Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFF4YZ7)

• DOT Name: Hamartin (TSC1)
• Synonyms: Tuberous sclerosis 1 protein
• Gene Name: TSC1
• Related Disease:
  Cognitive impairment
  Lymphangioleiomyomatosis
  Tuberculosis
  Tuberous sclerosis
  Tuberous sclerosis 1
  Action myoclonus-renal failure syndrome
  Advanced cancer
  Astrocytoma
  Autism
  Autosomal recessive polycystic kidney disease
  Brain disease
  Carcinoma
  Chordoma
  Clear cell renal carcinoma
  Colorectal carcinoma
  Cystic kidney disease
  Dentatorubral-pallidoluysian atrophy
  Fleck corneal dystrophy
  Glioblastoma multiforme
  Hamartoma
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Lung lymphangioleiomyomatosis
  Neoplasm with perivascular epithelioid cell differentiation
  Obesity
  Papillary renal cell carcinoma
  Pneumothorax
  Progressive myoclonus epilepsy
  Renal cell carcinoma
  Spasm
  Tuberous sclerosis 2
  West syndrome
  Autism spectrum disorder
  Squamous cell carcinoma
  Obsolete tuberous sclerosis complex
  Acute monocytic leukemia
  Adenocarcinoma
  Adult hepatocellular carcinoma
  Kidney neoplasm
  Lung cancer
  Lung carcinoma
• UniProt ID: TSC1_HUMAN
• PDB ID: 4Z6Y; 5EJC; 7DL2
• Pfam ID: PF04388
• Sequence:
  MAQQANVGELLAMLDSPMLGVRDDVTAVFKENLNSDRGPMLVNTLVDYYLETSSQPALHI
  LTTLQEPHDKHLLDRINEYVGKAATRLSILSLLGHVIRLQPSWKHKLSQAPLLPSLLKCL
  KMDTDVVVLTTGVLVLITMLPMIPQSGKQHLLDFFDIFGRLSSWCLKKPGHVAEVYLVHL
  HASVYALFHRLYGMYPCNFVSFLRSHYSMKENLETFEEVVKPMMEHVRIHPELVTGSKDH
  ELDPRRWKRLETHDVVIECAKISLDPTEASYEDGYSVSHQISARFPHRSADVTTSPYADT
  QNSYGCATSTPYSTSRLMLLNMPGQLPQTLSSPSTRLITEPPQATLWSPSMVCGMTTPPT
  SPGNVPPDLSHPYSKVFGTTAGGKGTPLGTPATSPPPAPLCHSDDYVHISLPQATVTPPR
  KEERMDSARPCLHRQHHLLNDRGSEEPPGSKGSVTLSDLPGFLGDLASEEDSIEKDKEEA
  AISRELSEITTAEAEPVVPRGGFDSPFYRDSLPGSQRKTHSAASSSQGASVNPEPLHSSL
  DKLGPDTPKQAFTPIDLPCGSADESPAGDRECQTSLETSIFTPSPCKIPPPTRVGFGSGQ
  PPPYDHLFEVALPKTAHHFVIRKTEELLKKAKGNTEEDGVPSTSPMEVLDRLIQQGADAH
  SKELNKLPLPSKSVDWTHFGGSPPSDEIRTLRDQLLLLHNQLLYERFKRQQHALRNRRLL
  RKVIKAAALEEHNAAMKDQLKLQEKDIQMWKVSLQKEQARYNQLQEQRDTMVTKLHSQIR
  QLQHDREEFYNQSQELQTKLEDCRNMIAELRIELKKANNKVCHTELLLSQVSQKLSNSES
  VQQQMEFLNRQLLVLGEVNELYLEQLQNKHSDTTKEVEMMKAAYRKELEKNRSHVLQQTQ
  RLDTSQKRILELESHLAKKDHLLLEQKKYLEDVKLQARGQLQAAESRYEAQKRITQVFEL
  EILDLYGRLEKDGLLKKLEEEKAEAAEAAEERLDCCNDGCSDSMVGHNEEASGHNGETKT
  PRPSSARGSSGSRGGGGSSSSSSELSTPEKPPHQRAGPFSSRWETTMGEASASIPTTVGS
  LPSSKSFLGMKARELFRNKSESQCDEDGMTSSLSESLKTELGKDLGVEAKIPLNLDGPHP
  SPPTPDSVGQLHIMDYNETHHEHS
• Function: Non-catalytic component of the TSC-TBC complex, a multiprotein complex that acts as a negative regulator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule biosynthesis to promote cellular biomass generation and growth. The TSC-TBC complex acts as a GTPase-activating protein (GAP) for the small GTPase RHEB, a direct activator of the protein kinase activity of mTORC1. In absence of nutrients, the TSC-TBC complex inhibits mTORC1, thereby preventing phosphorylation of ribosomal protein S6 kinase (RPS6KB1 and RPS6KB2) and EIF4EBP1 (4E-BP1) by the mTORC1 signaling. The TSC-TBC complex is inactivated in response to nutrients, relieving inhibition of mTORC1. Within the TSC-TBC complex, TSC1 stabilizes TSC2 and prevents TSC2 self-aggregation. Acts as a tumor suppressor. Involved in microtubule-mediated protein transport via its ability to regulate mTORC1 signaling. Also acts as a co-chaperone for HSP90AA1 facilitating HSP90AA1 chaperoning of protein clients such as kinases, TSC2 and glucocorticoid receptor NR3C1. Increases ATP binding to HSP90AA1 and inhibits HSP90AA1 ATPase activity. Competes with the activating co-chaperone AHSA1 for binding to HSP90AA1, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins. Recruits TSC2 to HSP90AA1 and stabilizes TSC2 by preventing the interaction between TSC2 and ubiquitin ligase HERC1.
• Tissue Specificity: Highly expressed in skeletal muscle, followed by heart, brain, placenta, pancreas, lung, liver and kidney . Also expressed in embryonic kidney cells .
• KEGG Pathway:
  Phospholipase D sig.ling pathway (hsa04072)
  Autophagy - animal (hsa04140)
  mTOR sig.ling pathway (hsa04150)
  PI3K-Akt sig.ling pathway (hsa04151)
  AMPK sig.ling pathway (hsa04152)
  Longevity regulating pathway (hsa04211)
  Cellular senescence (hsa04218)
  Thermogenesis (hsa04714)
  Insulin sig.ling pathway (hsa04910)
  Human cytomegalovirus infection (hsa05163)
  Human papillomavirus infection (hsa05165)
  Herpes simplex virus 1 infection (hsa05168)
  Choline metabolism in cancer (hsa05231)
• Reactome Pathway:
  Inhibition of TSC complex formation by PKB (R-HSA-165181)
  Energy dependent regulation of mTOR by LKB1-AMPK (R-HSA-380972)
  TP53 Regulates Metabolic Genes (R-HSA-5628897)
  TBC/RABGAPs (R-HSA-8854214)
  Macroautophagy (R-HSA-1632852)

Molecular Interaction Atlas (MIA) of This DOT

41 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cognitive impairment	DISH2ERD	Definitive	Biomarker	[1]
Lymphangioleiomyomatosis	DISR0RNB	Definitive	Autosomal dominant	[2]
Tuberculosis	DIS2YIMD	Definitive	Biomarker	[3]
Tuberous sclerosis	DISEMUGZ	Definitive	Autosomal dominant	[4]
Tuberous sclerosis 1	DIS07GDN	Definitive	Autosomal dominant	[5]
Action myoclonus-renal failure syndrome	DISI2BZN	Strong	Biomarker	[6]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[7]
Astrocytoma	DISL3V18	Strong	Biomarker	[8]
Autism	DISV4V1Z	Strong	Biomarker	[9]
Autosomal recessive polycystic kidney disease	DISPUS40	Strong	Biomarker	[10]
Brain disease	DIS6ZC3X	Strong	Biomarker	[11]
Carcinoma	DISH9F1N	Strong	Genetic Variation	[12]
Chordoma	DISCHJE7	Strong	Genetic Variation	[13]
Clear cell renal carcinoma	DISBXRFJ	Strong	Genetic Variation	[14]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[15]
Cystic kidney disease	DISRT1LM	Strong	Biomarker	[16]
Dentatorubral-pallidoluysian atrophy	DISHWE0K	Strong	Biomarker	[6]
Fleck corneal dystrophy	DISERQJ1	Strong	Genetic Variation	[17]
Glioblastoma multiforme	DISK8246	Strong	Genetic Variation	[18]
Hamartoma	DIS0I87H	Strong	Genetic Variation	[19]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[20]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[21]
Lung lymphangioleiomyomatosis	DISFL3YB	Strong	Autosomal dominant	[22]
Neoplasm with perivascular epithelioid cell differentiation	DIS8V0NT	Strong	Genetic Variation	[23]
Obesity	DIS47Y1K	Strong	Biomarker	[24]
Papillary renal cell carcinoma	DIS25HBV	Strong	Biomarker	[25]
Pneumothorax	DISP86H1	Strong	Biomarker	[26]
Progressive myoclonus epilepsy	DISAMCNS	Strong	Biomarker	[6]
Renal cell carcinoma	DISQZ2X8	Strong	Genetic Variation	[14]
Spasm	DIS51WT2	Strong	Biomarker	[27]
Tuberous sclerosis 2	DISR6GKZ	Strong	Genetic Variation	[28]
West syndrome	DISLIAU9	Strong	Genetic Variation	[29]
Autism spectrum disorder	DISXK8NV	moderate	Altered Expression	[30]
Squamous cell carcinoma	DISQVIFL	moderate	Altered Expression	[31]
Obsolete tuberous sclerosis complex	DIS46L2J	Supportive	Autosomal dominant	[32]
Acute monocytic leukemia	DIS28NEL	Limited	Biomarker	[33]
Adenocarcinoma	DIS3IHTY	Limited	Genetic Variation	[34]
Adult hepatocellular carcinoma	DIS6ZPAI	Limited	Genetic Variation	[21]
Kidney neoplasm	DISBNZTN	Limited	Biomarker	[35]
Lung cancer	DISCM4YA	Limited	Biomarker	[36]
Lung carcinoma	DISTR26C	Limited	Biomarker	[36]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Hamartin (TSC1).	[37]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Hamartin (TSC1).	[38]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Hamartin (TSC1).	[39]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Hamartin (TSC1).	[40]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Hamartin (TSC1).	[41]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Hamartin (TSC1).	[42]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Hamartin (TSC1).	[43]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Hamartin (TSC1).	[44]
Marinol	DM70IK5	Approved	Marinol increases the expression of Hamartin (TSC1).	[45]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Hamartin (TSC1).	[43]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Hamartin (TSC1).	[48]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Hamartin (TSC1).	[49]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Hamartin (TSC1).	[46]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Hamartin (TSC1).	[47]

References

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