Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR7Q75L)

• DOT Name: Latent-transforming growth factor beta-binding protein 1 (LTBP1)
• Synonyms: LTBP-1; Transforming growth factor beta-1-binding protein 1; TGF-beta1-BP-1
• Gene Name: LTBP1
• Related Disease:
  Breast neoplasm
  CARASIL syndrome
  Coronary atherosclerosis
  Cutis laxa, autosomal recessive, type 2E
  Diabetic kidney disease
  Epithelial ovarian cancer
  Glomerulonephritis
  Knee osteoarthritis
  Leiomyoma
  Mucinous adenocarcinoma
  Neoplasm
  Osteoarthritis
  Ovarian cancer
  Ovarian neoplasm
  Uterine fibroids
  Acute myelogenous leukaemia
  Coronary heart disease
  Hepatocellular carcinoma
  Malignant glioma
  Carpal tunnel syndrome
  Malignant mesothelioma
• UniProt ID: LTBP1_HUMAN
• PDB ID: 1KSQ
• Pfam ID: PF12662 ; PF07645 ; PF00683
• Sequence:
  MAGAWLRWGLLLWAGLLASSAHGRLRRITYVVHPGPGLAAGALPLSGPPRSRTFNVALNA
  RYSRSSAAAGAPSRASPGVPSERTRRTSKPGGAALQGLRPPPPPPPEPARPAVPGGQLHP
  NPGGHPAAAPFTKQGRQVVRSKVPQETQSGGGSRLQVHQKQQLQGVNVCGGRCCHGWSKA
  PGSQRCTKPSCVPPCQNGGMCLRPQLCVCKPGTKGKACETIAAQDTSSPVFGGQSPGAAS
  SWGPPEQAAKHTSSKKADTLPRVSPVAQMTLTLKPKPSVGLPQQIHSQVTPLSSQSVVIH
  HGQTQEYVLKPKYFPAQKGISGEQSTEGSFPLRYVQDQVAAPFQLSNHTGRIKVVFTPSI
  CKVTCTKGSCQNSCEKGNTTTLISENGHAADTLTATNFRVVICHLPCMNGGQCSSRDKCQ
  CPPNFTGKLCQIPVHGASVPKLYQHSQQPGKALGTHVIHSTHTLPLTVTSQQGVKVKFPP
  NIVNIHVKHPPEASVQIHQVSRIDGPTGQKTKEAQPGQSQVSYQGLPVQKTQTIHSTYSH
  QQVIPHVYPVAAKTQLGRCFQETIGSQCGKALPGLSKQEDCCGTVGTSWGFNKCQKCPKK
  PSYHGYNQMMECLPGYKRVNNTFCQDINECQLQGVCPNGECLNTMGSYRCTCKIGFGPDP
  TFSSCVPDPPVISEEKGPCYRLVSSGRQCMHPLSVHLTKQLCCCSVGKAWGPHCEKCPLP
  GTAAFKEICPGGMGYTVSGVHRRRPIHHHVGKGPVFVKPKNTQPVAKSTHPPPLPAKEEP
  VEALTFSREHGPGVAEPEVATAPPEKEIPSLDQEKTKLEPGQPQLSPGISTIHLHPQFPV
  VIEKTSPPVPVEVAPEASTSSASQVIAPTQVTEINECTVNPDICGAGHCINLPVRYTCIC
  YEGYRFSEQQRKCVDIDECTQVQHLCSQGRCENTEGSFLCICPAGFMASEEGTNCIDVDE
  CLRPDVCGEGHCVNTVGAFRCEYCDSGYRMTQRGRCEDIDECLNPSTCPDEQCVNSPGSY
  QCVPCTEGFRGWNGQCLDVDECLEPNVCANGDCSNLEGSYMCSCHKGYTRTPDHKHCRDI
  DECQQGNLCVNGQCKNTEGSFRCTCGQGYQLSAAKDQCEDIDECQHRHLCAHGQCRNTEG
  SFQCVCDQGYRASGLGDHCEDINECLEDKSVCQRGDCINTAGSYDCTCPDGFQLDDNKTC
  QDINECEHPGLCGPQGECLNTEGSFHCVCQQGFSISADGRTCEDIDECVNNTVCDSHGFC
  DNTAGSFRCLCYQGFQAPQDGQGCVDVNECELLSGVCGEAFCENVEGSFLCVCADENQEY
  SPMTGQCRSRTSTDLDVDVDQPKEEKKECYYNLNDASLCDNVLAPNVTKQECCCTSGVGW
  GDNCEIFPCPVLGTAEFTEMCPKGKGFVPAGESSSEAGGENYKDADECLLFGQEICKNGF
  CLNTRPGYECYCKQGTYYDPVKLQCFDMDECQDPSSCIDGQCVNTEGSYNCFCTHPMVLD
  ASEKRCIRPAESNEQIEETDVYQDLCWEHLSDEYVCSRPLVGKQTTYTECCCLYGEAWGM
  QCALCPLKDSDDYAQLCNIPVTGRRQPYGRDALVDFSEQYTPEADPYFIQDRFLNSFEEL
  QAEECGILNGCENGRCVRVQEGYTCDCFDGYHLDTAKMTCVDVNECDELNNRMSLCKNAK
  CINTDGSYKCLCLPGYVPSDKPNYCTPLNTALNLEKDSDLE
• Function: Key regulator of transforming growth factor beta (TGFB1, TGFB2 and TGFB3) that controls TGF-beta activation by maintaining it in a latent state during storage in extracellular space. Associates specifically via disulfide bonds with the Latency-associated peptide (LAP), which is the regulatory chain of TGF-beta, and regulates integrin-dependent activation of TGF-beta. Outcompeted by LRRC32/GARP for binding to LAP regulatory chain of TGF-beta.
• Tissue Specificity: Expressed in the aorta (at protein level) . Isoform Long: Expressed in fibroblasts .
• KEGG Pathway: TGF-beta sig.ling pathway (hsa04350)
• Reactome Pathway:
  TGF-beta receptor signaling activates SMADs (R-HSA-2173789)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
  Post-translational protein phosphorylation (R-HSA-8957275)
  Molecules associated with elastic fibres (R-HSA-2129379)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast neoplasm	DISNGJLM	Strong	Biomarker	[1]
CARASIL syndrome	DIS7KGGR	Strong	Biomarker	[2]
Coronary atherosclerosis	DISKNDYU	Strong	Altered Expression	[3]
Cutis laxa, autosomal recessive, type 2E	DISBKQL6	Strong	Autosomal recessive	[4]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[5]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[6]
Glomerulonephritis	DISPZIQ3	Strong	Biomarker	[7]
Knee osteoarthritis	DISLSNBJ	Strong	Genetic Variation	[8]
Leiomyoma	DISLDDFN	Strong	Altered Expression	[9]
Mucinous adenocarcinoma	DISKNFE8	Strong	Altered Expression	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Osteoarthritis	DIS05URM	Strong	Genetic Variation	[8]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[6]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[6]
Uterine fibroids	DISBZRMJ	Strong	Altered Expression	[9]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[12]
Coronary heart disease	DIS5OIP1	moderate	Altered Expression	[13]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[14]
Malignant glioma	DISFXKOV	moderate	Altered Expression	[15]
Carpal tunnel syndrome	DISHQ3BE	Limited	Genetic Variation	[16]
Malignant mesothelioma	DISTHJGH	Limited	Biomarker	[17]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
L-glutamine	DM69G8X	Approved	Latent-transforming growth factor beta-binding protein 1 (LTBP1) increases the Apoptosis ADR of L-glutamine.	[35]

4 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 Latent-transforming growth factor beta-binding protein 1 (LTBP1).	[18]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Latent-transforming growth factor beta-binding protein 1 (LTBP1).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Latent-transforming growth factor beta-binding protein 1 (LTBP1).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Latent-transforming growth factor beta-binding protein 1 (LTBP1).	[32]

13 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 Latent-transforming growth factor beta-binding protein 1 (LTBP1).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Latent-transforming growth factor beta-binding protein 1 (LTBP1).	[20]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Latent-transforming growth factor beta-binding protein 1 (LTBP1).	[21]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Latent-transforming growth factor beta-binding protein 1 (LTBP1).	[22]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Latent-transforming growth factor beta-binding protein 1 (LTBP1).	[24]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Latent-transforming growth factor beta-binding protein 1 (LTBP1).	[25]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Latent-transforming growth factor beta-binding protein 1 (LTBP1).	[26]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Latent-transforming growth factor beta-binding protein 1 (LTBP1).	[27]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Latent-transforming growth factor beta-binding protein 1 (LTBP1).	[28]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Latent-transforming growth factor beta-binding protein 1 (LTBP1).	[29]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of Latent-transforming growth factor beta-binding protein 1 (LTBP1).	[30]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Latent-transforming growth factor beta-binding protein 1 (LTBP1).	[33]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Latent-transforming growth factor beta-binding protein 1 (LTBP1).	[34]

References

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• [4] Bi-allelic premature truncating variants in LTBP1 cause cutis laxa syndrome. Am J Hum Genet. 2021 Jun 3;108(6):1095-1114. doi: 10.1016/j.ajhg.2021.04.016. Epub 2021 May 14.
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