Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ4FGI9)

• DOT Name: Hypocretin neuropeptide precursor (HCRT)
• Synonyms: Hypocretin; Hcrt; Orexin precursor; Prepro-orexin; Preprohypocretin
• Gene Name: HCRT
• Related Disease: Narcolepsy 1
• UniProt ID: OREX_HUMAN
• PDB ID: 1CQ0; 1R02; 1UVQ; 1WSO; 7L1U
• Pfam ID: PF02072
• Sequence:
  MNLPSTKVSWAAVTLLLLLLLLPPALLSSGAAAQPLPDCCRQKTCSCRLYELLHGAGNHA
  AGILTLGKRRSGPPGLQGRLQRLLQASGNHAAGILTMGRRAGAEPAPRPCLGRRCSAPAA
  ASVAPGGQSGI
• Function: Neuropeptides that play a significant role in the regulation of food intake and sleep-wakefulness, possibly by coordinating the complex behavioral and physiologic responses of these complementary homeostatic functions. A broader role in the homeostatic regulation of energy metabolism, autonomic function, hormonal balance and the regulation of body fluids, is also suggested; [Orexin-A]: Binds to orexin receptors HCRTR1/OX1R and HCRTR2/OX2R with a high affinity. Stimulates food intake. Modulates pituitary luteinizing hormone secretion in an ovarian steroid-dependent manner; [Orexin-B]: Binds to orexin receptor HCRTR2/OX2R only. Stimulates food intake. Modulates pituitary luteinizing hormone secretion in an ovarian steroid-dependent manner.
• Tissue Specificity: Abundantly expressed in subthalamic nucleus but undetectable in other brain regions tested (hypothalamus was not tested) and in heart, placenta, lung, liver, skeletal muscle, kidney and pancreas.
• KEGG Pathway: Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  Orexin and neuropeptides FF and QRFP bind to their respective receptors (R-HSA-389397)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Narcolepsy 1	DISTYYJ6	No Known	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Hypocretin neuropeptide precursor (HCRT).	[2]
Triclosan	DMZUR4N	Approved	Triclosan increases the methylation of Hypocretin neuropeptide precursor (HCRT).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Hypocretin neuropeptide precursor (HCRT).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Hypocretin neuropeptide precursor (HCRT).	[4]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [2] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [3] Pregnancy exposure to synthetic phenols and placental DNA methylation - An epigenome-wide association study in male infants from the EDEN cohort. Environ Pollut. 2021 Dec 1;290:118024. doi: 10.1016/j.envpol.2021.118024. Epub 2021 Aug 21.
• [4] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [5] 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.