Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEQWU6Q)

• DOT Name: Fumarate hydratase, mitochondrial (FH)
• Synonyms: Fumarase; HsFH; EC 4.2.1.2
• Gene Name: FH
• Related Disease:
  Fumaric aciduria
  Hereditary leiomyomatosis and renal cell cancer
  Acute myelogenous leukaemia
  Autoimmune disease
  Autoimmune hepatitis
  Breast carcinoma
  Burkitt lymphoma
  Crohn disease
  Cystic kidney disease
  Hereditary neoplastic syndrome
  Leukemia
  Multiple sclerosis
  Neoplasm
  Paraganglioma
  Pheochromocytoma
  Pheochromocytoma-paraganglioma
  Polycythemia
  Prostate cancer
  Prostate carcinoma
  Rectal carcinoma
  Schizophrenia
  Small lymphocytic lymphoma
  Systemic mastocytosis
  Trichohepatoenteric syndrome
  BAP1-related tumor predisposition syndrome
  Leiomyomatosis
  Leiomyosarcoma
  leukaemia
  Osteoarthritis
  Pancreatic cancer
  Plasma cell myeloma
  Urinary bladder cancer
  Hereditary pheochromocytoma-paraganglioma
  Breast cancer
  Gastric cancer
  Stomach cancer
  Systemic lupus erythematosus
  B-cell neoplasm
  Carcinoma
  Colon cancer
  Colon carcinoma
  Lymphoma
  Lymphoma, non-Hodgkin, familial
  Nasopharyngeal carcinoma
  Neuroblastoma
  Non-hodgkin lymphoma
  Papillary renal cell carcinoma
• UniProt ID: FUMH_HUMAN
• PDB ID: 3E04; 5D6B; 5UPP; 6EBT; 6V8F; 6VBE; 7LUB
• EC Number: 4.2.1.2
• Pfam ID: PF10415 ; PF00206
• Sequence:
  MYRALRLLARSRPLVRAPAAALASAPGLGGAAVPSFWPPNAARMASQNSFRIEYDTFGEL
  KVPNDKYYGAQTVRSTMNFKIGGVTERMPTPVIKAFGILKRAAAEVNQDYGLDPKIANAI
  MKAADEVAEGKLNDHFPLVVWQTGSGTQTNMNVNEVISNRAIEMLGGELGSKIPVHPNDH
  VNKSQSSNDTFPTAMHIAAAIEVHEVLLPGLQKLHDALDAKSKEFAQIIKIGRTHTQDAV
  PLTLGQEFSGYVQQVKYAMTRIKAAMPRIYELAAGGTAVGTGLNTRIGFAEKVAAKVAAL
  TGLPFVTAPNKFEALAAHDALVELSGAMNTTACSLMKIANDIRFLGSGPRSGLGELILPE
  NEPGSSIMPGKVNPTQCEAMTMVAAQVMGNHVAVTVGGSNGHFELNVFKPMMIKNVLHSA
  RLLGDASVSFTENCVVGIQANTERINKLMNESLMLVTALNPHIGYDKAAKIAKTAHKNGS
  TLKETAIELGYLTAEQFDEWVKPKDMLGPK
• Function: Catalyzes the reversible stereospecific interconversion of fumarate to L-malate. Experiments in other species have demonstrated that specific isoforms of this protein act in defined pathways and favor one direction over the other (Probable); [Isoform Mitochondrial]: Catalyzes the hydration of fumarate to L-malate in the tricarboxylic acid (TCA) cycle to facilitate a transition step in the production of energy in the form of NADH; [Isoform Cytoplasmic]: Catalyzes the dehydration of L-malate to fumarate. Fumarate metabolism in the cytosol plays a role during urea cycle and arginine metabolism; fumarate being a by-product of the urea cycle and amino-acid catabolism. Also plays a role in DNA repair by promoting non-homologous end-joining (NHEJ). In response to DNA damage and phosphorylation by PRKDC, translocates to the nucleus and accumulates at DNA double-strand breaks (DSBs): acts by catalyzing formation of fumarate, an inhibitor of KDM2B histone demethylase activity, resulting in enhanced dimethylation of histone H3 'Lys-36' (H3K36me2).
• Tissue Specificity: Expressed in red blood cells; underexpressed in red blood cells (cytoplasm) of patients with hereditary non-spherocytic hemolytic anemia of unknown etiology.
• KEGG Pathway:
  Citrate cycle (TCA cycle) (hsa00020)
  Pyruvate metabolism (hsa00620)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
  Cushing syndrome (hsa04934)
  Pathways in cancer (hsa05200)
  Re.l cell carcinoma (hsa05211)
• Reactome Pathway: Citric acid cycle (TCA cycle) (R-HSA-71403)
• BioCyc Pathway: MetaCyc:ENSG00000091483-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fumaric aciduria	DISKL869	Definitive	Autosomal recessive	[1]
Hereditary leiomyomatosis and renal cell cancer	DISN22G2	Definitive	Autosomal dominant	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[3]
Autoimmune disease	DISORMTM	Strong	Biomarker	[4]
Autoimmune hepatitis	DISOX03Q	Strong	Altered Expression	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Burkitt lymphoma	DIS9D5XU	Strong	Biomarker	[7]
Crohn disease	DIS2C5Q8	Strong	Altered Expression	[8]
Cystic kidney disease	DISRT1LM	Strong	Genetic Variation	[9]
Hereditary neoplastic syndrome	DISGXLG5	Strong	Altered Expression	[10]
Leukemia	DISNAKFL	Strong	Biomarker	[11]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[12]
Paraganglioma	DIS2XXH5	Strong	Biomarker	[13]
Pheochromocytoma	DIS56IFV	Strong	Biomarker	[13]
Pheochromocytoma-paraganglioma	DISQ1KM0	Strong	Autosomal dominant	[14]
Polycythemia	DIS8B6VW	Strong	Genetic Variation	[15]
Prostate cancer	DISF190Y	Strong	Biomarker	[16]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[16]
Rectal carcinoma	DIS8FRR7	Strong	Genetic Variation	[17]
Schizophrenia	DISSRV2N	Strong	Biomarker	[18]
Small lymphocytic lymphoma	DIS30POX	Strong	Genetic Variation	[19]
Systemic mastocytosis	DISNQ2OY	Strong	Genetic Variation	[20]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[21]
BAP1-related tumor predisposition syndrome	DISO4FCC	moderate	Genetic Variation	[22]
Leiomyomatosis	DISNOOME	moderate	Biomarker	[23]
Leiomyosarcoma	DIS6COXM	Moderate	Autosomal dominant	[24]
leukaemia	DISS7D1V	moderate	Biomarker	[11]
Osteoarthritis	DIS05URM	moderate	Genetic Variation	[25]
Pancreatic cancer	DISJC981	moderate	Altered Expression	[26]
Plasma cell myeloma	DIS0DFZ0	moderate	Altered Expression	[27]
Urinary bladder cancer	DISDV4T7	moderate	Altered Expression	[28]
Hereditary pheochromocytoma-paraganglioma	DISP9K7L	Supportive	Autosomal dominant	[29]
Breast cancer	DIS7DPX1	Disputed	Biomarker	[6]
Gastric cancer	DISXGOUK	Disputed	Biomarker	[30]
Stomach cancer	DISKIJSX	Disputed	Biomarker	[30]
Systemic lupus erythematosus	DISI1SZ7	Disputed	Biomarker	[31]
B-cell neoplasm	DISVY326	Limited	Biomarker	[32]
Carcinoma	DISH9F1N	Limited	Biomarker	[33]
Colon cancer	DISVC52G	Limited	Genetic Variation	[17]
Colon carcinoma	DISJYKUO	Limited	Genetic Variation	[17]
Lymphoma	DISN6V4S	Limited	Altered Expression	[34]
Lymphoma, non-Hodgkin, familial	DISCXYIZ	Limited	Biomarker	[35]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Altered Expression	[36]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[37]
Non-hodgkin lymphoma	DISS2Y8A	Limited	Biomarker	[35]
Papillary renal cell carcinoma	DIS25HBV	Limited	Genetic Variation	[38]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Olaparib	DM8QB1D	Approved	Fumarate hydratase, mitochondrial (FH) increases the response to substance of Olaparib.	[60]
Talazoparib	DM1KS78	Approved	Fumarate hydratase, mitochondrial (FH) increases the response to substance of Talazoparib.	[60]
Piperazinyl methyl quinazolinone derivative 2	DM913KS	Patented	Fumarate hydratase, mitochondrial (FH) decreases the response to substance of Piperazinyl methyl quinazolinone derivative 2.	[61]

22 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 Fumarate hydratase, mitochondrial (FH).	[39]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Fumarate hydratase, mitochondrial (FH).	[40]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Fumarate hydratase, mitochondrial (FH).	[41]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Fumarate hydratase, mitochondrial (FH).	[42]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Fumarate hydratase, mitochondrial (FH).	[43]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Fumarate hydratase, mitochondrial (FH).	[44]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Fumarate hydratase, mitochondrial (FH).	[45]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Fumarate hydratase, mitochondrial (FH).	[46]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Fumarate hydratase, mitochondrial (FH).	[47]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Fumarate hydratase, mitochondrial (FH).	[48]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Fumarate hydratase, mitochondrial (FH).	[49]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Fumarate hydratase, mitochondrial (FH).	[50]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Fumarate hydratase, mitochondrial (FH).	[51]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Fumarate hydratase, mitochondrial (FH).	[52]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Fumarate hydratase, mitochondrial (FH).	[53]
Acocantherin	DM7JT24	Approved	Acocantherin affects the expression of Fumarate hydratase, mitochondrial (FH).	[54]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Fumarate hydratase, mitochondrial (FH).	[55]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Fumarate hydratase, mitochondrial (FH).	[56]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Fumarate hydratase, mitochondrial (FH).	[57]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Fumarate hydratase, mitochondrial (FH).	[58]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Fumarate hydratase, mitochondrial (FH).	[52]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Fumarate hydratase, mitochondrial (FH).	[59]

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