Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOYSQG7)

• DOT Name: Beta-Ala-His dipeptidase (CNDP1)
• Synonyms: EC 3.4.13.20; CNDP dipeptidase 1; Carnosine dipeptidase 1; Glutamate carboxypeptidase-like protein 2; Serum carnosinase
• Gene Name: CNDP1
• Related Disease:
  Hepatocellular carcinoma
  Advanced cancer
  Cardiovascular disease
  Chronic renal failure
  Cyclic hematopoiesis
  End-stage renal disease
  Glioblastoma multiforme
  Glomerulonephritis
  Intellectual disability
  Kidney failure
  Late-onset Parkinson disease
  Nephropathy
  Obesity
  Type-1/2 diabetes
  Nervous system disease
  Hyperglycemia
• UniProt ID: CNDP1_HUMAN
• PDB ID: 3DLJ
• EC Number: 3.4.13.20
• Pfam ID: PF07687 ; PF01546
• Sequence:
  MDPKLGRMAASLLAVLLLLLERGMFSSPSPPPALLEKVFQYIDLHQDEFVQTLKEWVAIE
  SDSVQPVPRFRQELFRMMAVAADTLQRLGARVASVDMGPQQLPDGQSLPIPPVILAELGS
  DPTKGTVCFYGHLDVQPADRGDGWLTDPYVLTEVDGKLYGRGATDNKGPVLAWINAVSAF
  RALEQDLPVNIKFIIEGMEEAGSVALEELVEKEKDRFFSGVDYIVISDNLWISQRKPAIT
  YGTRGNSYFMVEVKCRDQDFHSGTFGGILHEPMADLVALLGSLVDSSGHILVPGIYDEVV
  PLTEEEINTYKAIHLDLEEYRNSSRVEKFLFDTKEEILMHLWRYPSLSIHGIEGAFDEPG
  TKTVIPGRVIGKFSIRLVPHMNVSAVEKQVTRHLEDVFSKRNSSNKMVVSMTLGLHPWIA
  NIDDTQYLAAKRAIRTVFGTEPDMIRDGSTIPIAKMFQEIVHKSVVLIPLGAVDDGEHSQ
  NEKINRWNYIEGTKLFAAFFLEMAQLH
• Function: Catalyzes the peptide bond hydrolysis in Xaa-His dipeptides, displaying the highest activity toward carnosine (beta-alanyl-L-histidine) and anserine (beta-alanyl-3-methyl-histidine).
• Tissue Specificity: Found in serum and adult nervous central system. Absent in serum from patients with homocarnosinosis.
• KEGG Pathway:
  Arginine and proline metabolism (hsa00330)
  Histidine metabolism (hsa00340)
  beta-Alanine metabolism (hsa00410)
  Metabolic pathways (hsa01100)
• BioCyc Pathway: MetaCyc:HS07681-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[3]
Chronic renal failure	DISGG7K6	Strong	Biomarker	[4]
Cyclic hematopoiesis	DISQQOM4	Strong	Biomarker	[5]
End-stage renal disease	DISXA7GG	Strong	Biomarker	[4]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[6]
Glomerulonephritis	DISPZIQ3	Strong	Genetic Variation	[7]
Intellectual disability	DISMBNXP	Strong	Biomarker	[8]
Kidney failure	DISOVQ9P	Strong	Biomarker	[4]
Late-onset Parkinson disease	DIS9IOUI	Strong	Genetic Variation	[3]
Nephropathy	DISXWP4P	Strong	Biomarker	[9]
Obesity	DIS47Y1K	Strong	Genetic Variation	[10]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[11]
Nervous system disease	DISJ7GGT	moderate	Altered Expression	[2]
Hyperglycemia	DIS0BZB5	Limited	Altered Expression	[12]

1 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 Beta-Ala-His dipeptidase (CNDP1).	[13]

3 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 Beta-Ala-His dipeptidase (CNDP1).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Beta-Ala-His dipeptidase (CNDP1).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Beta-Ala-His dipeptidase (CNDP1).	[16]

References

• [1] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [2] Carnosinases, their substrates and diseases.Molecules. 2014 Feb 21;19(2):2299-329. doi: 10.3390/molecules19022299.
• [3] Relationship between carnosinase gene CNDP1 leucine repeat polymorphism and the clinical outcome of Chinese PD patients.Clin Nephrol. 2010 Nov;74(5):343-5. doi: 10.5414/cnp74343.
• [4] Monoclonal Antibody RYSK173 Recognizes the Dinuclear Zn Center of Serum Carnosinase 1 (CN-1): Possible Consequences of Zn Binding for CN-1 Recognition by RYSK173.PLoS One. 2016 Jan 22;11(1):e0146831. doi: 10.1371/journal.pone.0146831. eCollection 2016.
• [5] Analysis of bilirubin UDP-glucuronosyltransferase gene mutations in an unusual Crigler-Najjar syndrome patient.Mol Med Rep. 2012 Sep;6(3):667-9. doi: 10.3892/mmr.2012.950. Epub 2012 Jun 15.
• [6] Proteins with altered levels in plasma from glioblastoma patients as revealed by iTRAQ-based quantitative proteomic analysis.PLoS One. 2012;7(9):e46153. doi: 10.1371/journal.pone.0046153. Epub 2012 Sep 28.
• [7] Carnosinase, diabetes mellitus and the potential relevance of carnosinase deficiency.J Inherit Metab Dis. 2018 Jan;41(1):39-47. doi: 10.1007/s10545-017-0099-2. Epub 2017 Oct 13.
• [8] Serum carnosinase deficiency concomitant with mental retardation.Pediatr Res. 1973 Jul;7(7):601-6. doi: 10.1203/00006450-197307000-00001.
• [9] Carnosinase concentration, activity, and CNDP1 genotype in patients with type 2 diabetes with and without nephropathy.Amino Acids. 2019 Apr;51(4):611-617. doi: 10.1007/s00726-018-02692-0. Epub 2019 Jan 4.
• [10] 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.
• [11] Detection of carnosinase-1 in urine of healthy individuals and patients with type 2 diabetes: correlation with albuminuria and renal function.Amino Acids. 2019 Jan;51(1):17-25. doi: 10.1007/s00726-018-2602-y. Epub 2018 Jun 30.
• [12] N-glycosylation of carnosinase influences protein secretion and enzyme activity: implications for hyperglycemia.Diabetes. 2010 Aug;59(8):1984-90. doi: 10.2337/db09-0868. Epub 2010 May 11.
• [13] 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.
• [14] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [15] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [16] 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.