Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOG2BXF)

• DOT Name: Sonic hedgehog protein (SHH)
• Synonyms: SHH; EC 3.1.-.-; HHG-1; Shh unprocessed N-terminal signaling and C-terminal autoprocessing domains; ShhNC
• Gene Name: SHH
• Related Disease:
  Holoprosencephaly 3
  Microphthalmia, isolated, with coloboma 5
  Polydactyly of a triphalangeal thumb
  Solitary median maxillary central incisor syndrome
  Skeletal system disorder
  Autosomal dominant preaxial polydactyly-upperback hypertrichosis syndrome
  Holoprosencephaly
  Microphthalmia, isolated, with coloboma
  Obsolete hypoplastic tibiae-postaxial polydactyly syndrome
  Syndactyly type 4
  Triphalangeal thumb-polysyndactyly syndrome
• UniProt ID: SHH_HUMAN
• PDB ID: 3HO5; 3M1N; 3MXW; 6DMY; 6E1H; 6N7G; 6N7H; 6N7K; 6OEV; 6PJV; 6RMG; 6RVD; 7E2I; 7MHZ; 7RHQ; 7URF
• EC Number: 3.1.-.-
• Pfam ID: PF01085 ; PF01079
• Sequence:
  MLLLARCLLLVLVSSLLVCSGLACGPGRGFGKRRHPKKLTPLAYKQFIPNVAEKTLGASG
  RYEGKISRNSERFKELTPNYNPDIIFKDEENTGADRLMTQRCKDKLNALAISVMNQWPGV
  KLRVTEGWDEDGHHSEESLHYEGRAVDITTSDRDRSKYGMLARLAVEAGFDWVYYESKAH
  IHCSVKAENSVAAKSGGCFPGSATVHLEQGGTKLVKDLSPGDRVLAADDQGRLLYSDFLT
  FLDRDDGAKKVFYVIETREPRERLLLTAAHLLFVAPHNDSATGEPEASSGSGPPSGGALG
  PRALFASRVRPGQRVYVVAERDGDRRLLPAAVHSVTLSEEAAGAYAPLTAQGTILINRVL
  ASCYAVIEEHSWAHRAFAPFRLAHALLAALAPARTDRGGDSGGGDRGGGGGRVALTAPGA
  ADAPGAGATAGIHWYSQLLYQIGTWLLDSEALHPLGMAVKSS
• Function: [Sonic hedgehog protein]: The C-terminal part of the sonic hedgehog protein precursor displays an autoproteolysis and a cholesterol transferase activity. Both activities result in the cleavage of the full-length protein into two parts (ShhN and ShhC) followed by the covalent attachment of a cholesterol moiety to the C-terminal of the newly generated ShhN. Both activities occur in the reticulum endoplasmic. Once cleaved, ShhC is degraded in the endoplasmic reticulum; [Sonic hedgehog protein N-product]: The dually lipidated sonic hedgehog protein N-product (ShhNp) is a morphogen which is essential for a variety of patterning events during development. Induces ventral cell fate in the neural tube and somites. Involved in the patterning of the anterior-posterior axis of the developing limb bud. Essential for axon guidance. Binds to the patched (PTCH1) receptor, which functions in association with smoothened (SMO), to activate the transcription of target genes. In the absence of SHH, PTCH1 represses the constitutive signaling activity of SMO.
• KEGG Pathway:
  Hedgehog sig.ling pathway (hsa04340)
  Axon guidance (hsa04360)
  Pathways in cancer (hsa05200)
  Proteoglycans in cancer (hsa05205)
  Basal cell carcinoma (hsa05217)
  Gastric cancer (hsa05226)
• Reactome Pathway:
  Hedgehog ligand biogenesis (R-HSA-5358346)
  Hh mutants are degraded by ERAD (R-HSA-5362768)
  Release of Hh-Np from the secreting cell (R-HSA-5362798)
  Ligand-receptor interactions (R-HSA-5632681)
  Hedgehog 'on' state (R-HSA-5632684)
  Activation of SMO (R-HSA-5635838)
  HHAT G278V doesn't palmitoylate Hh-Np (R-HSA-5658034)
  Formation of lateral plate mesoderm (R-HSA-9758920)
  Formation of axial mesoderm (R-HSA-9796292)
  Class B/2 (Secretin family receptors) (R-HSA-373080)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Holoprosencephaly 3	DISSDSO9	Definitive	Autosomal dominant	[1]
Microphthalmia, isolated, with coloboma 5	DISLHJX9	Definitive	Autosomal dominant	[2]
Polydactyly of a triphalangeal thumb	DIS7WCFY	Definitive	Autosomal dominant	[3]
Solitary median maxillary central incisor syndrome	DISEWCUH	Definitive	Autosomal dominant	[3]
Skeletal system disorder	DIS5PU87	Moderate	Autosomal dominant	[1]
Autosomal dominant preaxial polydactyly-upperback hypertrichosis syndrome	DISQ9APO	Supportive	Autosomal dominant	[4]
Holoprosencephaly	DISR35EC	Supportive	Autosomal recessive	[5]
Microphthalmia, isolated, with coloboma	DISLSEUJ	Supportive	Autosomal dominant	[2]
Obsolete hypoplastic tibiae-postaxial polydactyly syndrome	DISA748M	Supportive	Autosomal dominant	[6]
Syndactyly type 4	DISMKGLC	Supportive	Autosomal dominant	[7]
Triphalangeal thumb-polysyndactyly syndrome	DIS2V1ZD	Supportive	Autosomal dominant	[8]

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 Sonic hedgehog protein (SHH).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Sonic hedgehog protein (SHH).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Sonic hedgehog protein (SHH).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Sonic hedgehog protein (SHH).	[11]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Sonic hedgehog protein (SHH).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the activity of Sonic hedgehog protein (SHH).	[13]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Sonic hedgehog protein (SHH).	[14]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Sonic hedgehog protein (SHH).	[15]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Sonic hedgehog protein (SHH).	[16]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Sonic hedgehog protein (SHH).	[17]
Gemcitabine	DMSE3I7	Approved	Gemcitabine decreases the expression of Sonic hedgehog protein (SHH).	[18]
Bexarotene	DMOBIKY	Approved	Bexarotene increases the expression of Sonic hedgehog protein (SHH).	[17]
Tofacitinib	DMBS370	Approved	Tofacitinib increases the expression of Sonic hedgehog protein (SHH).	[19]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Sonic hedgehog protein (SHH).	[20]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Sonic hedgehog protein (SHH).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Sonic hedgehog protein (SHH).	[23]
U0126	DM31OGF	Investigative	U0126 decreases the expression of Sonic hedgehog protein (SHH).	[14]
SAG	DMHOG7W	Investigative	SAG increases the expression of Sonic hedgehog protein (SHH).	[24]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Novel mutation in sonic hedgehog in non-syndromic colobomatous microphthalmia. Am J Med Genet A. 2003 Jan 30;116A(3):215-21. doi: 10.1002/ajmg.a.10884.
• [3] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [4] The disruption of a novel limb cis-regulatory element of SHH is associated with autosomal dominant preaxial polydactyly-hypertrichosis. Eur J Hum Genet. 2016 Jan;24(1):37-43. doi: 10.1038/ejhg.2015.53. Epub 2015 Mar 18.
• [5] Recent advances in understanding inheritance of holoprosencephaly. Am J Med Genet C Semin Med Genet. 2018 Jun;178(2):258-269. doi: 10.1002/ajmg.c.31619. Epub 2018 May 22.
• [6] A specific mutation in the distant sonic hedgehog (SHH) cis-regulator (ZRS) causes Werner mesomelic syndrome (WMS) while complete ZRS duplications underlie Haas type polysyndactyly and preaxial polydactyly (PPD) with or without triphalangeal thumb. Hum Mutat. 2010 Jan;31(1):81-9. doi: 10.1002/humu.21142.
• [7] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [8] A microduplication of the long range SHH limb regulator (ZRS) is associated with triphalangeal thumb-polysyndactyly syndrome. J Med Genet. 2008 Jun;45(6):370-5. doi: 10.1136/jmg.2007.055699. Epub 2008 Jan 4.
• [9] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [10] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] Quercetin suppresses pancreatic ductal adenocarcinoma progression via inhibition of SHH and TGF-/Smad signaling pathways. Cell Biol Toxicol. 2021 Jun;37(3):479-496. doi: 10.1007/s10565-020-09562-0. Epub 2020 Oct 17.
• [13] Arsenic trioxide prevents osteosarcoma growth by inhibition of GLI transcription via DNA damage accumulation. PLoS One. 2013 Jul 8;8(7):e69466. doi: 10.1371/journal.pone.0069466. Print 2013.
• [14] Ovarian steroids, mitogen-activated protein kinases, and/or aspartic proteinases cooperate to control endometrial remodeling by regulating gene expression in the stroma and glands. Endocrinology. 2010 Sep;151(9):4515-26. doi: 10.1210/en.2009-1398. Epub 2010 Jul 21.
• [15] Down-regulation of Sonic hedgehog signaling pathway activity is involved in 5-fluorouracil-induced apoptosis and motility inhibition in Hep3B cells. Acta Biochim Biophys Sin (Shanghai). 2008 Sep;40(9):819-29.
• [16] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [17] Pituitary specific retinoid-X receptor ligand interactions with thyroid hormone receptor signaling revealed by high throughput reporter and endogenous gene responses. Toxicol In Vitro. 2015 Oct;29(7):1609-18. doi: 10.1016/j.tiv.2015.06.018. Epub 2015 Jun 19.
• [18] A fine-needle aspirate-based vulnerability assay identifies polo-like kinase 1 as a mediator of gemcitabine resistance in pancreatic cancer. Mol Cancer Ther. 2010 Feb;9(2):311-8. doi: 10.1158/1535-7163.MCT-09-0693. Epub 2010 Jan 26.
• [19] White-to-brown metabolic conversion of human adipocytes by JAK inhibition. Nat Cell Biol. 2015 Jan;17(1):57-67. doi: 10.1038/ncb3075. Epub 2014 Dec 8.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] Grape resveratrol increases serum adiponectin and downregulates inflammatory genes in peripheral blood mononuclear cells: a triple-blind, placebo-controlled, one-year clinical trial in patients with stable coronary artery disease. Cardiovasc Drugs Ther. 2013 Feb;27(1):37-48. doi: 10.1007/s10557-012-6427-8.
• [22] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [23] Bisphenol A stimulates adrenal cortical cell proliferation via ER-mediated activation of the sonic hedgehog signalling pathway. J Steroid Biochem Mol Biol. 2018 Apr;178:254-262. doi: 10.1016/j.jsbmb.2018.01.004. Epub 2018 Jan 4.
• [24] Differential role of Pax6 and its interaction with Shh-Gli1-IDH2 axis in regulation of glioma growth and chemoresistance. J Biochem Mol Toxicol. 2023 Feb;37(2):e23241. doi: 10.1002/jbt.23241. Epub 2022 Oct 7.