Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO557N2)

• DOT Name: Trifunctional enzyme subunit alpha, mitochondrial (HADHA)
• Synonyms: 78 kDa gastrin-binding protein; Monolysocardiolipin acyltransferase; EC 2.3.1.-; TP-alpha
• Gene Name: HADHA
• Related Disease:
  Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
  Metabolic disorder
  Non-insulin dependent diabetes
  Prostatitis
  Abetalipoproteinemia
  Adrenogenital syndrome
  Adult respiratory distress syndrome
  Alpha-1 antitrypsin deficiency
  Barth syndrome
  Cardiac failure
  Cardiomyopathy
  Carnitine palmitoyltransferase II deficiency
  Carnitine-acylcarnitine translocase deficiency
  Castration-resistant prostate carcinoma
  Congenital adrenal hyperplasia
  Congestive heart failure
  Cytochrome-c oxidase deficiency disease
  Disorder of glycogen metabolism
  Fatty liver disease
  Fetal growth restriction
  Hepatitis C virus infection
  HIV infectious disease
  Hydrops fetalis
  Hypoglycemia
  Inborn error of metabolism
  Inflammatory bowel disease
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Mitochondrial trifunctional protein deficiency
  Myocardial ischemia
  Neoplasm
  Peripheral neuropathy
  Polyp
  Prostate cancer
  Prostate carcinoma
  Retinitis pigmentosa
  Von Willebrand disease type 2N
  Dilated cardiomyopathy
  Amyotrophic lateral sclerosis
  Breast cancer
  Lactic acidosis
  Osteoarthritis
• UniProt ID: ECHA_HUMAN
• PDB ID: 5ZQZ; 5ZRV; 6DV2
• EC Number: 1.1.1.211; 2.3.1.-; 4.2.1.17
• Pfam ID: PF00725 ; PF02737 ; PF00378
• Sequence:
  MVACRAIGILSRFSAFRILRSRGYICRNFTGSSALLTRTHINYGVKGDVAVVRINSPNSK
  VNTLSKELHSEFSEVMNEIWASDQIRSAVLISSKPGCFIAGADINMLAACKTLQEVTQLS
  QEAQRIVEKLEKSTKPIVAAINGSCLGGGLEVAISCQYRIATKDRKTVLGTPEVLLGALP
  GAGGTQRLPKMVGVPAALDMMLTGRSIRADRAKKMGLVDQLVEPLGPGLKPPEERTIEYL
  EEVAITFAKGLADKKISPKRDKGLVEKLTAYAMTIPFVRQQVYKKVEEKVRKQTKGLYPA
  PLKIIDVVKTGIEQGSDAGYLCESQKFGELVMTKESKALMGLYHGQVLCKKNKFGAPQKD
  VKHLAILGAGLMGAGIAQVSVDKGLKTILKDATLTALDRGQQQVFKGLNDKVKKKALTSF
  ERDSIFSNLTGQLDYQGFEKADMVIEAVFEDLSLKHRVLKEVEAVIPDHCIFASNTSALP
  ISEIAAVSKRPEKVIGMHYFSPVDKMQLLEIITTEKTSKDTSASAVAVGLKQGKVIIVVK
  DGPGFYTTRCLAPMMSEVIRILQEGVDPKKLDSLTTSFGFPVGAATLVDEVGVDVAKHVA
  EDLGKVFGERFGGGNPELLTQMVSKGFLGRKSGKGFYIYQEGVKRKDLNSDMDSILASLK
  LPPKSEVSSDEDIQFRLVTRFVNEAVMCLQEGILATPAEGDIGAVFGLGFPPCLGGPFRF
  VDLYGAQKIVDRLKKYEAAYGKQFTPCQLLADHANSPNKKFYQ
• Function: Mitochondrial trifunctional enzyme catalyzes the last three of the four reactions of the mitochondrial beta-oxidation pathway. The mitochondrial beta-oxidation pathway is the major energy-producing process in tissues and is performed through four consecutive reactions breaking down fatty acids into acetyl-CoA. Among the enzymes involved in this pathway, the trifunctional enzyme exhibits specificity for long-chain fatty acids. Mitochondrial trifunctional enzyme is a heterotetrameric complex composed of two proteins, the trifunctional enzyme subunit alpha/HADHA described here carries the 2,3-enoyl-CoA hydratase and the 3-hydroxyacyl-CoA dehydrogenase activities while the trifunctional enzyme subunit beta/HADHB bears the 3-ketoacyl-CoA thiolase activity. Independently of the subunit beta, the trifunctional enzyme subunit alpha/HADHA also has a monolysocardiolipin acyltransferase activity. It acylates monolysocardiolipin into cardiolipin, a major mitochondrial membrane phospholipid which plays a key role in apoptosis and supports mitochondrial respiratory chain complexes in the generation of ATP. Allows the acylation of monolysocardiolipin with different acyl-CoA substrates including oleoyl-CoA for which it displays the highest activity.
• KEGG Pathway:
  Fatty acid elongation (hsa00062)
  Fatty acid degradation (hsa00071)
  Valine, leucine and isoleucine degradation (hsa00280)
  Lysine degradation (hsa00310)
  Tryptophan metabolism (hsa00380)
  beta-Alanine metabolism (hsa00410)
  Propanoate metabolism (hsa00640)
  Butanoate metabolism (hsa00650)
  Metabolic pathways (hsa01100)
  Fatty acid metabolism (hsa01212)
• Reactome Pathway:
  Beta oxidation of myristoyl-CoA to lauroyl-CoA (R-HSA-77285)
  mitochondrial fatty acid beta-oxidation of unsaturated fatty acids (R-HSA-77288)
  Beta oxidation of palmitoyl-CoA to myristoyl-CoA (R-HSA-77305)
  Beta oxidation of lauroyl-CoA to decanoyl-CoA-CoA (R-HSA-77310)
  Beta oxidation of decanoyl-CoA to octanoyl-CoA-CoA (R-HSA-77346)
  Beta oxidation of octanoyl-CoA to hexanoyl-CoA (R-HSA-77348)
  Beta oxidation of hexanoyl-CoA to butanoyl-CoA (R-HSA-77350)
  Acyl chain remodeling of CL (R-HSA-1482798)
• BioCyc Pathway: MetaCyc:HS01481-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

43 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	DIS4F710	Definitive	Autosomal recessive	[1]
Metabolic disorder	DIS71G5H	Definitive	Biomarker	[2]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Genetic Variation	[3]
Prostatitis	DISL8OGN	Definitive	Altered Expression	[4]
Abetalipoproteinemia	DISMSS7T	Strong	Genetic Variation	[5]
Adrenogenital syndrome	DIS2N76U	Strong	Genetic Variation	[6]
Adult respiratory distress syndrome	DISIJV47	Strong	Biomarker	[7]
Alpha-1 antitrypsin deficiency	DISQKEHW	Strong	Genetic Variation	[6]
Barth syndrome	DISDI4KU	Strong	Altered Expression	[8]
Cardiac failure	DISDC067	Strong	Biomarker	[9]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[10]
Carnitine palmitoyltransferase II deficiency	DIS3GFD9	Strong	Biomarker	[11]
Carnitine-acylcarnitine translocase deficiency	DISR2O7P	Strong	Biomarker	[11]
Castration-resistant prostate carcinoma	DISVGAE6	Strong	Altered Expression	[12]
Congenital adrenal hyperplasia	DISG873W	Strong	Genetic Variation	[6]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[9]
Cytochrome-c oxidase deficiency disease	DISK7N3G	Strong	Genetic Variation	[6]
Disorder of glycogen metabolism	DISYGNOB	Strong	Biomarker	[13]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[14]
Fetal growth restriction	DIS5WEJ5	Strong	Altered Expression	[15]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[16]
HIV infectious disease	DISO97HC	Strong	Biomarker	[17]
Hydrops fetalis	DISD9BBF	Strong	Biomarker	[18]
Hypoglycemia	DISRCKR7	Strong	Biomarker	[19]
Inborn error of metabolism	DISO5FAY	Strong	Biomarker	[20]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[21]
Lung cancer	DISCM4YA	Strong	Biomarker	[22]
Lung carcinoma	DISTR26C	Strong	Biomarker	[22]
Lung neoplasm	DISVARNB	Strong	Biomarker	[22]
Mitochondrial trifunctional protein deficiency	DIS2MYYR	Strong	Autosomal recessive	[23]
Myocardial ischemia	DISFTVXF	Strong	Biomarker	[24]
Neoplasm	DISZKGEW	Strong	Biomarker	[25]
Peripheral neuropathy	DIS7KN5G	Strong	Biomarker	[18]
Polyp	DISRSLYF	Strong	Genetic Variation	[26]
Prostate cancer	DISF190Y	Strong	Biomarker	[12]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[12]
Retinitis pigmentosa	DISCGPY8	Strong	Genetic Variation	[6]
Von Willebrand disease type 2N	DIS7S2QL	Strong	Genetic Variation	[6]
Dilated cardiomyopathy	DISX608J	moderate	Genetic Variation	[27]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[28]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[29]
Lactic acidosis	DISZI1ZK	Limited	Biomarker	[30]
Osteoarthritis	DIS05URM	Limited	Biomarker	[31]

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 Trifunctional enzyme subunit alpha, mitochondrial (HADHA).	[32]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Trifunctional enzyme subunit alpha, mitochondrial (HADHA).	[43]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Trifunctional enzyme subunit alpha, mitochondrial (HADHA).	[33]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Trifunctional enzyme subunit alpha, mitochondrial (HADHA).	[34]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Trifunctional enzyme subunit alpha, mitochondrial (HADHA).	[35]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Trifunctional enzyme subunit alpha, mitochondrial (HADHA).	[36]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Trifunctional enzyme subunit alpha, mitochondrial (HADHA).	[37]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Trifunctional enzyme subunit alpha, mitochondrial (HADHA).	[38]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Trifunctional enzyme subunit alpha, mitochondrial (HADHA).	[39]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Trifunctional enzyme subunit alpha, mitochondrial (HADHA).	[40]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Trifunctional enzyme subunit alpha, mitochondrial (HADHA).	[36]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Trifunctional enzyme subunit alpha, mitochondrial (HADHA).	[42]
SB-431542	DM0YOXQ	Preclinical	SB-431542 increases the expression of Trifunctional enzyme subunit alpha, mitochondrial (HADHA).	[44]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Trifunctional enzyme subunit alpha, mitochondrial (HADHA).	[45]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Trifunctional enzyme subunit alpha, mitochondrial (HADHA).	[46]
Oleic acid	DM54O1Z	Investigative	Oleic acid increases the expression of Trifunctional enzyme subunit alpha, mitochondrial (HADHA).	[47]
GW7647	DM9RD0C	Investigative	GW7647 increases the expression of Trifunctional enzyme subunit alpha, mitochondrial (HADHA).	[47]
Benzoquinone	DMNBA0G	Investigative	Benzoquinone decreases the expression of Trifunctional enzyme subunit alpha, mitochondrial (HADHA).	[48]
Farnesol	DMV2X1B	Investigative	Farnesol increases the expression of Trifunctional enzyme subunit alpha, mitochondrial (HADHA).	[47]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Trifunctional enzyme subunit alpha, mitochondrial (HADHA).	[41]

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