Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5HUR28)

• DOT Name: Carboxypeptidase Z (CPZ)
• Synonyms: CPZ; EC 3.4.17.-
• Gene Name: CPZ
• Related Disease:
  Anxiety
  Anxiety disorder
  Neoplasm
  Methicillin-resistant staphylococci infection
  Neuroblastoma
  Psychotic disorder
• UniProt ID: CBPZ_HUMAN
• EC Number: 3.4.17.-
• Pfam ID: PF13620 ; PF01392 ; PF00246
• Sequence:
  MPPPLPLLLLTVLVVAAARPGCEFERNPAGECHRPPAADSATCVDLQLRTCSDAAYNHTT
  FPNLLQHRSWEVVEASSEYILLSVLHQLLEGQCNPDLRLLGCAVLAPRCEGGWVRRPCRH
  ICEGLREVCQPAFDAIDMAWPYFLDCHRYFTREDEGCYDPLEKLRGGLEADEALPSGLPP
  TFIRFSHHSYAQMVRVLRRTASRCAHVARTYSIGRSFDGRELLVIEFSSRPGQHELMEPE
  VKLIGNIHGNEVAGREMLIYLAQYLCSEYLLGNPRIQRLLNTTRIHLLPSMNPDGYEVAA
  AEGAGYNGWTSGRQNAQNLDLNRNFPDLTSEYYRLAETRGARSDHIPIPQHYWWGKVAPE
  TKAIMKWMQTIPFVLSASLHGGDLVVSYPFDFSKHPQEEKMFSPTPDEKMFKLLSRAYAD
  VHPMMMDRSENRCGGNFLKRGSIINGADWYSFTGGMSDFNYLHTNCFEITVELGCVKFPP
  EEALYILWQHNKESLLNFVETVHRGIKGVVTDKFGKPVKNARISVKGIRHDITTAPDGDY
  WRLLPPGIHIVIAQAPGYAKVIKKVIIPARMKRAGRVDFILQPLGMGPKNFIHGLRRTGP
  HDPLGGASSLGEATEPDPLRARRQPSADGSKPWWWSYFTSLSTHRPRWLLKY
• Function: Cleaves substrates with C-terminal arginine residues. Probably modulates the Wnt signaling pathway, by cleaving some undefined protein. May play a role in cleavage during prohormone processing.
• Tissue Specificity: In placenta, it is present within invasive trophoblasts and in the surrounding extracellular space. Also present in amnion cells, but is not readily apparent in the extracellular matrix of this cell type. Present in normal pituitary gland and neoplastic pituitary gland (especially POMC-, GH- and PRL-producing adenomas) (at protein level). Widely expressed.

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anxiety	DISIJDBA	Definitive	Altered Expression	[1]
Anxiety disorder	DISBI2BT	Definitive	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Methicillin-resistant staphylococci infection	DIS6DRDZ	moderate	Biomarker	[3]
Neuroblastoma	DISVZBI4	Limited	Genetic Variation	[4]
Psychotic disorder	DIS4UQOT	Limited	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Carboxypeptidase Z (CPZ).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Carboxypeptidase Z (CPZ).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Carboxypeptidase Z (CPZ).	[8]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Carboxypeptidase Z (CPZ).	[9]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Carboxypeptidase Z (CPZ).	[10]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Carboxypeptidase Z (CPZ).	[11]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of Carboxypeptidase Z (CPZ).	[12]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of Carboxypeptidase Z (CPZ).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Carboxypeptidase Z (CPZ).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Carboxypeptidase Z (CPZ).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Carboxypeptidase Z (CPZ).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Carboxypeptidase Z (CPZ).	[16]

References

• [1] Long lasting behavioural effects on cuprizone fed mice after neurotoxicant withdrawal.Behav Brain Res. 2019 May 2;363:38-44. doi: 10.1016/j.bbr.2019.01.036. Epub 2019 Jan 28.
• [2] A novel tumor targeting drug carrier for optical imaging and therapy.Theranostics. 2014 Mar 24;4(6):642-59. doi: 10.7150/thno.8527. eCollection 2014.
• [3] Near-infrared-triggered antibacterial and antifungal photodynamic therapy based on lanthanide-doped upconversion nanoparticles.Nanoscale. 2018 Aug 23;10(33):15485-15495. doi: 10.1039/c8nr01967c.
• [4] RSRC1 and CPZ gene polymorphisms with neuroblastoma susceptibility in Chinese children.Gene. 2018 Jul 1;662:83-87. doi: 10.1016/j.gene.2018.04.015. Epub 2018 Apr 10.
• [5] The antipsychotic agent chlorpromazine induces autophagic cell death by inhibiting the Akt/mTOR pathway in human U-87MG glioma cells.Carcinogenesis. 2013 Sep;34(9):2080-9. doi: 10.1093/carcin/bgt169. Epub 2013 May 20.
• [6] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [7] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [8] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [11] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [12] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [13] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [14] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [15] 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.
• [16] 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.
• [17] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.