Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0TSW09)

• DOT Name: Aromatic-L-amino-acid decarboxylase (DDC)
• Synonyms: AADC; EC 4.1.1.28; DOPA decarboxylase; DDC
• Gene Name: DDC
• Related Disease: Aromatic L-amino acid decarboxylase deficiency
• UniProt ID: DDC_HUMAN
• PDB ID: 3RBF; 3RBL; 3RCH
• EC Number: 4.1.1.28
• Pfam ID: PF00282
• Sequence:
  MNASEFRRRGKEMVDYMANYMEGIEGRQVYPDVEPGYLRPLIPAAAPQEPDTFEDIINDV
  EKIIMPGVTHWHSPYFFAYFPTASSYPAMLADMLCGAIGCIGFSWAASPACTELETVMMD
  WLGKMLELPKAFLNEKAGEGGGVIQGSASEATLVALLAARTKVIHRLQAASPELTQAAIM
  EKLVAYSSDQAHSSVERAGLIGGVKLKAIPSDGNFAMRASALQEALERDKAAGLIPFFMV
  ATLGTTTCCSFDNLLEVGPICNKEDIWLHVDAAYAGSAFICPEFRHLLNGVEFADSFNFN
  PHKWLLVNFDCSAMWVKKRTDLTGAFRLDPTYLKHSHQDSGLITDYRHWQIPLGRRFRSL
  KMWFVFRMYGVKGLQAYIRKHVQLSHEFESLVRQDPRFEICVEVILGLVCFRLKGSNKVN
  EALLQRINSAKKIHLVPCHLRDKFVLRFAICSRTVESAHVQRAWEHIKELAADVLRAERE
• Function: Catalyzes the decarboxylation of L-3,4-dihydroxyphenylalanine (DOPA) to dopamine and L-5-hydroxytryptophan to serotonin.
• Tissue Specificity: .High expression in kidney.
• KEGG Pathway:
  Tyrosine metabolism (hsa00350)
  Phenylalanine metabolism (hsa00360)
  Tryptophan metabolism (hsa00380)
  Metabolic pathways (hsa01100)
  Serotonergic sy.pse (hsa04726)
  Dopaminergic sy.pse (hsa04728)
  Cocaine addiction (hsa05030)
  Amphetamine addiction (hsa05031)
  Alcoholism (hsa05034)
• Reactome Pathway:
  Serotonin and melatonin biosynthesis (R-HSA-209931)
  Catecholamine biosynthesis (R-HSA-209905)
• BioCyc Pathway: MetaCyc:HS05635-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Aromatic L-amino acid decarboxylase deficiency	DIS3C407	Definitive	Autosomal recessive	[1]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Dexamethasone	DMMWZET	Approved	Aromatic-L-amino-acid decarboxylase (DDC) increases the Gastrointestinal disorders ADR of Dexamethasone.	[23]
Levodopa	DMN3E57	Approved	Aromatic-L-amino-acid decarboxylase (DDC) increases the response to substance of Levodopa.	[24]

23 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 Aromatic-L-amino-acid decarboxylase (DDC).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Aromatic-L-amino-acid decarboxylase (DDC).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Aromatic-L-amino-acid decarboxylase (DDC).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Aromatic-L-amino-acid decarboxylase (DDC).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Aromatic-L-amino-acid decarboxylase (DDC).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Aromatic-L-amino-acid decarboxylase (DDC).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Aromatic-L-amino-acid decarboxylase (DDC).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Aromatic-L-amino-acid decarboxylase (DDC).	[9]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Aromatic-L-amino-acid decarboxylase (DDC).	[10]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Aromatic-L-amino-acid decarboxylase (DDC).	[11]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Aromatic-L-amino-acid decarboxylase (DDC).	[12]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Aromatic-L-amino-acid decarboxylase (DDC).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Aromatic-L-amino-acid decarboxylase (DDC).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Aromatic-L-amino-acid decarboxylase (DDC).	[9]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Aromatic-L-amino-acid decarboxylase (DDC).	[16]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Aromatic-L-amino-acid decarboxylase (DDC).	[17]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Aromatic-L-amino-acid decarboxylase (DDC).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Aromatic-L-amino-acid decarboxylase (DDC).	[3]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Aromatic-L-amino-acid decarboxylase (DDC).	[18]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Aromatic-L-amino-acid decarboxylase (DDC).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Aromatic-L-amino-acid decarboxylase (DDC).	[20]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Aromatic-L-amino-acid decarboxylase (DDC).	[21]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE decreases the activity of Aromatic-L-amino-acid decarboxylase (DDC).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Isoflurophate	DMBSK7X	Approved	Isoflurophate affects the binding of Aromatic-L-amino-acid decarboxylase (DDC).	[14]
Glyphosate	DM0AFY7	Investigative	Glyphosate affects the binding of Aromatic-L-amino-acid decarboxylase (DDC).	[14]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos affects the binding of Aromatic-L-amino-acid decarboxylase (DDC).	[14]
Paraoxon	DMN4ZKC	Investigative	Paraoxon affects the binding of Aromatic-L-amino-acid decarboxylase (DDC).	[14]
Chlorphrifos oxon	DMGBT68	Investigative	Chlorphrifos oxon affects the binding of Aromatic-L-amino-acid decarboxylase (DDC).	[14]

References

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• [12] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [13] 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.
• [14] Decarboxylases as hypothetical targets for actions of organophosphates: Molecular modeling for prediction of hidden and unexpected health threats. Food Chem Toxicol. 2022 Mar;161:112856. doi: 10.1016/j.fct.2022.112856. Epub 2022 Feb 11.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] Differential effects of resveratrol on androgen-responsive LNCaP human prostate cancer cells in vitro and in vivo. Carcinogenesis. 2008 Oct;29(10):2001-10.
• [17] Using DNA microarray analyses to elucidate the effects of genistein in androgen-responsive prostate cancer cells: identification of novel targets. Mol Carcinog. 2004 Oct;41(2):108-119.
• [18] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [19] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [20] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [21] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [22] Inhibition of human brain aromatic L-amino acid decarboxylase by cooked food-derived 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) and other heterocyclic amines. Neurosci Lett. 1990 Aug 24;116(3):372-8.
• [23] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [24] Focal striatal dopamine may potentiate dyskinesias in parkinsonian monkeys. Exp Neurol. 2006 Feb;197(2):363-72. doi: 10.1016/j.expneurol.2005.10.022. Epub 2005 Dec 9.