Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ9Z6QK)

• DOT Name: Glutamate carboxypeptidase 2 (FOLH1)
• Synonyms: EC 3.4.17.21; Cell growth-inhibiting gene 27 protein; Folate hydrolase 1; Folylpoly-gamma-glutamate carboxypeptidase; FGCP; Glutamate carboxypeptidase II; GCPII; Membrane glutamate carboxypeptidase; mGCP; N-acetylated-alpha-linked acidic dipeptidase I; NAALADase I; Prostate-specific membrane antigen; PSM; PSMA; Pteroylpoly-gamma-glutamate carboxypeptidase
• Gene Name: FOLH1
• UniProt ID: FOLH1_HUMAN
• PDB ID: 1Z8L ; 2C6C ; 2C6G ; 2C6P ; 2CIJ ; 2JBJ ; 2JBK ; 2OOT ; 2OR4 ; 2PVV ; 2PVW ; 2XEF ; 2XEG ; 2XEI ; 2XEJ ; 3BHX ; 3BI0 ; 3BI1 ; 3BXM ; 3D7D ; 3D7F ; 3D7G ; 3D7H ; 3IWW ; 3RBU ; 3SJE ; 3SJF ; 3SJG ; 3SJX ; 4JYW ; 4JZ0 ; 4LQG ; 4MCP ; 4MCQ ; 4MCR ; 4MCS ; 4NGM ; 4NGN ; 4NGP ; 4NGQ ; 4NGR ; 4NGS ; 4NGT ; 4OC0 ; 4OC1 ; 4OC2 ; 4OC3 ; 4OC4 ; 4OC5 ; 4OME ; 4P44 ; 4P45 ; 4P4B ; 4P4D ; 4P4E ; 4P4F ; 4P4I ; 4P4J ; 4W9Y ; 4X3R ; 5D29 ; 5ELY ; 5F09 ; 5O5R ; 5O5T ; 5O5U ; 5OF0 ; 6ETY ; 6EZ9 ; 6F5L ; 6FE5 ; 6H7Y ; 6H7Z ; 6HKJ ; 6HKZ ; 6RBC ; 6RTI ; 6S1X ; 6SGP ; 6SKH ; 7BFZ ; 8BO8 ; 8BOL ; 8BOW
• EC Number: 3.4.17.21
• Pfam ID: PF02225 ; PF04389 ; PF04253
• Sequence:
  MWNLLHETDSAVATARRPRWLCAGALVLAGGFFLLGFLFGWFIKSSNEATNITPKHNMKA
  FLDELKAENIKKFLYNFTQIPHLAGTEQNFQLAKQIQSQWKEFGLDSVELAHYDVLLSYP
  NKTHPNYISIINEDGNEIFNTSLFEPPPPGYENVSDIVPPFSAFSPQGMPEGDLVYVNYA
  RTEDFFKLERDMKINCSGKIVIARYGKVFRGNKVKNAQLAGAKGVILYSDPADYFAPGVK
  SYPDGWNLPGGGVQRGNILNLNGAGDPLTPGYPANEYAYRRGIAEAVGLPSIPVHPIGYY
  DAQKLLEKMGGSAPPDSSWRGSLKVPYNVGPGFTGNFSTQKVKMHIHSTNEVTRIYNVIG
  TLRGAVEPDRYVILGGHRDSWVFGGIDPQSGAAVVHEIVRSFGTLKKEGWRPRRTILFAS
  WDAEEFGLLGSTEWAEENSRLLQERGVAYINADSSIEGNYTLRVDCTPLMYSLVHNLTKE
  LKSPDEGFEGKSLYESWTKKSPSPEFSGMPRISKLGSGNDFEVFFQRLGIASGRARYTKN
  WETNKFSGYPLYHSVYETYELVEKFYDPMFKYHLTVAQVRGGMVFELANSIVLPFDCRDY
  AVVLRKYADKIYSISMKHPQEMKTYSVSFDSLFSAVKNFTEIASKFSERLQDFDKSNPIV
  LRMMNDQLMFLERAFIDPLGLPDRPFYRHVIYAPSSHNKYAGESFPGIYDALFDIESKVD
  PSKAWGEVKRQIYVAAFTVQAAAETLSEVA
• Function: Has both folate hydrolase and N-acetylated-alpha-linked-acidic dipeptidase (NAALADase) activity. Has a preference for tri-alpha-glutamate peptides. In the intestine, required for the uptake of folate. In the brain, modulates excitatory neurotransmission through the hydrolysis of the neuropeptide, N-aceylaspartylglutamate (NAAG), thereby releasing glutamate. Involved in prostate tumor progression.; Also exhibits a dipeptidyl-peptidase IV type activity. In vitro, cleaves Gly-Pro-AMC.
• Tissue Specificity: Highly expressed in prostate epithelium. Detected in urinary bladder, kidney, testis, ovary, fallopian tube, breast, adrenal gland, liver, esophagus, stomach, small intestine, colon and brain (at protein level). Detected in the small intestine, brain, kidney, liver, spleen, colon, trachea, spinal cord and the capillary endothelium of a variety of tumors. Expressed specifically in jejunum brush border membranes. In the brain, highly expressed in the ventral striatum and brain stem. Also expressed in fetal liver and kidney. Isoform PSMA' is the most abundant form in normal prostate. Isoform PSMA-1 is the most abundant form in primary prostate tumors. Isoform PSMA-9 is specifically expressed in prostate cancer.
• KEGG Pathway:
  Alanine, aspartate and glutamate metabolism (hsa00250)
  Metabolic pathways (hsa01100)
  Vitamin digestion and absorption (hsa04977)
• Reactome Pathway: Aspartate and asparagine metabolism (R-HSA-8963693)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Pentobarbital	DMFNH7L	Approved	Glutamate carboxypeptidase 2 (FOLH1) increases the response to substance of Pentobarbital.	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Glutamate carboxypeptidase 2 (FOLH1).	[1]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Glutamate carboxypeptidase 2 (FOLH1).	[2]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Glutamate carboxypeptidase 2 (FOLH1).	[3]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Glutamate carboxypeptidase 2 (FOLH1).	[4]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Glutamate carboxypeptidase 2 (FOLH1).	[3]
ACYLINE	DM9GRTK	Phase 2	ACYLINE increases the expression of Glutamate carboxypeptidase 2 (FOLH1).	[5]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone decreases the expression of Glutamate carboxypeptidase 2 (FOLH1).	[4]
1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane	DMDJYHK	Investigative	1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane decreases the expression of Glutamate carboxypeptidase 2 (FOLH1).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Glutamate carboxypeptidase 2 (FOLH1).	[6]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
NAAG	DMFGOW0	Investigative	NAAG affects the binding of Glutamate carboxypeptidase 2 (FOLH1).	[8]

References

• [1] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [2] 1alpha,25-Dihydroxyvitamin D3 down-regulates expression of prostate specific membrane antigen in prostate cancer cells. Prostate. 2008 May 15;68(7):773-83. doi: 10.1002/pros.20739.
• [3] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [4] Characterisation of gene expression patterns in 22RV1 cells for determination of environmental androgenic/antiandrogenic compounds. J Steroid Biochem Mol Biol. 2003 Feb;84(2-3):231-8. doi: 10.1016/s0960-0760(03)00033-5.
• [5] Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Res. 2007 May 15;67(10):5033-41.
• [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] The Effects of the Organic Flame-Retardant 1,2-Dibromo-4-(1,2-dibromoethyl) Cyclohexane (TBECH) on Androgen Signaling in Human Prostate Cancer Cell Lines. J Biochem Mol Toxicol. 2016 May;30(5):239-42. doi: 10.1002/jbt.21784. Epub 2016 Jan 5.
• [8] Synthesis and biological evaluation of copper-64 radiolabeled [DUPA-6-Ahx-(NODAGA)-5-Ava-BBN(7-14)NH2], a novel bivalent targeting vector having affinity for two distinct biomarkers (GRPr/PSMA) of prostate cancer. Nucl Med Biol. 2014 Apr;41(4):355-63. doi: 10.1016/j.nucmedbio.2014.01.001. Epub 2014 Jan 10.
• [9] [Development of oral vaccine carrying GCPII gene and its role in reducing the dosage of pentobarbital in rat: a primitive research]. Zhonghua Yi Xue Za Zhi. 2004 Jul 17;84(14):1152-6.