Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT43RD23)

• DOT Name: Carboxypeptidase A6 (CPA6)
• Synonyms: EC 3.4.17.-
• Gene Name: CPA6
• Related Disease:
  Hepatocellular carcinoma
  Non-insulin dependent diabetes
  Childhood epilepsy with centrotemporal spikes
  Duane retraction syndrome
  Osteoarthritis
  Focal epilepsy
  Neurodevelopmental disorder
  Temporal lobe epilepsy
  Obsolete benign familial mesial temporal lobe epilepsy
  Obsolete familial mesial temporal lobe epilepsy with febrile seizures
  Epilepsy
  Familial temporal lobe epilepsy 5
  Febrile seizures, familial, 11
  Juvenile myoclonic epilepsy
• UniProt ID: CBPA6_HUMAN
• EC Number: 3.4.17.-
• Pfam ID: PF00246 ; PF02244
• Sequence:
  MKCLGKRRGQAAAFLPLCWLFLKILQPGHSHLYNNRYAGDKVIRFIPKTEEEAYALKKIS
  YQLKVDLWQPSSISYVSEGTVTDVHIPQNGSRALLAFLQEANIQYKVLIEDLQKTLEKGS
  SLHTQRNRRSLSGYNYEVYHSLEEIQNWMHHLNKTHSGLIHMFSIGRSYEGRSLFILKLG
  RRSRLKRAVWIDCGIHAREWIGPAFCQWFVKEALLTYKSDPAMRKMLNHLYFYIMPVFNV
  DGYHFSWTNDRFWRKTRSRNSRFRCRGVDANRNWKVKWCDEGASMHPCDDTYCGPFPESE
  PEVKAVANFLRKHRKHIRAYLSFHAYAQMLLYPYSYKYATIPNFRCVESAAYKAVNALQS
  VYGVRYRYGPASTTLYVSSGSSMDWAYKNGIPYAFAFELRDTGYFGFLLPEMLIKPTCTE
  TMLAVKNITMHLLKKCP
• Function: May be involved in the proteolytic inactivation of enkephalins and neurotensin in some brain areas. May convert inactive angiotensin I into the biologically active angiotensin II. Releases a C-terminal amino acid, with preference for large hydrophobic C-terminal amino acids and shows only very weak activity toward small amino acids and histidine.
• Tissue Specificity: Expressed in the hippocampus, nucleus raphe, and cortex.

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Biomarker	[2]
Childhood epilepsy with centrotemporal spikes	DISKT2L5	Strong	CausalMutation	[3]
Duane retraction syndrome	DISOEBK2	Strong	Biomarker	[4]
Osteoarthritis	DIS05URM	Strong	Biomarker	[5]
Focal epilepsy	DIS4LY5L	moderate	Posttranslational Modification	[6]
Neurodevelopmental disorder	DIS372XH	moderate	Biomarker	[4]
Temporal lobe epilepsy	DISNOPXX	moderate	Genetic Variation	[7]
Obsolete benign familial mesial temporal lobe epilepsy	DISV7PWN	Supportive	Autosomal dominant	[8]
Obsolete familial mesial temporal lobe epilepsy with febrile seizures	DIS9PIC7	Supportive	Autosomal dominant	[8]
Epilepsy	DISBB28L	Disputed	Autosomal recessive	[9]
Familial temporal lobe epilepsy 5	DIS8GCK6	Limited	Autosomal dominant	[10]
Febrile seizures, familial, 11	DISMTFHO	Limited	Autosomal recessive	[10]
Juvenile myoclonic epilepsy	DISYXV1N	Limited	Genetic Variation	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
NAPQI	DM8F5LR	Investigative	Carboxypeptidase A6 (CPA6) affects the response to substance of NAPQI.	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Carboxypeptidase A6 (CPA6).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Carboxypeptidase A6 (CPA6).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Carboxypeptidase A6 (CPA6).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Carboxypeptidase A6 (CPA6).	[15]
PEITC	DMOMN31	Phase 2	PEITC increases the expression of Carboxypeptidase A6 (CPA6).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Carboxypeptidase A6 (CPA6).	[17]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Carboxypeptidase A6 (CPA6).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Carboxypeptidase A6 (CPA6).	[13]

References

• [1] Carboxypeptidase A6 Promotes the Proliferation and Migration of Hepatocellular Carcinoma by Up-regulating AKT Signaling Pathway.Curr Med Sci. 2019 Oct;39(5):727-733. doi: 10.1007/s11596-019-2098-z. Epub 2019 Oct 14.
• [2] Genetic Variants in CPA6 and PRPF31 Are Associated With Variation in Response to Metformin in Individuals With Type 2 Diabetes.Diabetes. 2018 Jul;67(7):1428-1440. doi: 10.2337/db17-1164. Epub 2018 Apr 12.
• [3] Exome-wide analysis of mutational burden in patients with typical and atypical Rolandic epilepsy.Eur J Hum Genet. 2018 Feb;26(2):258-264. doi: 10.1038/s41431-017-0034-x. Epub 2018 Jan 22.
• [4] Substrate specificity of human carboxypeptidase A6.J Biol Chem. 2010 Dec 3;285(49):38234-42. doi: 10.1074/jbc.M110.158626. Epub 2010 Sep 20.
• [5] Brief report: carboxypeptidase B serves as a protective mediator in osteoarthritis.Arthritis Rheumatol. 2014 Jan;66(1):101-106. doi: 10.1002/art.38213.
• [6] Increased CPA6 promoter methylation in focal epilepsy and in febrile seizures.Epilepsy Res. 2014 Jan;108(1):144-8. doi: 10.1016/j.eplepsyres.2013.10.007. Epub 2013 Oct 24.
• [7] Novel carboxypeptidase A6 (CPA6) mutations identified in patients with juvenile myoclonic and generalized epilepsy.PLoS One. 2015 Apr 13;10(4):e0123180. doi: 10.1371/journal.pone.0123180. eCollection 2015.
• [8] Carboxypeptidase A6 gene (CPA6) mutations in a recessive familial form of febrile seizures and temporal lobe epilepsy and in sporadic temporal lobe epilepsy. Hum Mutat. 2012 Jan;33(1):124-35. doi: 10.1002/humu.21613. Epub 2011 Oct 31.
• [9] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [10] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [11] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [12] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [13] 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.
• [14] 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.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells. Environ Toxicol. 2017 Jan;32(1):176-187.
• [17] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [18] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [19] Acetaminophen-NAPQI hepatotoxicity: a cell line model system genome-wide association study. Toxicol Sci. 2011 Mar;120(1):33-41. doi: 10.1093/toxsci/kfq375. Epub 2010 Dec 22.