Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNWHUJ1)

• DOT Name: 4-trimethylaminobutyraldehyde dehydrogenase (ALDH9A1)
• Synonyms: TMABA-DH; TMABALDH; EC 1.2.1.47; Aldehyde dehydrogenase E3 isozyme; Aldehyde dehydrogenase family 9 member A1; EC 1.2.1.3; Formaldehyde dehydrogenase; EC 1.2.1.46; Gamma-aminobutyraldehyde dehydrogenase; EC 1.2.1.19; R-aminobutyraldehyde dehydrogenase
• Gene Name: ALDH9A1
• Related Disease:
  Advanced cancer
  Cardiovascular disease
  Hemolytic anemia
  Kidney cancer
  Renal carcinoma
• UniProt ID: AL9A1_HUMAN
• PDB ID: 6QAK; 6QAO; 6QAP; 6VR6; 6VWF
• EC Number: 1.2.1.19; 1.2.1.3; 1.2.1.46; 1.2.1.47
• Pfam ID: PF00171
• Sequence:
  MSTGTFVVSQPLNYRGGARVEPADASGTEKAFEPATGRVIATFTCSGEKEVNLAVQNAKA
  AFKIWSQKSGMERCRILLEAARIIREREDEIATMECINNGKSIFEARLDIDISWQCLEYY
  AGLAASMAGEHIQLPGGSFGYTRREPLGVCVGIGAWNYPFQIASWKSAPALACGNAMVFK
  PSPFTPVSALLLAEIYSEAGVPPGLFNVVQGGAATGQFLCQHPDVAKVSFTGSVPTGMKI
  MEMSAKGIKPVTLELGGKSPLIIFSDCDMNNAVKGALMANFLTQGQVCCNGTRVFVQKEI
  LDKFTEEVVKQTQRIKIGDPLLEDTRMGPLINRPHLERVLGFVKVAKEQGAKVLCGGDIY
  VPEDPKLKDGYYMRPCVLTNCRDDMTCVKEEIFGPVMSILSFDTEAEVLERANDTTFGLA
  AGVFTRDIQRAHRVVAELQAGTCFINNYNVSPVELPFGGYKKSGFGRENGRVTIEYYSQL
  KTVCVEMGDVESAF
• Function: Converts gamma-trimethylaminobutyraldehyde into gamma-butyrobetaine with high efficiency (in vitro). Can catalyze the irreversible oxidation of a broad range of aldehydes to the corresponding acids in an NAD-dependent reaction, but with low efficiency. Catalyzes the oxidation of aldehydes arising from biogenic amines and polyamines.
• Tissue Specificity: Detected in brain (at protein level) . High expression in adult liver, skeletal muscle, and kidney. Low levels in heart, pancreas, lung and brain . Expressed in all regions of the brain. Expression levels are variable in the different brain areas, with the highest levels in the spinal cord and the lowest in the occipital pole.
• KEGG Pathway:
  Glycolysis / Gluconeogenesis (hsa00010)
  Ascorbate and aldarate metabolism (hsa00053)
  Fatty acid degradation (hsa00071)
  Valine, leucine and isoleucine degradation (hsa00280)
  Lysine degradation (hsa00310)
  Arginine and proline metabolism (hsa00330)
  Histidine metabolism (hsa00340)
  Tryptophan metabolism (hsa00380)
  beta-Alanine metabolism (hsa00410)
  Glycerolipid metabolism (hsa00561)
  Pyruvate metabolism (hsa00620)
  Metabolic pathways (hsa01100)
  Alcoholic liver disease (hsa04936)
• Reactome Pathway: Carnitine synthesis (R-HSA-71262)
• BioCyc Pathway: MetaCyc:HS06992-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[1]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[1]
Hemolytic anemia	DIS803XQ	Strong	Genetic Variation	[1]
Kidney cancer	DISBIPKM	Strong	Genetic Variation	[2]
Renal carcinoma	DISER9XT	Strong	Genetic Variation	[2]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaldehyde	DMJFKG4	Investigative	4-trimethylaminobutyraldehyde dehydrogenase (ALDH9A1) increases the oxidation of Acetaldehyde.	[19]

16 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 4-trimethylaminobutyraldehyde dehydrogenase (ALDH9A1).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of 4-trimethylaminobutyraldehyde dehydrogenase (ALDH9A1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of 4-trimethylaminobutyraldehyde dehydrogenase (ALDH9A1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 4-trimethylaminobutyraldehyde dehydrogenase (ALDH9A1).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 4-trimethylaminobutyraldehyde dehydrogenase (ALDH9A1).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of 4-trimethylaminobutyraldehyde dehydrogenase (ALDH9A1).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of 4-trimethylaminobutyraldehyde dehydrogenase (ALDH9A1).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 4-trimethylaminobutyraldehyde dehydrogenase (ALDH9A1).	[10]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of 4-trimethylaminobutyraldehyde dehydrogenase (ALDH9A1).	[11]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of 4-trimethylaminobutyraldehyde dehydrogenase (ALDH9A1).	[12]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the expression of 4-trimethylaminobutyraldehyde dehydrogenase (ALDH9A1).	[13]
Arecoline	DMFJZK3	Phase 1	Arecoline decreases the expression of 4-trimethylaminobutyraldehyde dehydrogenase (ALDH9A1).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of 4-trimethylaminobutyraldehyde dehydrogenase (ALDH9A1).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of 4-trimethylaminobutyraldehyde dehydrogenase (ALDH9A1).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of 4-trimethylaminobutyraldehyde dehydrogenase (ALDH9A1).	[17]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of 4-trimethylaminobutyraldehyde dehydrogenase (ALDH9A1).	[18]

References

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• [2] Common variation at 1q24.1 (ALDH9A1) is a potential risk factor for renal cancer.PLoS One. 2015 Mar 31;10(3):e0122589. doi: 10.1371/journal.pone.0122589. eCollection 2015.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [5] 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.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [10] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [11] Xenobiotic CAR activators induce Dlk1-Dio3 locus noncoding RNA expression in mouse liver. Toxicol Sci. 2017 Aug 1;158(2):367-378.
• [12] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [13] Proteomic analysis of anti-cancer effects by paclitaxel treatment in cervical cancer cells. Gynecol Oncol. 2005 Jul;98(1):45-53. doi: 10.1016/j.ygyno.2005.04.010.
• [14] Characterization of arecoline-induced effects on cytotoxicity in normal human gingival fibroblasts by global gene expression profiling. Toxicol Sci. 2007 Nov;100(1):66-74.
• [15] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [16] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [18] Evaluation of an in vitro model of androgen ablation and identification of the androgen responsive proteome in LNCaP cells. Proteomics. 2007 Jan;7(1):47-63.
• [19] Human aldehyde dehydrogenase-catalyzed oxidation of ethylene glycol ether aldehydes. Chem Biol Interact. 2009 Mar 16;178(1-3):56-63. doi: 10.1016/j.cbi.2008.09.025. Epub 2008 Oct 1.