastic fibres (R-HSA-2129379)
  TGF-beta receptor signaling activates SMADs (R-HSA-2173789)
  ECM proteoglycans (R-HSA-3000178)
  Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Rienhoff syndrome	DISWC4XA	Definitive	Autosomal dominant	[1]
Familial thoracic aortic aneurysm and aortic dissection	DIS069FB	Supportive	Autosomal dominant	[2]
Arrhythmogenic right ventricular cardiomyopathy	DIS3V2BE	Limited	Autosomal dominant	[3]
Arrhythmogenic right ventricular dysplasia 1	DIS6FOCK	Limited	Autosomal dominant	[4]
Loeys-Dietz syndrome	DIS4FUPZ	Limited	Autosomal recessive	[4]

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 Transforming growth factor beta-3 proprotein (TGFB3).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Transforming growth factor beta-3 proprotein (TGFB3).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Transforming growth factor beta-3 proprotein (TGFB3).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transforming growth factor beta-3 proprotein (TGFB3).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Transforming growth factor beta-3 proprotein (TGFB3).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Transforming growth factor beta-3 proprotein (TGFB3).	[9]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Transforming growth factor beta-3 proprotein (TGFB3).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Transforming growth factor beta-3 proprotein (TGFB3).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Transforming growth factor beta-3 proprotein (TGFB3).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Transforming growth factor beta-3 proprotein (TGFB3).	[13]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Transforming growth factor beta-3 proprotein (TGFB3).	[13]
Marinol	DM70IK5	Approved	Marinol affects the expression of Transforming growth factor beta-3 proprotein (TGFB3).	[14]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Transforming growth factor beta-3 proprotein (TGFB3).	[15]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Transforming growth factor beta-3 proprotein (TGFB3).	[16]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Transforming growth factor beta-3 proprotein (TGFB3).	[17]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of Transforming growth factor beta-3 proprotein (TGFB3).	[18]
Acocantherin	DM7JT24	Approved	Acocantherin decreases the expression of Transforming growth factor beta-3 proprotein (TGFB3).	[19]
Phenytoin	DMNOKBV	Approved	Phenytoin increases the expression of Transforming growth factor beta-3 proprotein (TGFB3).	[20]
Vitamin A	DMJ2AH4	Approved	Vitamin A increases the expression of Transforming growth factor beta-3 proprotein (TGFB3).	[21]
Diazepam	DM08E9O	Approved	Diazepam decreases the expression of Transforming growth factor beta-3 proprotein (TGFB3).	[22]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Transforming growth factor beta-3 proprotein (TGFB3).	[23]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Transforming growth factor beta-3 proprotein (TGFB3).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Transforming growth factor beta-3 proprotein (TGFB3).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Transforming growth factor beta-3 proprotein (TGFB3).	[23]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Transforming growth factor beta-3 proprotein (TGFB3).	[27]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Transforming growth factor beta-3 proprotein (TGFB3).	[28]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid increases the expression of Transforming growth factor beta-3 proprotein (TGFB3).	[29]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Cordycepin	DM72Y01	Investigative	Cordycepin increases the secretion of Transforming growth factor beta-3 proprotein (TGFB3).	[30]

References

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• [2] A mutation in TGFB3 associated with a syndrome of low muscle mass, growth retardation, distal arthrogryposis and clinical features overlapping with Marfan and Loeys-Dietz syndrome. Am J Med Genet A. 2013 Aug;161A(8):2040-6. doi: 10.1002/ajmg.a.36056. Epub 2013 Jul 3.
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