Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7M23Z9)

• DOT Name: Collagen alpha-1(XXV) chain (COL25A1)
• Synonyms: Alzheimer disease amyloid-associated protein; AMY; CLAC-P
• Gene Name: COL25A1
• Related Disease:
  Periodontitis
  Amyloidosis
  Atrial conduction disease
  Dementia
  Fibrosis of extraocular muscles, congenital, 5
  Hepatocellular carcinoma
  Obesity
  Duane retraction syndrome
  Ptosis, hereditary congenital, 1
  Alzheimer disease
  Phenylketonuria
  Substance dependence
• UniProt ID: COPA1_HUMAN
• Pfam ID: PF01391
• Sequence:
  MLLKKHAGKGGGREPRSEDPTPAEQHCARTMPPCAVLAALLSVVAVVSCLYLGVKTNDLQ
  ARIAALESAKGAPSIHLLPDTLDHLKTMVQEKVERLLAQKSYEHMAKIRIAREAPSECNC
  PAGPPGKRGKRGRRGESGPPGQPGPQGPPGPKGDKGEQGDQGPRMVFPKINHGFLSADQQ
  LIKRRLIKGDQGQAGPPGPPGPPGPRGPPGDTGKDGPRGMPGVPGEPGKPGEQGLMGPLG
  PPGQKGSIGAPGIPGMNGQKGEPGLPGAVGQNGIPGPKGEPGEQGEKGDAGENGPKGDTG
  EKGDPGSSAAGIKGEPGESGRPGQKGEPGLPGLPGLPGIKGEPGFIGPQGEPGLPGLPGT
  KGERGEAGPPGRGERGEPGAPGPKGKQGESGTRGPKGSKGDRGEKGDSGAQGPRGPPGQK
  GDQGATEIIDYNGNLHEALQRITTLTVTGPPGPPGPQGLQGPKGEQGSPGIPGMDGEQGL
  KGSKGDMGDPGMTGEKGGIGLPGLPGANGMKGEKGDSGMPGPQGPSIIGPPGPPGPHGPP
  GPMGPHGLPGPKGTDGPMGPHGPAGPKGERGEKGAMGEPGPRGPYGLPGKDGEPGLDGFP
  GPRGEKGDLGEKGEKGFRGVKGEKGEPGQPGLDGLDAPCQLGPDGLPMPGCWQK
• Function: Inhibits fibrillization of amyloid-beta peptide during the elongation phase. Has also been shown to assemble amyloid fibrils into protease-resistant aggregates. Binds heparin.
• Tissue Specificity: Expressed predominantly in brain. Deposited preferentially in primitive or neuritic amyloid plaques which are typical of Alzheimer disease.
• KEGG Pathway: Protein digestion and absorption (hsa04974)
• Reactome Pathway:
  Collagen biosynthesis and modifying enzymes (R-HSA-1650814)
  Collagen chain trimerization (R-HSA-8948216)
  Collagen degradation (R-HSA-1442490)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Periodontitis	DISI9JOI	Definitive	Biomarker	[1]
Amyloidosis	DISHTAI2	Strong	Biomarker	[2]
Atrial conduction disease	DIS0QP8G	Strong	Biomarker	[3]
Dementia	DISXL1WY	Strong	Biomarker	[2]
Fibrosis of extraocular muscles, congenital, 5	DISCP5U8	Strong	Autosomal recessive	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[4]
Obesity	DIS47Y1K	Strong	Biomarker	[5]
Duane retraction syndrome	DISOEBK2	moderate	Genetic Variation	[6]
Ptosis, hereditary congenital, 1	DISEV6XS	Supportive	Autosomal dominant	[7]
Alzheimer disease	DISF8S70	Limited	Altered Expression	[8]
Phenylketonuria	DISCU56J	Limited	Genetic Variation	[9]
Substance dependence	DISDRAAR	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Collagen alpha-1(XXV) chain (COL25A1).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Collagen alpha-1(XXV) chain (COL25A1).	[11]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Collagen alpha-1(XXV) chain (COL25A1).	[13]

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 decreases the methylation of Collagen alpha-1(XXV) chain (COL25A1).	[12]

References

• [1] Complement-Dependent Mechanisms and Interventions in Periodontal Disease.Front Immunol. 2019 Mar 12;10:406. doi: 10.3389/fimmu.2019.00406. eCollection 2019.
• [2] Metabolic correlates of reserve and resilience in MCI due to Alzheimer's Disease (AD).Alzheimers Res Ther. 2018 Apr 3;10(1):35. doi: 10.1186/s13195-018-0366-y.
• [3] Recessive mutations in COL25A1 are a cause of congenital cranial dysinnervation disorder. Am J Hum Genet. 2015 Jan 8;96(1):147-52. doi: 10.1016/j.ajhg.2014.11.006. Epub 2014 Dec 11.
• [4] A restriction endonuclease assay for expression of human alpha-amylase isozymes.Clin Chim Acta. 2002 Aug;322(1-2):113-6. doi: 10.1016/s0009-8981(02)00161-4.
• [5] Alterations in circadian and meal-induced gut peptide levels in lean and obese rats.Exp Biol Med (Maywood). 2017 Dec;242(18):1786-1794. doi: 10.1177/1535370217732041. Epub 2017 Sep 15.
• [6] Exotropic Duane syndrome with synergistic divergence and no mutations in COL25A1.J AAPOS. 2016 Dec;20(6):542-544.e2. doi: 10.1016/j.jaapos.2016.05.019. Epub 2016 Sep 20.
• [7] Recessive COL25A1 mutations cause isolated congenital ptosis or exotropic Duane syndrome with synergistic divergence. J AAPOS. 2015 Oct;19(5):463-5. doi: 10.1016/j.jaapos.2015.04.011.
• [8] Association of COL25A1 with comorbid antisocial personality disorder and substance dependence.Biol Psychiatry. 2012 Apr 15;71(8):733-40. doi: 10.1016/j.biopsych.2011.12.011. Epub 2012 Jan 31.
• [9] A maximum likelihood map of chromosome 1.Am J Hum Genet. 1979 Nov;31(6):680-96.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [12] 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.
• [13] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.