Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJR9436)

• DOT Name: Cytosolic non-specific dipeptidase (CNDP2)
• Synonyms: EC 3.4.13.18; CNDP dipeptidase 2; Glutamate carboxypeptidase-like protein 1; Peptidase A; Threonyl dipeptidase
• Gene Name: CNDP2
• Related Disease:
  Acute myelogenous leukaemia
  Nephropathy
  Acute lymphocytic leukaemia
  Childhood acute lymphoblastic leukemia
  Colon cancer
  Colon carcinoma
  Epithelial ovarian cancer
  Fatty liver disease
  Gastric cancer
  Gastric neoplasm
  Gilbert syndrome
  Hepatocellular carcinoma
  Laryngeal carcinoma
  leukaemia
  Leukemia
  Mood disorder
  Neoplasm
  Non-small-cell lung cancer
  Obesity
  Ovarian cancer
  Ovarian neoplasm
  Pancreatic cancer
  Refractive error
  Stomach cancer
  Non-insulin dependent diabetes
• UniProt ID: CNDP2_HUMAN
• PDB ID: 4RUH
• EC Number: 3.4.13.18
• Pfam ID: PF07687 ; PF01546
• Sequence:
  MAALTTLFKYIDENQDRYIKKLAKWVAIQSVSAWPEKRGEIRRMMEVAAADVKQLGGSVE
  LVDIGKQKLPDGSEIPLPPILLGRLGSDPQKKTVCIYGHLDVQPAALEDGWDSEPFTLVE
  RDGKLYGRGSTDDKGPVAGWINALEAYQKTGQEIPVNVRFCLEGMEESGSEGLDELIFAR
  KDTFFKDVDYVCISDNYWLGKKKPCITYGLRGICYFFIEVECSNKDLHSGVYGGSVHEAM
  TDLILLMGSLVDKRGNILIPGINEAVAAVTEEEHKLYDDIDFDIEEFAKDVGAQILLHSH
  KKDILMHRWRYPSLSLHGIEGAFSGSGAKTVIPRKVVGKFSIRLVPNMTPEVVGEQVTSY
  LTKKFAELRSPNEFKVYMGHGGKPWVSDFSHPHYLAGRRAMKTVFGVEPDLTREGGSIPV
  TLTFQEATGKNVMLLPVGSADDGAHSQNEKLNRYNYIEGTKMLAAYLYEVSQLKD
• Function: Catalyzes the peptide bond hydrolysis in dipeptides, displaying a non-redundant activity toward threonyl dipeptides. Mediates threonyl dipeptide catabolism in a tissue-specific way. Has high dipeptidase activity toward cysteinylglycine, an intermediate metabolite in glutathione metabolism. Metabolizes N-lactoyl-amino acids, both through hydrolysis to form lactic acid and amino acids, as well as through their formation by reverse proteolysis. Plays a role in the regulation of cell cycle arrest and apoptosis.
• Tissue Specificity: .Ubiquitously expressed with higher levels in kidney and liver (at protein level). Expressed in peripheral blood leukocytes . Expressed in gastric mucosa and down-regulated in gastric cancer mucosal tissues (at protein level) .; [Isoform 2]: Broadly expressed in fetal tissues. Expressed in adult liver and placenta.
• KEGG Pathway:
  Arginine and proline metabolism (hsa00330)
  Histidine metabolism (hsa00340)
  beta-Alanine metabolism (hsa00410)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Paracetamol ADME (R-HSA-9753281)
  Glutathione synthesis and recycling (R-HSA-174403)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Genetic Variation	[1]
Nephropathy	DISXWP4P	Definitive	Biomarker	[2]
Acute lymphocytic leukaemia	DISPX75S	Strong	Genetic Variation	[3]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Genetic Variation	[3]
Colon cancer	DISVC52G	Strong	Biomarker	[4]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[4]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[5]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[6]
Gastric cancer	DISXGOUK	Strong	Biomarker	[7]
Gastric neoplasm	DISOKN4Y	Strong	Altered Expression	[7]
Gilbert syndrome	DISMUZF4	Strong	Genetic Variation	[8]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[9]
Laryngeal carcinoma	DISNHCIV	Strong	Biomarker	[10]
leukaemia	DISS7D1V	Strong	Altered Expression	[11]
Leukemia	DISNAKFL	Strong	Altered Expression	[11]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[12]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[13]
Obesity	DIS47Y1K	Strong	Genetic Variation	[14]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[5]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[5]
Pancreatic cancer	DISJC981	Strong	Biomarker	[15]
Refractive error	DISWNEQ1	Strong	Genetic Variation	[16]
Stomach cancer	DISKIJSX	Strong	Biomarker	[7]
Non-insulin dependent diabetes	DISK1O5Z	moderate	Genetic Variation	[17]

3 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 Cytosolic non-specific dipeptidase (CNDP2).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Cytosolic non-specific dipeptidase (CNDP2).	[26]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Cytosolic non-specific dipeptidase (CNDP2).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Cytosolic non-specific dipeptidase (CNDP2).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cytosolic non-specific dipeptidase (CNDP2).	[20]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cytosolic non-specific dipeptidase (CNDP2).	[21]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Cytosolic non-specific dipeptidase (CNDP2).	[22]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Cytosolic non-specific dipeptidase (CNDP2).	[23]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Cytosolic non-specific dipeptidase (CNDP2).	[24]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Cytosolic non-specific dipeptidase (CNDP2).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Cytosolic non-specific dipeptidase (CNDP2).	[28]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Cytosolic non-specific dipeptidase (CNDP2).	[29]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Cytosolic non-specific dipeptidase (CNDP2).	[30]

References

• [1] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [2] Common variants in CNDP1 and CNDP2, and risk of nephropathy in type 2 diabetes.Diabetologia. 2011 Sep;54(9):2295-302. doi: 10.1007/s00125-011-2178-5. Epub 2011 May 15.
• [3] Oligomeric interface modulation causes misregulation of purine 5-nucleotidase in relapsed leukemia.BMC Biol. 2016 Oct 19;14(1):91. doi: 10.1186/s12915-016-0313-y.
• [4] Up-regulation of CNDP2 facilitates the proliferation of colon cancer.BMC Gastroenterol. 2014 May 21;14:96. doi: 10.1186/1471-230X-14-96.
• [5] CNDP2 Acts as an Activator for Human Ovarian Cancer Growth and Metastasis via the PI3K/AKT Pathway.Technol Cancer Res Treat. 2019 Jan 1;18:1533033819874773. doi: 10.1177/1533033819874773.
• [6] Characterization of chemically induced liver injuries using gene co-expression modules.PLoS One. 2014 Sep 16;9(9):e107230. doi: 10.1371/journal.pone.0107230. eCollection 2014.
• [7] Underexpressed CNDP2 participates in gastric cancer growth inhibition through activating the MAPK signaling pathway.Mol Med. 2014 Mar 13;20(1):17-28. doi: 10.2119/molmed.2013.00102.
• [8] Contribution of two missense mutations (G71R and Y486D) of the bilirubin UDP glycosyltransferase (UGT1A1) gene to phenotypes of Gilbert's syndrome and Crigler-Najjar syndrome type II.Biochim Biophys Acta. 1998 Apr 28;1406(3):267-73. doi: 10.1016/s0925-4439(98)00013-1.
• [9] Identification of carboxypeptidase of glutamate like-B as a candidate suppressor in cell growth and metastasis in human hepatocellular carcinoma.Clin Cancer Res. 2006 Nov 15;12(22):6617-25. doi: 10.1158/1078-0432.CCR-06-1307.
• [10] Quantitative proteomics approach to screening of potential diagnostic and therapeutic targets for laryngeal carcinoma.PLoS One. 2014 Feb 27;9(2):e90181. doi: 10.1371/journal.pone.0090181. eCollection 2014.
• [11] Cytotoxic activity of gemcitabine and correlation with expression profile of drug-related genes in human lymphoid cells.Pharmacol Res. 2007 Apr;55(4):343-9. doi: 10.1016/j.phrs.2007.01.003. Epub 2007 Jan 16.
• [12] Search for biological/genetic markers in a long-term epidemiological and morbid risk study of affective disorders.J Psychiatr Res. 1984;18(4):425-45. doi: 10.1016/0022-3956(84)90031-1.
• [13] 5'-nucleotidase cN-II emerges as a new predictive biomarker of response to gemcitabine/platinum combination chemotherapy in non-small cell lung cancer.Oncotarget. 2018 Feb 16;9(23):16437-16450. doi: 10.18632/oncotarget.24505. eCollection 2018 Mar 27.
• [14] The Combined Effects of Genetic Variation in the CNDP1 and CNDP2 Genes and Dietary Carbohydrate and Carotene Intake on Obesity Risk.J Nutrigenet Nutrigenomics. 2017;10(5-6):146-154. doi: 10.1159/000485798. Epub 2018 Jan 17.
• [15] Loss of 18q22.3 involving the carboxypeptidase of glutamate-like gene is associated with poor prognosis in resected pancreatic cancer.Clin Cancer Res. 2012 Jan 15;18(2):524-33. doi: 10.1158/1078-0432.CCR-11-1903. Epub 2011 Nov 29.
• [16] Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia.Nat Genet. 2013 Mar;45(3):314-8. doi: 10.1038/ng.2554. Epub 2013 Feb 10.
• [17] The influence of a single nucleotide polymorphism within CNDP1 on susceptibility to diabetic nephropathy in Japanese women with type 2 diabetes.PLoS One. 2013;8(1):e54064. doi: 10.1371/journal.pone.0054064. Epub 2013 Jan 16.
• [18] 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.
• [19] Proteomics investigations of drug-induced hepatotoxicity in HepG2 cells. Toxicol Sci. 2011 Mar;120(1):109-22.
• [20] 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.
• [21] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [22] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [23] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [24] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [25] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [26] 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.
• [27] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [28] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [29] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [30] Evaluation of an in vitro model of androgen ablation and identification of the androgen responsive proteome in LNCaP cells. Proteomics. 2007 Jan;7(1):47-63.