Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1NYNNW)

• DOT Name: Parkin coregulated gene protein (PACRG)
• Synonyms: Molecular chaperone/chaperonin-binding protein; PARK2 coregulated gene protein
• Gene Name: PACRG
• Related Disease:
  Acute lymphocytic leukaemia
  Blast phase chronic myelogenous leukemia, BCR-ABL1 positive
  Clear cell renal carcinoma
  Leukemia
  Neoplasm
  Nephronophthisis
  Neuroblastoma
  Paratyphoid fever
  Parkinson disease
  Typhoid fever
  Leprosy
  Parkinsonian disorder
  Tuberculosis
• UniProt ID: PACRG_HUMAN
• PDB ID: 6NDU; 6NEP; 6UCC; 7UNG; 8J07
• Pfam ID: PF10274
• Sequence:
  MVAEKETLSLNKCPDKMPKRTKLLAQQPLPVHQPHSLVSEGFTVKAMMKNSVVRGPPAAG
  AFKERPTKPTAFRKFYERGDFPIALEHDSKGNKIAWKVEIEKLDYHHYLPLFFDGLCEMT
  FPYEFFARQGIHDMLEHGGNKILPVLPQLIIPIKNALNLRNRQVICVTLKVLQHLVVSAE
  MVGKALVPYYRQILPVLNIFKNMNGSYSLPRLECSGAIMARCNLDHLGSSDPPTSASQVA
  EIIVNSGDGIDYSQQKRENIGDLIQETLEAFERYGGENAFINIKYVVPTYESCLLN
• Function: Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating. Suppresses cell death induced by accumulation of unfolded Pael receptor (Pael-R, a substrate of Parkin). Facilitates the formation of inclusions consisting of Pael-R, molecular chaperones, protein degradation molecules and itself when proteasome is inhibited. May play an important role in the formation of Lewy bodies and protection of dopaminergic neurons against Parkinson disease.
• Tissue Specificity: Expressed in all immune tissues, spleen, lymph nodes, thymus, tonsils, leukocyte and bone marrow. Expressed also in heart, brain, skeletal muscle, kidney, lung and pancreas. Expressed in primary Schwann cells and very weakly by monocyte-derived macrophages the primary host cells of Mycobacterium leprae, the causative agent of leprosy. Component of Lewy bodies, intraneuronal inclusions found in the brain of Parkinson disease patients.

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[1]
Blast phase chronic myelogenous leukemia, BCR-ABL1 positive	DIS3KLUX	Strong	Genetic Variation	[1]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[2]
Leukemia	DISNAKFL	Strong	Genetic Variation	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Nephronophthisis	DISXU4HY	Strong	Biomarker	[3]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[1]
Paratyphoid fever	DISUPPJ5	Strong	Genetic Variation	[4]
Parkinson disease	DISQVHKL	Strong	Biomarker	[5]
Typhoid fever	DISP3NHR	Strong	Genetic Variation	[4]
Leprosy	DISAA4UI	Limited	Biomarker	[6]
Parkinsonian disorder	DISHGY45	Limited	Posttranslational Modification	[7]
Tuberculosis	DIS2YIMD	Limited	Genetic Variation	[8]

4 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 Parkin coregulated gene protein (PACRG).	[9]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Parkin coregulated gene protein (PACRG).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Parkin coregulated gene protein (PACRG).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Parkin coregulated gene protein (PACRG).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Parkin coregulated gene protein (PACRG).	[12]

References

• [1] Abnormal methylation of the common PARK2 and PACRG promoter is associated with downregulation of gene expression in acute lymphoblastic leukemia and chronic myeloid leukemia.Int J Cancer. 2006 Apr 15;118(8):1945-53. doi: 10.1002/ijc.21584.
• [2] PARK2 and PACRG are commonly downregulated in clear-cell renal cell carcinoma and are associated with aggressive disease and poor clinical outcome.Genes Chromosomes Cancer. 2013 Mar;52(3):265-73. doi: 10.1002/gcc.22026. Epub 2012 Nov 2.
• [3] Proteomic analysis of isolated chlamydomonas centrioles reveals orthologs of ciliary-disease genes.Curr Biol. 2005 Jun 21;15(12):1090-8. doi: 10.1016/j.cub.2005.05.024.
• [4] PARK2/PACRG polymorphisms and susceptibility to typhoid and paratyphoid fever.Clin Exp Immunol. 2006 Jun;144(3):425-31. doi: 10.1111/j.1365-2249.2006.03087.x.
• [5] Parkin Co-Regulated Gene (PACRG) is regulated by the ubiquitin-proteasomal system and is present in the pathological features of Parkinsonian diseases.Neurobiol Dis. 2007 Aug;27(2):238-47. doi: 10.1016/j.nbd.2007.04.014. Epub 2007 May 18.
• [6] Linkage disequilibrium pattern and age-at-diagnosis are critical for replicating genetic associations across ethnic groups in leprosy.Hum Genet. 2013 Jan;132(1):107-16. doi: 10.1007/s00439-012-1227-6. Epub 2012 Sep 29.
• [7] Deletion of the parkin and PACRG gene promoter in early-onset parkinsonism.Hum Mutat. 2007 Jan;28(1):27-32. doi: 10.1002/humu.20436.
• [8] [Study of the polymorphic markers--the PARK2 and PACRG genes due to the incidence of pulmonary tuberculosis in two districts of the Republic of Tyva].Probl Tuberk Bolezn Legk. 2007;(7):27-9.
• [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] 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.
• [11] 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.
• [12] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [13] 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.