Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8LCZCT)

• DOT Name: Methylmalonate-semialdehyde/malonate-semialdehyde dehydrogenase , mitochondrial (ALDH6A1)
• Synonyms: MMSDH; EC 1.2.1.27; Aldehyde dehydrogenase family 6 member A1; Malonate-semialdehyde dehydrogenase
• Gene Name: ALDH6A1
• Related Disease:
  3-hydroxyisobutyric aciduria
  Epilepsy
  Inborn disorder of amino acid metabolism
  Methylmalonate semialdehyde dehydrogenase deficiency
  Methylmalonic acidemia
  Myocardial ischemia
  Obesity
  Clear cell renal carcinoma
  Metastatic malignant neoplasm
  Non-insulin dependent diabetes
• UniProt ID: MMSA_HUMAN
• EC Number: 1.2.1.27
• Pfam ID: PF00171
• Sequence:
  MAALLAAAAVRARILQVSSKVKSSPTWYSASSFSSSVPTVKLFIGGKFVESKSDKWIDIH
  NPATNEVIGRVPQATKAEMDAAIASCKRAFPAWADTSVLSRQQVLLRYQQLIKENLKEIA
  KLITLEQGKTLADAEGDVFRGLQVVEHACSVTSLMMGETMPSITKDMDLYSYRLPLGVCA
  GIAPFNFPAMIPLWMFPMAMVCGNTFLMKPSERVPGATMLLAKLLQDSGAPDGTLNIIHG
  QHEAVNFICDHPDIKAISFVGSNKAGEYIFERGSRHGKRVQANMGAKNHGVVMPDANKEN
  TLNQLVGAAFGAAGQRCMALSTAVLVGEAKKWLPELVEHAKNLRVNAGDQPGADLGPLIT
  PQAKERVCNLIDSGTKEGASILLDGRKIKVKGYENGNFVGPTIISNVKPNMTCYKEEIFG
  PVLVVLETETLDEAIQIVNNNPYGNGTAIFTTNGATARKYAHLVDVGQVGVNVPIPVPLP
  MFSFTGSRSSFRGDTNFYGKQGIQFYTQLKTITSQWKEEDATLSSPAVVMPTMGR
• Function: Malonate and methylmalonate semialdehyde dehydrogenase involved in the catabolism of valine, thymine, and compounds catabolized by way of beta-alanine, including uracil and cytidine.
• KEGG Pathway:
  Valine, leucine and isoleucine degradation (hsa00280)
  beta-Alanine metabolism (hsa00410)
  Inositol phosphate metabolism (hsa00562)
  Propanoate metabolism (hsa00640)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
• Reactome Pathway: Branched-chain amino acid catabolism (R-HSA-70895)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
3-hydroxyisobutyric aciduria	DISXIPQ9	Strong	Genetic Variation	[1]
Epilepsy	DISBB28L	Strong	Biomarker	[2]
Inborn disorder of amino acid metabolism	DISFWXCM	Strong	Biomarker	[3]
Methylmalonate semialdehyde dehydrogenase deficiency	DISWOV3J	Strong	Autosomal recessive	[3]
Methylmalonic acidemia	DISHY8VB	Strong	Genetic Variation	[4]
Myocardial ischemia	DISFTVXF	Strong	Biomarker	[5]
Obesity	DIS47Y1K	Strong	Biomarker	[6]
Clear cell renal carcinoma	DISBXRFJ	Limited	Biomarker	[7]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[8]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Methylmalonate-semialdehyde/malonate-semialdehyde dehydrogenase , mitochondrial (ALDH6A1).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Methylmalonate-semialdehyde/malonate-semialdehyde dehydrogenase , mitochondrial (ALDH6A1).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Methylmalonate-semialdehyde/malonate-semialdehyde dehydrogenase , mitochondrial (ALDH6A1).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Methylmalonate-semialdehyde/malonate-semialdehyde dehydrogenase , mitochondrial (ALDH6A1).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Methylmalonate-semialdehyde/malonate-semialdehyde dehydrogenase , mitochondrial (ALDH6A1).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Methylmalonate-semialdehyde/malonate-semialdehyde dehydrogenase , mitochondrial (ALDH6A1).	[15]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Methylmalonate-semialdehyde/malonate-semialdehyde dehydrogenase , mitochondrial (ALDH6A1).	[16]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Methylmalonate-semialdehyde/malonate-semialdehyde dehydrogenase , mitochondrial (ALDH6A1).	[17]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Methylmalonate-semialdehyde/malonate-semialdehyde dehydrogenase , mitochondrial (ALDH6A1).	[18]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Methylmalonate-semialdehyde/malonate-semialdehyde dehydrogenase , mitochondrial (ALDH6A1).	[19]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of Methylmalonate-semialdehyde/malonate-semialdehyde dehydrogenase , mitochondrial (ALDH6A1).	[20]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Methylmalonate-semialdehyde/malonate-semialdehyde dehydrogenase , mitochondrial (ALDH6A1).	[21]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Methylmalonate-semialdehyde/malonate-semialdehyde dehydrogenase , mitochondrial (ALDH6A1).	[22]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Methylmalonate-semialdehyde/malonate-semialdehyde dehydrogenase , mitochondrial (ALDH6A1).	[23]
Gemcitabine	DMSE3I7	Approved	Gemcitabine increases the expression of Methylmalonate-semialdehyde/malonate-semialdehyde dehydrogenase , mitochondrial (ALDH6A1).	[24]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Methylmalonate-semialdehyde/malonate-semialdehyde dehydrogenase , mitochondrial (ALDH6A1).	[25]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of Methylmalonate-semialdehyde/malonate-semialdehyde dehydrogenase , mitochondrial (ALDH6A1).	[26]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium decreases the expression of Methylmalonate-semialdehyde/malonate-semialdehyde dehydrogenase , mitochondrial (ALDH6A1).	[26]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Methylmalonate-semialdehyde/malonate-semialdehyde dehydrogenase , mitochondrial (ALDH6A1).	[27]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Methylmalonate-semialdehyde/malonate-semialdehyde dehydrogenase , mitochondrial (ALDH6A1).	[28]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Methylmalonate-semialdehyde/malonate-semialdehyde dehydrogenase , mitochondrial (ALDH6A1).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Methylmalonate-semialdehyde/malonate-semialdehyde dehydrogenase , mitochondrial (ALDH6A1).	[16]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Methylmalonate-semialdehyde/malonate-semialdehyde dehydrogenase , mitochondrial (ALDH6A1).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Methylmalonate-semialdehyde/malonate-semialdehyde dehydrogenase , mitochondrial (ALDH6A1).	[31]
chlordane	DMMHU8G	Investigative	chlordane decreases the expression of Methylmalonate-semialdehyde/malonate-semialdehyde dehydrogenase , mitochondrial (ALDH6A1).	[32]

References

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• [2] Quantitative Proteomic Analysis To Identify Differentially Expressed Proteins in Myocardium of Epilepsy Using iTRAQ Coupled with Nano-LC-MS/MS.J Proteome Res. 2018 Jan 5;17(1):305-314. doi: 10.1021/acs.jproteome.7b00579. Epub 2017 Nov 8.
• [3] Molecular characterization of methylmalonate semialdehyde dehydrogenase deficiency. J Inherit Metab Dis. 2000 Jul;23(5):497-504. doi: 10.1023/a:1005616315087.
• [4] Mutations in ALDH6A1 encoding methylmalonate semialdehyde dehydrogenase are associated with dysmyelination and transient methylmalonic aciduria.Orphanet J Rare Dis. 2013 Jul 9;8:98. doi: 10.1186/1750-1172-8-98.
• [5] Cardioplegia prevents ischemia-induced transcriptional alterations of cytoprotective genes in rat hearts: a DNA microarray study.J Thorac Cardiovasc Surg. 2005 Oct;130(4):1151. doi: 10.1016/j.jtcvs.2005.06.027.
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• [9] Downregulation of the acetyl-CoA metabolic network in adipose tissue of obese diabetic individuals and recovery after weight loss.Diabetologia. 2014 Nov;57(11):2384-92. doi: 10.1007/s00125-014-3347-0. Epub 2014 Aug 7.
• [10] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
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• [12] 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.
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• [16] 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.
• [17] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [18] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [19] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [20] DNA methylation inhibits p53-mediated survivin repression. Oncogene. 2009 May 14;28(19):2046-50. doi: 10.1038/onc.2009.62. Epub 2009 Apr 13.
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• [22] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [23] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [24] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [25] Linalool is a PPARalpha ligand that reduces plasma TG levels and rewires the hepatic transcriptome and plasma metabolome. J Lipid Res. 2014 Jun;55(6):1098-110.
• [26] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
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