Details of Drug Off-Target (DOT)

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

• DOT Name: Bifunctional epoxide hydrolase 2 (EPHX2)
• Gene Name: EPHX2
• Related Disease: Hypercholesterolemia, familial, 1
• UniProt ID: HYES_HUMAN
• PDB ID: 1S8O ; 1VJ5 ; 1ZD2 ; 1ZD3 ; 1ZD4 ; 1ZD5 ; 3ANS ; 3ANT ; 3I1Y ; 3I28 ; 3KOO ; 3OTQ ; 3PDC ; 3WK4 ; 3WK5 ; 3WK6 ; 3WK7 ; 3WK8 ; 3WK9 ; 3WKA ; 3WKB ; 3WKC ; 3WKD ; 3WKE ; 4C4X ; 4C4Y ; 4C4Z ; 4HAI ; 4J03 ; 4JNC ; 4OCZ ; 4OD0 ; 4X6X ; 4X6Y ; 4Y2J ; 4Y2P ; 4Y2Q ; 4Y2R ; 4Y2S ; 4Y2T ; 4Y2U ; 4Y2V ; 4Y2X ; 4Y2Y ; 5AHX ; 5AI0 ; 5AI4 ; 5AI5 ; 5AI6 ; 5AI8 ; 5AI9 ; 5AIA ; 5AIB ; 5AIC ; 5AK3 ; 5AK4 ; 5AK5 ; 5AK6 ; 5AKE ; 5AKG ; 5AKH ; 5AKI ; 5AKJ ; 5AKK ; 5AKL ; 5AKX ; 5AKY ; 5AKZ ; 5ALD ; 5ALE ; 5ALF ; 5ALG ; 5ALH ; 5ALI ; 5ALJ ; 5ALK ; 5ALL ; 5ALM ; 5ALN ; 5ALO ; 5ALP ; 5ALQ ; 5ALR ; 5ALS ; 5ALT ; 5ALU ; 5ALV ; 5ALW ; 5ALX ; 5ALY ; 5ALZ ; 5AM0 ; 5AM1 ; 5AM2 ; 5AM3 ; 5AM4 ; 5AM5 ; 5FP0 ; 5MWA ; 6AUM ; 6I5E ; 6I5G ; 7EBA
• EC Number: 3.1.3.76; 3.3.2.10
• Pfam ID: PF00561 ; PF00702
• Sequence:
  MTLRAAVFDLDGVLALPAVFGVLGRTEEALALPRGLLNDAFQKGGPEGATTRLMKGEITL
  SQWIPLMEENCRKCSETAKVCLPKNFSIKEIFDKAISARKINRPMLQAALMLRKKGFTTA
  ILTNTWLDDRAERDGLAQLMCELKMHFDFLIESCQVGMVKPEPQIYKFLLDTLKASPSEV
  VFLDDIGANLKPARDLGMVTILVQDTDTALKELEKVTGIQLLNTPAPLPTSCNPSDMSHG
  YVTVKPRVRLHFVELGSGPAVCLCHGFPESWYSWRYQIPALAQAGYRVLAMDMKGYGESS
  APPEIEEYCMEVLCKEMVTFLDKLGLSQAVFIGHDWGGMLVWYMALFYPERVRAVASLNT
  PFIPANPNMSPLESIKANPVFDYQLYFQEPGVAEAELEQNLSRTFKSLFRASDESVLSMH
  KVCEAGGLFVNSPEEPSLSRMVTEEEIQFYVQQFKKSGFRGPLNWYRNMERNWKWACKSL
  GRKILIPALMVTAEKDFVLVPQMSQHMEDWIPHLKRGHIEDCGHWTQMDKPTEVNQILIK
  WLDSDARNPPVVSKM
• Function: Bifunctional enzyme. The C-terminal domain has epoxide hydrolase activity and acts on epoxides (alkene oxides, oxiranes) and arene oxides. Plays a role in xenobiotic metabolism by degrading potentially toxic epoxides. Also determines steady-state levels of physiological mediators ; Bifunctional enzyme. The N-terminal domain has lipid phosphatase activity, with the highest activity towards threo-9,10-phosphonooxy-hydroxy-octadecanoic acid, followed by erythro-9,10-phosphonooxy-hydroxy-octadecanoic acid, 12-phosphonooxy-octadec-9Z-enoic acid and 12-phosphonooxy-octadec-9E-enoic acid. Has phosphatase activity toward lyso-glycerophospholipids with also some lower activity toward lysolipids of sphingolipid and isoprenoid phosphates.
• KEGG Pathway:
  Arachidonic acid metabolism (hsa00590)
  Metabolic pathways (hsa01100)
  Peroxisome (hsa04146)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
• Reactome Pathway:
  Biosynthesis of maresins (R-HSA-9018682)
  Peroxisomal protein import (R-HSA-9033241)
  Synthesis of epoxy (EET) and dihydroxyeicosatrienoic acids (DHET) (R-HSA-2142670)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypercholesterolemia, familial, 1	DISU411W	No Known	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Carbamazepine	DMZOLBI	Approved	Bifunctional epoxide hydrolase 2 (EPHX2) increases the Drug dependence ADR of Carbamazepine.	[26]
Phenytoin	DMNOKBV	Approved	Bifunctional epoxide hydrolase 2 (EPHX2) increases the Thrombocytopenia ADR of Phenytoin.	[26]
Cimetidine	DMH61ZB	Approved	Bifunctional epoxide hydrolase 2 (EPHX2) increases the Thrombocytopenia ADR of Cimetidine.	[26]

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 Bifunctional epoxide hydrolase 2 (EPHX2).	[2]

27 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 Bifunctional epoxide hydrolase 2 (EPHX2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Bifunctional epoxide hydrolase 2 (EPHX2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Bifunctional epoxide hydrolase 2 (EPHX2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Bifunctional epoxide hydrolase 2 (EPHX2).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Bifunctional epoxide hydrolase 2 (EPHX2).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Bifunctional epoxide hydrolase 2 (EPHX2).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Bifunctional epoxide hydrolase 2 (EPHX2).	[9]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Bifunctional epoxide hydrolase 2 (EPHX2).	[10]
Selenium	DM25CGV	Approved	Selenium increases the expression of Bifunctional epoxide hydrolase 2 (EPHX2).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Bifunctional epoxide hydrolase 2 (EPHX2).	[12]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Bifunctional epoxide hydrolase 2 (EPHX2).	[13]
Fenofibrate	DMFKXDY	Approved	Fenofibrate affects the expression of Bifunctional epoxide hydrolase 2 (EPHX2).	[14]
Bezafibrate	DMZDCS0	Approved	Bezafibrate affects the expression of Bifunctional epoxide hydrolase 2 (EPHX2).	[14]
Dihydroxyacetone	DMM1LG2	Approved	Dihydroxyacetone decreases the expression of Bifunctional epoxide hydrolase 2 (EPHX2).	[15]
Gemfibrozil	DMD8Q3J	Approved	Gemfibrozil affects the expression of Bifunctional epoxide hydrolase 2 (EPHX2).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Bifunctional epoxide hydrolase 2 (EPHX2).	[16]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Bifunctional epoxide hydrolase 2 (EPHX2).	[17]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Bifunctional epoxide hydrolase 2 (EPHX2).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Bifunctional epoxide hydrolase 2 (EPHX2).	[3]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Bifunctional epoxide hydrolase 2 (EPHX2).	[19]
PIRINIXIC ACID	DM82Y75	Preclinical	PIRINIXIC ACID affects the expression of Bifunctional epoxide hydrolase 2 (EPHX2).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Bifunctional epoxide hydrolase 2 (EPHX2).	[20]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Bifunctional epoxide hydrolase 2 (EPHX2).	[21]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the expression of Bifunctional epoxide hydrolase 2 (EPHX2).	[22]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Bifunctional epoxide hydrolase 2 (EPHX2).	[23]
Indirubin-3'-monoxime	DMLRQH0	Investigative	Indirubin-3'-monoxime decreases the expression of Bifunctional epoxide hydrolase 2 (EPHX2).	[24]
5S-HETE	DM3Z6G4	Investigative	5S-HETE increases the activity of Bifunctional epoxide hydrolase 2 (EPHX2).	[25]

References

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