Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT51C69M)

• DOT Name: Prokineticin receptor 2 (PROKR2)
• Synonyms: PK-R2; G-protein coupled receptor 73-like 1; G-protein coupled receptor I5E; GPR73b; GPRg2
• Gene Name: PROKR2
• Related Disease:
  Hypogonadotropic hypogonadism 3 with or without anosmia
  Hypogonadotropic hypogonadism
  Kallmann syndrome
  Septooptic dysplasia
• UniProt ID: PKR2_HUMAN
• Pfam ID: PF00001
• Sequence:
  MAAQNGNTSFTPNFNPPQDHASSLSFNFSYGDYDLPMDEDEDMTKTRTFFAAKIVIGIAL
  AGIMLVCGIGNFVFIAALTRYKKLRNLTNLLIANLAISDFLVAIICCPFEMDYYVVRQLS
  WEHGHVLCASVNYLRTVSLYVSTNALLAIAIDRYLAIVHPLKPRMNYQTASFLIALVWMV
  SILIAIPSAYFATETVLFIVKSQEKIFCGQIWPVDQQLYYKSYFLFIFGVEFVGPVVTMT
  LCYARISRELWFKAVPGFQTEQIRKRLRCRRKTVLVLMCILTAYVLCWAPFYGFTIVRDF
  FPTVFVKEKHYLTAFYVVECIAMSNSMINTVCFVTVKNNTMKYFKKMMLLHWRPSQRGSK
  SSADLDLRTNGVPTTEEVDCIRLK
• Function: Receptor for prokineticin 2. Exclusively coupled to the G(q) subclass of heteromeric G proteins. Activation leads to mobilization of calcium, stimulation of phosphoinositide turnover and activation of p44/p42 mitogen-activated protein kinase.
• Tissue Specificity: Expressed in the ileocecum, thyroid gland, pituitary gland, salivary gland, adrenal gland, testis, ovary and brain.
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  Peptide ligand-binding receptors (R-HSA-375276)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypogonadotropic hypogonadism 3 with or without anosmia	DIS06PTW	Definitive	Autosomal dominant	[1]
Hypogonadotropic hypogonadism	DIS8JSKR	Supportive	Autosomal dominant	[2]
Kallmann syndrome	DISO3HDG	Supportive	Autosomal dominant	[2]
Septooptic dysplasia	DISXYR1H	Supportive	Autosomal dominant	[3]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methamphetamine	DMPM4SK	Approved	Prokineticin receptor 2 (PROKR2) affects the response to substance of Methamphetamine.	[7]

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 Prokineticin receptor 2 (PROKR2).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Prokineticin receptor 2 (PROKR2).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Prokineticin receptor 2 (PROKR2).	[5]

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] Loss-of-function mutations in the genes encoding prokineticin-2 or prokineticin receptor-2 cause autosomal recessive Kallmann syndrome. J Clin Endocrinol Metab. 2008 Oct;93(10):4113-8. doi: 10.1210/jc.2008-0958. Epub 2008 Aug 5.
• [3] Genetic overlap in Kallmann syndrome, combined pituitary hormone deficiency, and septo-optic dysplasia. J Clin Endocrinol Metab. 2012 Apr;97(4):E694-9. doi: 10.1210/jc.2011-2938. Epub 2012 Feb 8.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] PROKR2 is associated with methamphetamine dependence in the Japanese population. Prog Neuropsychopharmacol Biol Psychiatry. 2010 Aug 16;34(6):1033-6. doi: 10.1016/j.pnpbp.2010.05.018. Epub 2010 May 24.