Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6SB8X5)

• DOT Name: Collagen alpha-3(IV) chain (COL4A3)
• Synonyms: Goodpasture antigen
• Gene Name: COL4A3
• Related Disease:
  Alport syndrome
  Autosomal dominant Alport syndrome
  Autosomal recessive Alport syndrome
  Age-related macular degeneration
  Andersen-Tawil syndrome
  Autoimmune disease
  Chronic kidney disease
  Clear cell renal carcinoma
  Colon carcinoma
  Glioblastoma multiforme
  Glioma
  Hematuria, benign familial, 1
  Hepatocellular carcinoma
  Hereditary nephritis
  Kidney failure
  Neoplasm
  Neovascular age-related macular degeneration
  Non-small-cell lung cancer
  Oral cancer
  Renal carcinoma
  Renal cell carcinoma
  Squamous cell carcinoma
  Tibial muscular dystrophy
  Acute myelogenous leukaemia
  Arterial tortuosity syndrome
  Bone osteosarcoma
  Congenital hereditary endothelial dystrophy of cornea
  Glomerulonephritis
  Osteosarcoma
  Prostate cancer
  Prostate carcinoma
  Posterior polymorphous corneal dystrophy
  Asthma
  Chronic obstructive pulmonary disease
  Hematuria, benign familial
  Lymphoma
  Myocardial infarction
  Nephritis
  Nephrotic syndrome, type 2
  Renal fibrosis
  Steroid-resistant nephrotic syndrome
  X-linked hydrocephalus with stenosis of the aqueduct of Sylvius
• UniProt ID: CO4A3_HUMAN
• PDB ID: 5NB0; 6WKU
• Pfam ID: PF01413 ; PF01391
• Sequence:
  MSARTAPRPQVLLLPLLLVLLAAAPAASKGCVCKDKGQCFCDGAKGEKGEKGFPGPPGSP
  GQKGFTGPEGLPGPQGPKGFPGLPGLTGSKGVRGISGLPGFSGSPGLPGTPGNTGPYGLV
  GVPGCSGSKGEQGFPGLPGTLGYPGIPGAAGLKGQKGAPAKEEDIELDAKGDPGLPGAPG
  PQGLPGPPGFPGPVGPPGPPGFFGFPGAMGPRGPKGHMGERVIGHKGERGVKGLTGPPGP
  PGTVIVTLTGPDNRTDLKGEKGDKGAMGEPGPPGPSGLPGESYGSEKGAPGDPGLQGKPG
  KDGVPGFPGSEGVKGNRGFPGLMGEDGIKGQKGDIGPPGFRGPTEYYDTYQEKGDEGTPG
  PPGPRGARGPQGPSGPPGVPGSPGSSRPGLRGAPGWPGLKGSKGERGRPGKDAMGTPGSP
  GCAGSPGLPGSPGPPGPPGDIVFRKGPPGDHGLPGYLGSPGIPGVDGPKGEPGLLCTQCP
  YIPGPPGLPGLPGLHGVKGIPGRQGAAGLKGSPGSPGNTGLPGFPGFPGAQGDPGLKGEK
  GETLQPEGQVGVPGDPGLRGQPGRKGLDGIPGTPGVKGLPGPKGELALSGEKGDQGPPGD
  PGSPGSPGPAGPAGPPGYGPQGEPGLQGTQGVPGAPGPPGEAGPRGELSVSTPVPGPPGP
  PGPPGHPGPQGPPGIPGSLGKCGDPGLPGPDGEPGIPGIGFPGPPGPKGDQGFPGTKGSL
  GCPGKMGEPGLPGKPGLPGAKGEPAVAMPGGPGTPGFPGERGNSGEHGEIGLPGLPGLPG
  TPGNEGLDGPRGDPGQPGPPGEQGPPGRCIEGPRGAQGLPGLNGLKGQQGRRGKTGPKGD
  PGIPGLDRSGFPGETGSPGIPGHQGEMGPLGQRGYPGNPGILGPPGEDGVIGMMGFPGAI
  GPPGPPGNPGTPGQRGSPGIPGVKGQRGTPGAKGEQGDKGNPGPSEISHVIGDKGEPGLK
  GFAGNPGEKGNRGVPGMPGLKGLKGLPGPAGPPGPRGDLGSTGNPGEPGLRGIPGSMGNM
  GMPGSKGKRGTLGFPGRAGRPGLPGIHGLQGDKGEPGYSEGTRPGPPGPTGDPGLPGDMG
  KKGEMGQPGPPGHLGPAGPEGAPGSPGSPGLPGKPGPHGDLGFKGIKGLLGPPGIRGPPG
  LPGFPGSPGPMGIRGDQGRDGIPGPAGEKGETGLLRAPPGPRGNPGAQGAKGDRGAPGFP
  GLPGRKGAMGDAGPRGPTGIEGFPGPPGLPGAIIPGQTGNRGPPGSRGSPGAPGPPGPPG
  SHVIGIKGDKGSMGHPGPKGPPGTAGDMGPPGRLGAPGTPGLPGPRGDPGFQGFPGVKGE
  KGNPGFLGSIGPPGPIGPKGPPGVRGDPGTLKIISLPGSPGPPGTPGEPGMQGEPGPPGP
  PGNLGPCGPRGKPGKDGKPGTPGPAGEKGNKGSKGEPGPAGSDGLPGLKGKRGDSGSPAT
  WTTRGFVFTRHSQTTAIPSCPEGTVPLYSGFSFLFVQGNQRAHGQDLGTLGSCLQRFTTM
  PFLFCNVNDVCNFASRNDYSYWLSTPALMPMNMAPITGRALEPYISRCTVCEGPAIAIAV
  HSQTTDIPPCPHGWISLWKGFSFIMFTSAGSEGTGQALASPGSCLEEFRASPFLECHGRG
  TCNYYSNSYSFWLASLNPERMFRKPIPSTVKAGELEKIISRCQVCMKKRH
• Function: Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a 'chicken-wire' meshwork together with laminins, proteoglycans and entactin/nidogen.; Tumstatin, a cleavage fragment corresponding to the collagen alpha 3(IV) NC1 domain, possesses both anti-angiogenic and anti-tumor cell activity; these two anti-tumor properties may be regulated via RGD-independent ITGB3-mediated mechanisms.
• Tissue Specificity: Alpha 3 and alpha 4 type IV collagens are colocalized and present in kidney, eye, basement membranes of lens capsule, cochlea, lung, skeletal muscle, aorta, synaptic fibers, fetal kidney and fetal lung. PubMed:8083201 reports similar levels of expression of alpha 3 and alpha 4 type IV collagens in kidney, but PubMed:7523402 reports that in kidney levels of alpha 3 type IV collagen are significantly lower than those of alpha 4 type IV collagen. According to PubMed:8083201, alpha 3 type IV collagen is not detected in heart, brain, placenta, liver, pancreas, extrasynaptic muscle fibers, endoneurial and perineurial nerves, fetal brain, fetal heart and fetal liver. According to PubMed:7523402, alpha 3 type IV collagen is strongly expressed in pancreas, neuroretina and calvaria and not expressed in adrenal, ileum and skin. Isoform 1 and isoform 3 are strongly expressed in kidney, lung, suprarenal capsule, muscle and spleen, in each of these tissues isoform 1 is more abundant than isoform 3. Isoform 1 and isoform 3 are expressed at low levels in artery, fat, pericardium and peripherical nerve, but not in placenta, mesangium, skin, pleura and cultured umbilical endothelial cells.
• KEGG Pathway:
  PI3K-Akt sig.ling pathway (hsa04151)
  Focal adhesion (hsa04510)
  ECM-receptor interaction (hsa04512)
  Cytoskeleton in muscle cells (hsa04820)
  Relaxin sig.ling pathway (hsa04926)
  AGE-RAGE sig.ling pathway in diabetic complications (hsa04933)
  Protein digestion and absorption (hsa04974)
  Amoebiasis (hsa05146)
  Human papillomavirus infection (hsa05165)
  Pathways in cancer (hsa05200)
  Small cell lung cancer (hsa05222)
• Reactome Pathway:
  Extracellular matrix organization (R-HSA-1474244)
  Collagen biosynthesis and modifying enzymes (R-HSA-1650814)
  Signaling by PDGF (R-HSA-186797)
  Assembly of collagen fibrils and other multimeric structures (R-HSA-2022090)
  Integrin cell surface interactions (R-HSA-216083)
  Anchoring fibril formation (R-HSA-2214320)
  Crosslinking of collagen fibrils (R-HSA-2243919)
  Laminin interactions (R-HSA-3000157)
  Non-integrin membrane-ECM interactions (R-HSA-3000171)
  ECM proteoglycans (R-HSA-3000178)
  NCAM1 interactions (R-HSA-419037)
  Collagen chain trimerization (R-HSA-8948216)
  Collagen degradation (R-HSA-1442490)

Molecular Interaction Atlas (MIA) of This DOT

42 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alport syndrome	DIS25AB4	Definitive	Semidominant	[1]
Autosomal dominant Alport syndrome	DIS3MD0D	Definitive	Autosomal dominant	[2]
Autosomal recessive Alport syndrome	DISFOQZB	Definitive	Autosomal recessive	[1]
Age-related macular degeneration	DIS0XS2C	Strong	Genetic Variation	[3]
Andersen-Tawil syndrome	DIS3IWZ7	Strong	Biomarker	[4]
Autoimmune disease	DISORMTM	Strong	Biomarker	[5]
Chronic kidney disease	DISW82R7	Strong	Biomarker	[6]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[7]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[8]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[9]
Glioma	DIS5RPEH	Strong	Altered Expression	[10]
Hematuria, benign familial, 1	DISSUA8W	Strong	Autosomal dominant	[11]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[12]
Hereditary nephritis	DISECBR1	Strong	Biomarker	[13]
Kidney failure	DISOVQ9P	Strong	Genetic Variation	[14]
Neoplasm	DISZKGEW	Strong	Biomarker	[15]
Neovascular age-related macular degeneration	DIS5S9R7	Strong	Genetic Variation	[3]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[16]
Oral cancer	DISLD42D	Strong	Biomarker	[17]
Renal carcinoma	DISER9XT	Strong	Altered Expression	[18]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[18]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[17]
Tibial muscular dystrophy	DIS8YQKI	Strong	Biomarker	[19]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[20]
Arterial tortuosity syndrome	DISWG36B	moderate	Biomarker	[4]
Bone osteosarcoma	DIST1004	moderate	Biomarker	[21]
Congenital hereditary endothelial dystrophy of cornea	DISHLPKQ	moderate	Altered Expression	[22]
Glomerulonephritis	DISPZIQ3	moderate	Biomarker	[23]
Osteosarcoma	DISLQ7E2	moderate	Biomarker	[21]
Prostate cancer	DISF190Y	moderate	Biomarker	[24]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[24]
Posterior polymorphous corneal dystrophy	DISHAYH6	Disputed	Altered Expression	[25]
Asthma	DISW9QNS	Limited	Biomarker	[26]
Chronic obstructive pulmonary disease	DISQCIRF	Limited	Biomarker	[27]
Hematuria, benign familial	DISCWU1L	Limited	Genetic Variation	[28]
Lymphoma	DISN6V4S	Limited	Biomarker	[29]
Myocardial infarction	DIS655KI	Limited	Biomarker	[30]
Nephritis	DISQZQ70	Limited	Genetic Variation	[31]
Nephrotic syndrome, type 2	DISIRFO1	Limited	GermlineModifyingMutation	[32]
Renal fibrosis	DISMHI3I	Limited	Biomarker	[33]
Steroid-resistant nephrotic syndrome	DISVEBC9	Limited	Genetic Variation	[34]
X-linked hydrocephalus with stenosis of the aqueduct of Sylvius	DIS6QXIR	Limited	Genetic Variation	[35]

2 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 Collagen alpha-3(IV) chain (COL4A3).	[36]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Collagen alpha-3(IV) chain (COL4A3).	[48]

15 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 Collagen alpha-3(IV) chain (COL4A3).	[37]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Collagen alpha-3(IV) chain (COL4A3).	[38]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Collagen alpha-3(IV) chain (COL4A3).	[39]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Collagen alpha-3(IV) chain (COL4A3).	[40]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Collagen alpha-3(IV) chain (COL4A3).	[41]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Collagen alpha-3(IV) chain (COL4A3).	[37]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Collagen alpha-3(IV) chain (COL4A3).	[42]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Collagen alpha-3(IV) chain (COL4A3).	[43]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Collagen alpha-3(IV) chain (COL4A3).	[44]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Collagen alpha-3(IV) chain (COL4A3).	[45]
Vandetanib	DMRICNP	Approved	Vandetanib increases the expression of Collagen alpha-3(IV) chain (COL4A3).	[46]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Collagen alpha-3(IV) chain (COL4A3).	[45]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Collagen alpha-3(IV) chain (COL4A3).	[47]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Collagen alpha-3(IV) chain (COL4A3).	[49]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Collagen alpha-3(IV) chain (COL4A3).	[37]

References

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