Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4Y1I62)

• DOT Name: Trifunctional enzyme subunit beta, mitochondrial (HADHB)
• Synonyms: TP-beta
• Gene Name: HADHB
• Related Disease:
  Melanoma
  Mitochondrial trifunctional protein deficiency
  Prostatitis
  Abetalipoproteinemia
  Advanced cancer
  Beta-ketothiolase deficiency
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Cardiac disease
  Castration-resistant prostate carcinoma
  Colorectal carcinoma
  Fatty liver disease
  Hypoparathyroidism
  Lipid metabolism disorder
  Myopathy
  Non-alcoholic fatty liver disease
  Polyneuropathy
  Prostate adenocarcinoma
  Prostate cancer
  Prostate carcinoma
  Adrenoleukodystrophy
  Axonal neuropathy
  Cardiomyopathy
  Neoplasm
• UniProt ID: ECHB_HUMAN
• PDB ID: 5ZQZ; 5ZRV; 6DV2
• EC Number: 2.3.1.155; 2.3.1.16
• Pfam ID: PF02803 ; PF00108
• Sequence:
  MTILTYPFKNLPTASKWALRFSIRPLSCSSQLRAAPAVQTKTKKTLAKPNIRNVVVVDGV
  RTPFLLSGTSYKDLMPHDLARAALTGLLHRTSVPKEVVDYIIFGTVIQEVKTSNVAREAA
  LGAGFSDKTPAHTVTMACISANQAMTTGVGLIASGQCDVIVAGGVELMSDVPIRHSRKMR
  KLMLDLNKAKSMGQRLSLISKFRFNFLAPELPAVSEFSTSETMGHSADRLAAAFAVSRLE
  QDEYALRSHSLAKKAQDEGLLSDVVPFKVPGKDTVTKDNGIRPSSLEQMAKLKPAFIKPY
  GTVTAANSSFLTDGASAMLIMAEEKALAMGYKPKAYLRDFMYVSQDPKDQLLLGPTYATP
  KVLEKAGLTMNDIDAFEFHEAFSGQILANFKAMDSDWFAENYMGRKTKVGLPPLEKFNNW
  GGSLSLGHPFGATGCRLVMAAANRLRKEGGQYGLVAACAAGGQGHAMIVEAYPK
• 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 carries the 2,3-enoyl-CoA hydratase and the 3-hydroxyacyl-CoA dehydrogenase activities, while the trifunctional enzyme subunit beta/HADHB described here bears the 3-ketoacyl-CoA thiolase activity.
• KEGG Pathway:
  Fatty acid elongation (hsa00062)
  Fatty acid degradation (hsa00071)
  Valine, leucine and isoleucine degradation (hsa00280)
  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:HS06436-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Melanoma	DIS1RRCY	Definitive	Biomarker	[1]
Mitochondrial trifunctional protein deficiency	DIS2MYYR	Definitive	Autosomal recessive	[2]
Prostatitis	DISL8OGN	Definitive	Altered Expression	[3]
Abetalipoproteinemia	DISMSS7T	Strong	Genetic Variation	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Beta-ketothiolase deficiency	DIS7NWEJ	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[7]
Cardiac disease	DISVO1I5	Strong	Biomarker	[8]
Castration-resistant prostate carcinoma	DISVGAE6	Strong	Biomarker	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[5]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[8]
Hypoparathyroidism	DISICS0V	Strong	Genetic Variation	[10]
Lipid metabolism disorder	DISEOA7S	Strong	Biomarker	[8]
Myopathy	DISOWG27	Strong	Genetic Variation	[4]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Altered Expression	[11]
Polyneuropathy	DISB9G3W	Strong	Genetic Variation	[10]
Prostate adenocarcinoma	DISBZYU8	Strong	Altered Expression	[12]
Prostate cancer	DISF190Y	Strong	Biomarker	[9]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[9]
Adrenoleukodystrophy	DISTUD1F	moderate	Biomarker	[13]
Axonal neuropathy	DIS5S2BC	Limited	Genetic Variation	[4]
Cardiomyopathy	DISUPZRG	Limited	Genetic Variation	[14]
Neoplasm	DISZKGEW	Limited	Biomarker	[5]

1 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 beta, mitochondrial (HADHB).	[15]

16 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 Trifunctional enzyme subunit beta, mitochondrial (HADHB).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Trifunctional enzyme subunit beta, mitochondrial (HADHB).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Trifunctional enzyme subunit beta, mitochondrial (HADHB).	[18]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Trifunctional enzyme subunit beta, mitochondrial (HADHB).	[19]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Trifunctional enzyme subunit beta, mitochondrial (HADHB).	[20]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Trifunctional enzyme subunit beta, mitochondrial (HADHB).	[21]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Trifunctional enzyme subunit beta, mitochondrial (HADHB).	[22]
Benzatropine	DMF7EXL	Approved	Benzatropine increases the expression of Trifunctional enzyme subunit beta, mitochondrial (HADHB).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Trifunctional enzyme subunit beta, mitochondrial (HADHB).	[23]
SB-431542	DM0YOXQ	Preclinical	SB-431542 increases the expression of Trifunctional enzyme subunit beta, mitochondrial (HADHB).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Trifunctional enzyme subunit beta, mitochondrial (HADHB).	[25]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Trifunctional enzyme subunit beta, mitochondrial (HADHB).	[26]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Trifunctional enzyme subunit beta, mitochondrial (HADHB).	[27]
Oleic acid	DM54O1Z	Investigative	Oleic acid increases the expression of Trifunctional enzyme subunit beta, mitochondrial (HADHB).	[28]
GW7647	DM9RD0C	Investigative	GW7647 increases the expression of Trifunctional enzyme subunit beta, mitochondrial (HADHB).	[28]
Farnesol	DMV2X1B	Investigative	Farnesol increases the expression of Trifunctional enzyme subunit beta, mitochondrial (HADHB).	[28]

References

• [1] Nuclear Receptor Nur77 Facilitates Melanoma Cell Survival under Metabolic Stress by Protecting Fatty Acid Oxidation.Mol Cell. 2018 Feb 1;69(3):480-492.e7. doi: 10.1016/j.molcel.2018.01.001. Epub 2018 Jan 27.
• [2] 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.
• [3] Differential expression of the TP and TP isoforms of the human T Prostanoid receptor during chronic inflammation of the prostate: Role for FOXP1 in the transcriptional regulation of TP during monocyte-macrophage differentiation.Exp Mol Pathol. 2019 Oct;110:104277. doi: 10.1016/j.yexmp.2019.104277. Epub 2019 Jul 2.
• [4] Neuron-specific knockdown of Drosophila HADHB induces a shortened lifespan, deficient locomotive ability, abnormal motor neuron terminal morphology and learning disability.Exp Cell Res. 2019 Jun 15;379(2):150-158. doi: 10.1016/j.yexcr.2019.03.040. Epub 2019 Apr 3.
• [5] Integrated analyses of multi-omics reveal global patterns of methylation and hydroxymethylation and screen the tumor suppressive roles of HADHB in colorectal cancer.Clin Epigenetics. 2018 Mar 2;10:30. doi: 10.1186/s13148-018-0458-3. eCollection 2018.
• [6] Characterization and outcome of 41 patients with beta-ketothiolase deficiency: 10?years' experience of a medical center in northern Vietnam. J Inherit Metab Dis. 2017 May;40(3):395-401. doi: 10.1007/s10545-017-0026-6. Epub 2017 Feb 20.
• [7] An integrative approach to identify YB-1-interacting proteins required for cisplatin resistance in MCF7 and MDA-MB-231 breast cancer cells. Cancer Sci. 2011 Jul;102(7):1410-7. doi: 10.1111/j.1349-7006.2011.01948.x. Epub 2011 May 5.
• [8] ENU mutagenesis identifies mice with cardiac fibrosis and hepatic steatosis caused by a mutation in the mitochondrial trifunctional protein beta-subunit.Hum Mol Genet. 2006 Dec 15;15(24):3569-77. doi: 10.1093/hmg/ddl433. Epub 2006 Nov 20.
• [9] Regulation of protein kinase C-related kinase (PRK) signalling by the TP and TP isoforms of the human thromboxane A(2) receptor: Implications for thromboxane- and androgen- dependent neoplastic and epigenetic responses in prostate cancer.Biochim Biophys Acta Mol Basis Dis. 2017 Apr;1863(4):838-856. doi: 10.1016/j.bbadis.2017.01.011. Epub 2017 Jan 18.
• [10] Mutations in HADHB, which encodes the -subunit of mitochondrial trifunctional protein, cause infantile onset hypoparathyroidism and peripheral polyneuropathy.Am J Med Genet A. 2014 May;164A(5):1180-7. doi: 10.1002/ajmg.a.36434. Epub 2014 Mar 24.
• [11] Hepatic miR-33a/miR-144 and their target gene ABCA1 are associated with steatohepatitis in morbidly obese subjects. Liver Int. 2016 Sep;36(9):1383-91.
• [12] Regulated expression of the TP isoform of the human T prostanoid receptor by the tumour suppressors FOXP1 and NKX3.1: Implications for the role of thromboxane in prostate cancer.Biochim Biophys Acta Mol Basis Dis. 2017 Dec;1863(12):3153-3169. doi: 10.1016/j.bbadis.2017.09.005. Epub 2017 Sep 8.
• [13] Peroxisomal beta-oxidation enzyme proteins in adrenoleukodystrophy: distinction between X-linked adrenoleukodystrophy and neonatal adrenoleukodystrophy.Proc Natl Acad Sci U S A. 1987 Mar;84(5):1425-8. doi: 10.1073/pnas.84.5.1425.
• [14] Fetal left ventricular noncompaction cardiomyopathy and fatal outcome due to complete deficiency of mitochondrial trifunctional protein.Eur J Pediatr. 2015 Dec;174(12):1689-92. doi: 10.1007/s00431-015-2574-9. Epub 2015 Jun 13.
• [15] 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.
• [16] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [17] 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.
• [18] 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.
• [19] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [20] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [21] 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.
• [22] 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.
• [23] Comparison of quantitation methods in proteomics to define relevant toxicological information on AhR activation of HepG2 cells by BaP. Toxicology. 2021 Jan 30;448:152652. doi: 10.1016/j.tox.2020.152652. Epub 2020 Dec 2.
• [24] Activin/nodal signaling switches the terminal fate of human embryonic stem cell-derived trophoblasts. J Biol Chem. 2015 Apr 3;290(14):8834-48.
• [25] 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.
• [26] Lipid Rafts Disruption Increases Ochratoxin A Cytotoxicity to Hepatocytes. J Biochem Mol Toxicol. 2016 Feb;30(2):71-9. doi: 10.1002/jbt.21738. Epub 2015 Aug 25.
• [27] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [28] Farnesol induces fatty acid oxidation and decreases triglyceride accumulation in steatotic HepaRG cells. Toxicol Appl Pharmacol. 2019 Feb 15;365:61-70.