Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6HTSJT)

• DOT Name: Basement membrane-specific heparan sulfate proteoglycan core protein (HSPG2)
• Synonyms: HSPG; Perlecan; PLC
• Gene Name: HSPG2
• Related Disease:
  Schwartz-Jampel syndrome type 1
  Silverman-Handmaker type dyssegmental dysplasia
  Schwartz-Jampel syndrome
• UniProt ID: PGBM_HUMAN
• PDB ID: 3SH4; 3SH5
• Pfam ID: PF00008 ; PF07679 ; PF13895 ; PF13927 ; PF00052 ; PF00053 ; PF00054 ; PF00057
• Sequence:
  MGWRAAGALLLALLLHGRLLAVTHGLRAYDGLSLPEDIETVTASQMRWTHSYLSDDEDML
  ADSISGDDLGSGDLGSGDFQMVYFRALVNFTRSIEYSPQLEDAGSREFREVSEAVVDTLE
  SEYLKIPGDQVVSVVFIKELDGWVFVELDVGSEGNADGAQIQEMLLRVISSGSVASYVTS
  PQGFQFRRLGTVPQFPRACTEAEFACHSYNECVALEYRCDRRPDCRDMSDELNCEEPVLG
  ISPTFSLLVETTSLPPRPETTIMRQPPVTHAPQPLLPGSVRPLPCGPQEAACRNGHCIPR
  DYLCDGQEDCEDGSDELDCGPPPPCEPNEFPCGNGHCALKLWRCDGDFDCEDRTDEANCP
  TKRPEEVCGPTQFRCVSTNMCIPASFHCDEESDCPDRSDEFGCMPPQVVTPPRESIQASR
  GQTVTFTCVAIGVPTPIINWRLNWGHIPSHPRVTVTSEGGRGTLIIRDVKESDQGAYTCE
  AMNARGMVFGIPDGVLELVPQRGPCPDGHFYLEHSAACLPCFCFGITSVCQSTRRFRDQI
  RLRFDQPDDFKGVNVTMPAQPGTPPLSSTQLQIDPSLHEFQLVDLSRRFLVHDSFWALPE
  QFLGNKVDSYGGSLRYNVRYELARGMLEPVQRPDVVLMGAGYRLLSRGHTPTQPGALNQR
  QVQFSEEHWVHESGRPVQRAELLQVLQSLEAVLIQTVYNTKMASVGLSDIAMDTTVTHAT
  SHGRAHSVEECRCPIGYSGLSCESCDAHFTRVPGGPYLGTCSGCNCNGHASSCDPVYGHC
  LNCQHNTEGPQCNKCKAGFFGDAMKATATSCRPCPCPYIDASRRFSDTCFLDTDGQATCD
  ACAPGYTGRRCESCAPGYEGNPIQPGGKCRPVNQEIVRCDERGSMGTSGEACRCKNNVVG
  RLCNECADGSFHLSTRNPDGCLKCFCMGVSRHCTSSSWSRAQLHGASEEPGHFSLTNAAS
  THTTNEGIFSPTPGELGFSSFHRLLSGPYFWSLPSRFLGDKVTSYGGELRFTVTQRSQPG
  STPLHGQPLVVLQGNNIILEHHVAQEPSPGQPSTFIVPFREQAWQRPDGQPATREHLLMA
  LAGIDTLLIRASYAQQPAESRVSGISMDVAVPEETGQDPALEVEQCSCPPGYRGPSCQDC
  DTGYTRTPSGLYLGTCERCSCHGHSEACEPETGACQGCQHHTEGPRCEQCQPGYYGDAQR
  GTPQDCQLCPCYGDPAAGQAAHTCFLDTDGHPTCDACSPGHSGRHCERCAPGYYGNPSQG
  QPCQRDSQVPGPIGCNCDPQGSVSSQCDAAGQCQCKAQVEGLTCSHCRPHHFHLSASNPD
  GCLPCFCMGITQQCASSAYTRHLISTHFAPGDFQGFALVNPQRNSRLTGEFTVEPVPEGA
  QLSFGNFAQLGHESFYWQLPETYQGDKVAAYGGKLRYTLSYTAGPQGSPLSDPDVQITGN
  NIMLVASQPALQGPERRSYEIMFREEFWRRPDGQPATREHLLMALADLDELLIRATFSSV
  PLAASISAVSLEVAQPGPSNRPRALEVEECRCPPGYIGLSCQDCAPGYTRTGSGLYLGHC
  ELCECNGHSDLCHPETGACSQCQHNAAGEFCELCAPGYYGDATAGTPEDCQPCACPLTNP
  ENMFSRTCESLGAGGYRCTACEPGYTGQYCEQCGPGYVGNPSVQGGQCLPETNQAPLVVE
  VHPARSIVPQGGSHSLRCQVSGSPPHYFYWSREDGRPVPSGTQQRHQGSELHFPSVQPSD
  AGVYICTCRNLHQSNTSRAELLVTEAPSKPITVTVEEQRSQSVRPGADVTFICTAKSKSP
  AYTLVWTRLHNGKLPTRAMDFNGILTIRNVQLSDAGTYVCTGSNMFAMDQGTATLHVQAS
  GTLSAPVVSIHPPQLTVQPGQLAEFRCSATGSPTPTLEWTGGPGGQLPAKAQIHGGILRL
  PAVEPTDQAQYLCRAHSSAGQQVARAVLHVHGGGGPRVQVSPERTQVHAGRTVRLYCRAA
  GVPSATITWRKEGGSLPPQARSERTDIATLLIPAITTADAGFYLCVATSPAGTAQARIQV
  VVLSASDASPPPVKIESSSPSVTEGQTLDLNCVVAGSAHAQVTWYRRGGSLPPHTQVHGS
  RLRLPQVSPADSGEYVCRVENGSGPKEASITVSVLHGTHSGPSYTPVPGSTRPIRIEPSS
  SHVAEGQTLDLNCVVPGQAHAQVTWHKRGGSLPARHQTHGSLLRLHQVTPADSGEYVCHV
  VGTSGPLEASVLVTIEASVIPGPIPPVRIESSSSTVAEGQTLDLSCVVAGQAHAQVTWYK
  RGGSLPARHQVRGSRLYIFQASPADAGQYVCRASNGMEASITVTVTGTQGANLAYPAGST
  QPIRIEPSSSQVAEGQTLDLNCVVPGQSHAQVTWHKRGGSLPVRHQTHGSLLRLYQASPA
  DSGEYVCRVLGSSVPLEASVLVTIEPAGSVPALGVTPTVRIESSSSQVAEGQTLDLNCLV
  AGQAHAQVTWHKRGGSLPARHQVHGSRLRLLQVTPADSGEYVCRVVGSSGTQEASVLVTI
  QQRLSGSHSQGVAYPVRIESSSASLANGHTLDLNCLVASQAPHTITWYKRGGSLPSRHQI
  VGSRLRIPQVTPADSGEYVCHVSNGAGSRETSLIVTIQGSGSSHVPSVSPPIRIESSSPT
  VVEGQTLDLNCVVARQPQAIITWYKRGGSLPSRHQTHGSHLRLHQMSVADSGEYVCRANN
  NIDALEASIVISVSPSAGSPSAPGSSMPIRIESSSSHVAEGETLDLNCVVPGQAHAQVTW
  HKRGGSLPSHHQTRGSRLRLHHVSPADSGEYVCRVMGSSGPLEASVLVTIEASGSSAVHV
  PAPGGAPPIRIEPSSSRVAEGQTLDLKCVVPGQAHAQVTWHKRGGNLPARHQVHGPLLRL
  NQVSPADSGEYSCQVTGSSGTLEASVLVTIEPSSPGPIPAPGLAQPIYIEASSSHVTEGQ
  TLDLNCVVPGQAHAQVTWYKRGGSLPARHQTHGSQLRLHLVSPADSGEYVCRAASGPGPE
  QEASFTVTVPPSEGSSYRLRSPVISIDPPSSTVQQGQDASFKCLIHDGAAPISLEWKTRN
  QELEDNVHISPNGSIITIVGTRPSNHGTYRCVASNAYGVAQSVVNLSVHGPPTVSVLPEG
  PVWVKVGKAVTLECVSAGEPRSSARWTRISSTPAKLEQRTYGLMDSHAVLQISSAKPSDA
  GTYVCLAQNALGTAQKQVEVIVDTGAMAPGAPQVQAEEAELTVEAGHTATLRCSATGSPA
  PTIHWSKLRSPLPWQHRLEGDTLIIPRVAQQDSGQYICNATSPAGHAEATIILHVESPPY
  ATTVPEHASVQAGETVQLQCLAHGTPPLTFQWSRVGSSLPGRATARNELLHFERAAPEDS
  GRYRCRVTNKVGSAEAFAQLLVQGPPGSLPATSIPAGSTPTVQVTPQLETKSIGASVEFH
  CAVPSDRGTQLRWFKEGGQLPPGHSVQDGVLRIQNLDQSCQGTYICQAHGPWGKAQASAQ
  LVIQALPSVLINIRTSVQTVVVGHAVEFECLALGDPKPQVTWSKVGGHLRPGIVQSGGVV
  RIAHVELADAGQYRCTATNAAGTTQSHVLLLVQALPQISMPQEVRVPAGSAAVFPCIASG
  YPTPDISWSKLDGSLPPDSRLENNMLMLPSVRPQDAGTYVCTATNRQGKVKAFAHLQVPE
  RVVPYFTQTPYSFLPLPTIKDAYRKFEIKITFRPDSADGMLLYNGQKRVPGSPTNLANRQ
  PDFISFGLVGGRPEFRFDAGSGMATIRHPTPLALGHFHTVTLLRSLTQGSLIVGDLAPVN
  GTSQGKFQGLDLNEELYLGGYPDYGAIPKAGLSSGFIGCVRELRIQGEEIVFHDLNLTAH
  GISHCPTCRDRPCQNGGQCHDSESSSYVCVCPAGFTGSRCEHSQALHCHPEACGPDATCV
  NRPDGRGYTCRCHLGRSGLRCEEGVTVTTPSLSGAGSYLALPALTNTHHELRLDVEFKPL
  APDGVLLFSGGKSGPVEDFVSLAMVGGHLEFRYELGSGLAVLRSAEPLALGRWHRVSAER
  LNKDGSLRVNGGRPVLRSSPGKSQGLNLHTLLYLGGVEPSVPLSPATNMSAHFRGCVGEV
  SVNGKRLDLTYSFLGSQGIGQCYDSSPCERQPCQHGATCMPAGEYEFQCLCRDGFKGDLC
  EHEENPCQLREPCLHGGTCQGTRCLCLPGFSGPRCQQGSGHGIAESDWHLEGSGGNDAPG
  QYGAYFHDDGFLAFPGHVFSRSLPEVPETIELEVRTSTASGLLLWQGVEVGEAGQGKDFI
  SLGLQDGHLVFRYQLGSGEARLVSEDPINDGEWHRVTALREGRRGSIQVDGEELVSGRSP
  GPNVAVNAKGSVYIGGAPDVATLTGGRFSSGITGCVKNLVLHSARPGAPPPQPLDLQHRA
  QAGANTRPCPS
• Function: Integral component of basement membranes. Component of the glomerular basement membrane (GBM), responsible for the fixed negative electrostatic membrane charge, and which provides a barrier which is both size- and charge-selective. It serves as an attachment substrate for cells. Plays essential roles in vascularization. Critical for normal heart development and for regulating the vascular response to injury. Also required for avascular cartilage development.; [Endorepellin]: Anti-angiogenic and anti-tumor peptide that inhibits endothelial cell migration, collagen-induced endothelial tube morphogenesis and blood vessel growth in the chorioallantoic membrane. Blocks endothelial cell adhesion to fibronectin and type I collagen. Anti-tumor agent in neovascularization. Interaction with its ligand, integrin alpha2/beta1, is required for the anti-angiogenic properties. Evokes a reduction in phosphorylation of receptor tyrosine kinases via alpha2/beta1 integrin-mediated activation of the tyrosine phosphatase, PTPN6.; [LG3 peptide]: Has anti-angiogenic properties that require binding of calcium ions for full activity.
• Tissue Specificity: Detected in cerebrospinal fluid, fibroblasts and urine (at protein level).
• KEGG Pathway:
  ECM-receptor interaction (hsa04512)
  Cytoskeleton in muscle cells (hsa04820)
  Hepatitis B (hsa05161)
  Proteoglycans in cancer (hsa05205)
• Reactome Pathway:
  A tetrasaccharide linker sequence is required for GAG synthesis (R-HSA-1971475)
  HS-GAG biosynthesis (R-HSA-2022928)
  HS-GAG degradation (R-HSA-2024096)
  Integrin cell surface interactions (R-HSA-216083)
  Laminin interactions (R-HSA-3000157)
  Non-integrin membrane-ECM interactions (R-HSA-3000171)
  ECM proteoglycans (R-HSA-3000178)
  Defective B4GALT7 causes EDS, progeroid type (R-HSA-3560783)
  Defective B3GAT3 causes JDSSDHD (R-HSA-3560801)
  Defective EXT2 causes exostoses 2 (R-HSA-3656237)
  Defective EXT1 causes exostoses 1, TRPS2 and CHDS (R-HSA-3656253)
  Defective B3GALT6 causes EDSP2 and SEMDJL1 (R-HSA-4420332)
  Attachment and Entry (R-HSA-9694614)
  Retinoid metabolism and transport (R-HSA-975634)
  Amyloid fiber formation (R-HSA-977225)
  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
Schwartz-Jampel syndrome type 1	DIS42TKQ	Definitive	Autosomal recessive	[1]
Silverman-Handmaker type dyssegmental dysplasia	DIS5R0E3	Definitive	Autosomal recessive	[1]
Schwartz-Jampel syndrome	DIS3HCR8	Supportive	Autosomal recessive	[2]

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 Basement membrane-specific heparan sulfate proteoglycan core protein (HSPG2).	[3]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Basement membrane-specific heparan sulfate proteoglycan core protein (HSPG2).	[15]

13 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 Basement membrane-specific heparan sulfate proteoglycan core protein (HSPG2).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Basement membrane-specific heparan sulfate proteoglycan core protein (HSPG2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Basement membrane-specific heparan sulfate proteoglycan core protein (HSPG2).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Basement membrane-specific heparan sulfate proteoglycan core protein (HSPG2).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Basement membrane-specific heparan sulfate proteoglycan core protein (HSPG2).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Basement membrane-specific heparan sulfate proteoglycan core protein (HSPG2).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Basement membrane-specific heparan sulfate proteoglycan core protein (HSPG2).	[10]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Basement membrane-specific heparan sulfate proteoglycan core protein (HSPG2).	[11]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol increases the expression of Basement membrane-specific heparan sulfate proteoglycan core protein (HSPG2).	[12]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Basement membrane-specific heparan sulfate proteoglycan core protein (HSPG2).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Basement membrane-specific heparan sulfate proteoglycan core protein (HSPG2).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Basement membrane-specific heparan sulfate proteoglycan core protein (HSPG2).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Basement membrane-specific heparan sulfate proteoglycan core protein (HSPG2).	[17]

References

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• [2] Electrophysiological studies in a mouse model of Schwartz-Jampel syndrome demonstrate muscle fiber hyperactivity of peripheral nerve origin. Muscle Nerve. 2009 Jul;40(1):55-61. doi: 10.1002/mus.21253.
• [3] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
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• [8] Multifaceted preventive effects of single agent quercetin on a human prostate adenocarcinoma cell line (PC-3): implications for nutritional transcriptomics and multi-target therapy. Med Oncol. 2011 Dec;28(4):1395-404. doi: 10.1007/s12032-010-9603-3. Epub 2010 Jul 2.
• [9] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [10] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [11] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [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] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [14] 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.
• [15] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [16] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [17] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.