Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4HITJ6)

• DOT Name: Complex I assembly factor ACAD9, mitochondrial (ACAD9)
• Synonyms: Acyl-CoA dehydrogenase family member 9; ACAD-9; EC 1.3.8.-
• Gene Name: ACAD9
• Related Disease:
  Acyl-CoA dehydrogenase 9 deficiency
  Cardiomyopathy
  Lactic acidosis
  Mitochondrial disease
  Mitochondrial encephalomyopathy
  Myopathy
  Hypertrophic cardiomyopathy
  Nervous system disease
  Parkinson disease
• UniProt ID: ACAD9_HUMAN
• EC Number: 1.3.8.-
• Pfam ID: PF21343 ; PF00441 ; PF02770 ; PF02771
• Sequence:
  MSGCGLFLRTTAAARACRGLVVSTANRRLLRTSPPVRAFAKELFLGKIKKKEVFPFPEVS
  QDELNEINQFLGPVEKFFTEEVDSRKIDQEGKIPDETLEKLKSLGLFGLQVPEEYGGLGF
  SNTMYSRLGEIISMDGSITVTLAAHQAIGLKGIILAGTEEQKAKYLPKLASGEHIAAFCL
  TEPASGSDAASIRSRATLSEDKKHYILNGSKVWITNGGLANIFTVFAKTEVVDSDGSVKD
  KITAFIVERDFGGVTNGKPEDKLGIRGSNTCEVHFENTKIPVENILGEVGDGFKVAMNIL
  NSGRFSMGSVVAGLLKRLIEMTAEYACTRKQFNKRLSEFGLIQEKFALMAQKAYVMESMT
  YLTAGMLDQPGFPDCSIEAAMVKVFSSEAAWQCVSEALQILGGLGYTRDYPYERILRDTR
  ILLIFEGTNEILRMYIALTGLQHAGRILTTRIHELKQAKVSTVMDTVGRRLRDSLGRTVD
  LGLTGNHGVVHPSLADSANKFEENTYCFGRTVETLLLRFGKTIMEEQLVLKRVANILINL
  YGMTAVLSRASRSIRIGLRNHDHEVLLANTFCVEAYLQNLFSLSQLDKYAPENLDEQIKK
  VSQQILEKRAYICAHPLDRTC
• Function: As part of the MCIA complex, primarily participates in the assembly of the mitochondrial complex I and therefore plays a role in oxidative phosphorylation. This moonlighting protein has also a dehydrogenase activity toward a broad range of substrates with greater specificity for long-chain unsaturated acyl-CoAs. However, in vivo, it does not seem to play a primary role in fatty acid oxidation. In addition, the function in complex I assembly is independent of the dehydrogenase activity of the protein.
• Tissue Specificity: Ubiquitously expressed in most normal human tissues and cancer cell lines with high level of expression in heart, skeletal muscles, brain, kidney and liver . In the cerebellum uniquely expressed in the granular layer (at protein level) .
• Reactome Pathway: Complex I biogenesis (R-HSA-6799198)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acyl-CoA dehydrogenase 9 deficiency	DIS9QKN7	Definitive	Autosomal recessive	[1]
Cardiomyopathy	DISUPZRG	Definitive	Biomarker	[2]
Lactic acidosis	DISZI1ZK	Strong	Genetic Variation	[3]
Mitochondrial disease	DISKAHA3	Strong	Genetic Variation	[4]
Mitochondrial encephalomyopathy	DISA6PTN	Strong	Genetic Variation	[5]
Myopathy	DISOWG27	Strong	Genetic Variation	[6]
Hypertrophic cardiomyopathy	DISQG2AI	Limited	Genetic Variation	[7]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[8]
Parkinson disease	DISQVHKL	Limited	Altered Expression	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Complex I assembly factor ACAD9, mitochondrial (ACAD9).	[10]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Complex I assembly factor ACAD9, mitochondrial (ACAD9).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Complex I assembly factor ACAD9, mitochondrial (ACAD9).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Complex I assembly factor ACAD9, mitochondrial (ACAD9).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Complex I assembly factor ACAD9, mitochondrial (ACAD9).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Complex I assembly factor ACAD9, mitochondrial (ACAD9).	[14]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Complex I assembly factor ACAD9, mitochondrial (ACAD9).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Complex I assembly factor ACAD9, mitochondrial (ACAD9).	[17]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Complex I assembly factor ACAD9, mitochondrial (ACAD9).	[18]
Oleic acid	DM54O1Z	Investigative	Oleic acid increases the expression of Complex I assembly factor ACAD9, mitochondrial (ACAD9).	[19]

References

• [1] 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.
• [2] Successful treatment of infantile-onset ACAD9-related cardiomyopathy with a combination of sodium pyruvate, beta-blocker, and coenzyme Q10.J Pediatr Endocrinol Metab. 2019 Oct 25;32(10):1181-1185. doi: 10.1515/jpem-2019-0205.
• [3] Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?.Orphanet J Rare Dis. 2018 Jul 19;13(1):120. doi: 10.1186/s13023-018-0784-8.
• [4] Update on clinical aspects and treatment of selected vitamin-responsive disorders II (riboflavin and CoQ 10).J Inherit Metab Dis. 2012 Jul;35(4):679-87. doi: 10.1007/s10545-011-9434-1. Epub 2012 Jan 10.
• [5] Mitochondrial encephalomyopathy due to a novel mutation in ACAD9.JAMA Neurol. 2013 Sep 1;70(9):1177-9. doi: 10.1001/jamaneurol.2013.3197.
• [6] Severe defect in mitochondrial complex I assembly with mitochondrial DNA deletions in ACAD9-deficient mild myopathy.Muscle Nerve. 2017 Jun;55(6):919-922. doi: 10.1002/mus.25262. Epub 2017 Mar 26.
• [7] Assembly defects of multiple respiratory chain complexes in a child with cardiac hypertrophy associated with a novel ACAD9 mutation.Mol Genet Metab. 2017 Jul;121(3):224-226. doi: 10.1016/j.ymgme.2017.05.002. Epub 2017 May 4.
• [8] Evidence of a wide spectrum of cardiac involvement due to ACAD9 mutations: Report on nine patients.Mol Genet Metab. 2016 Jul;118(3):185-189. doi: 10.1016/j.ymgme.2016.05.005. Epub 2016 May 13.
• [9] Impaired complex-I mitochondrial biogenesis in Parkinson disease frontal cortex.J Parkinsons Dis. 2012;2(1):67-76. doi: 10.3233/JPD-2012-11074.
• [10] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [11] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] 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.
• [15] 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.
• [16] New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids. Arch Toxicol. 2021 Aug;95(8):2691-2718. doi: 10.1007/s00204-021-03092-2. Epub 2021 Jun 20.
• [17] 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.
• [18] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [19] Diesel Exhaust Induces Mitochondrial Dysfunction, Hyperlipidemia, and Liver Steatosis. Arterioscler Thromb Vasc Biol. 2019 Sep;39(9):1776-1786. doi: 10.1161/ATVBAHA.119.312736. Epub 2019 Jul 25.