Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWVRR0K)

• DOT Name: Myelin-associated glycoprotein (MAG)
• Synonyms: Siglec-4a
• Gene Name: MAG
• Related Disease:
  Complex hereditary spastic paraplegia
  Hereditary spastic paraplegia 75
• UniProt ID: MAG_HUMAN
• Pfam ID: PF08205 ; PF13927
• Sequence:
  MIFLTALPLFWIMISASRGGHWGAWMPSSISAFEGTCVSIPCRFDFPDELRPAVVHGVWY
  FNSPYPKNYPPVVFKSRTQVVHESFQGRSRLLGDLGLRNCTLLLSNVSPELGGKYYFRGD
  LGGYNQYTFSEHSVLDIVNTPNIVVPPEVVAGTEVEVSCMVPDNCPELRPELSWLGHEGL
  GEPAVLGRLREDEGTWVQVSLLHFVPTREANGHRLGCQASFPNTTLQFEGYASMDVKYPP
  VIVEMNSSVEAIEGSHVSLLCGADSNPPPLLTWMRDGTVLREAVAESLLLELEEVTPAED
  GVYACLAENAYGQDNRTVGLSVMYAPWKPTVNGTMVAVEGETVSILCSTQSNPDPILTIF
  KEKQILSTVIYESELQLELPAVSPEDDGEYWCVAENQYGQRATAFNLSVEFAPVLLLESH
  CAAARDTVQCLCVVKSNPEPSVAFELPSRNVTVNESEREFVYSERSGLVLTSILTLRGQA
  QAPPRVICTARNLYGAKSLELPFQGAHRLMWAKIGPVGAVVAFAILIAIVCYITQTRRKK
  NVTESPSFSAGDNPPVLFSSDFRISGAPEKYESERRLGSERRLLGLRGEPPELDLSYSHS
  DLGKRPTKDSYTLTEELAEYAEIRVK
• Function: Adhesion molecule that mediates interactions between myelinating cells and neurons by binding to neuronal sialic acid-containing gangliosides and to the glycoproteins RTN4R and RTN4RL2. Not required for initial myelination, but seems to play a role in the maintenance of normal axon myelination. Protects motoneurons against apoptosis, also after injury; protection against apoptosis is probably mediated via interaction with neuronal RTN4R and RTN4RL2. Required to prevent degeneration of myelinated axons in adults; this probably depends on binding to gangliosides on the axon cell membrane. Negative regulator of neurite outgrowth; in dorsal root ganglion neurons the inhibition is mediated primarily via binding to neuronal RTN4R or RTN4RL2 and to a lesser degree via binding to neuronal gangliosides. In cerebellar granule cells the inhibition is mediated primarily via binding to neuronal gangliosides. In sensory neurons, inhibition of neurite extension depends only partially on RTN4R, RTN4RL2 and gangliosides. Inhibits axon longitudinal growth. Inhibits axon outgrowth by binding to RTN4R. Preferentially binds to alpha-2,3-linked sialic acid. Binds ganglioside Gt1b.
• Tissue Specificity: Both isoform 1 and isoform 2 are detected in myelinated structures in the central and peripheral nervous system, in periaxonal myelin and at Schmidt-Lanterman incisures . Detected in optic nerve, in oligodendroglia and in periaxonal myelin sheaths . Detected in compact myelin (at protein level) . Both isoform 1 and isoform 2 are detected in the central and peripheral nervous system .
• KEGG Pathway: Cell adhesion molecules (hsa04514)
• Reactome Pathway:
  Basigin interactions (R-HSA-210991)
  EGR2 and SOX10-mediated initiation of Schwann cell myelination (R-HSA-9619665)
  Axonal growth inhibition (RHOA activation) (R-HSA-193634)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex hereditary spastic paraplegia	DIS9KXQY	Definitive	Autosomal recessive	[1]
Hereditary spastic paraplegia 75	DIS3QZ88	Strong	Autosomal recessive	[2]

3 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 Myelin-associated glycoprotein (MAG).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Myelin-associated glycoprotein (MAG).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Myelin-associated glycoprotein (MAG).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Myelin-associated glycoprotein (MAG).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Myelin-associated glycoprotein (MAG).	[5]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Myelin-associated glycoprotein (MAG).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Myelin-associated glycoprotein (MAG).	[7]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Myelin-associated glycoprotein (MAG).	[9]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] [Carbon assimilation and taxonomic study of Bacillus subtillis and B. licheniformis]. Can J Microbiol. 1979 Apr;25(4):491-8.
• [3] 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.
• [4] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [5] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [6] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] 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.
• [9] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [10] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.