Details of Drug-Metabolizing Enzyme (DME)

General Information of Drug-Metabolizing Enzyme (DME) (ID: DE3GT9C)

• DME Name: Cytochrome P450 4F2 (CYP4F2)
• Synonyms: Cytochrome P450 family 4 subfamily F member 2; Arachidonic acid omega-hydroxylase; CYP4F2; CYPIVF2; Leukotriene-B(4) 20-monooxygenase 1; Leukotriene-B(4) omega-hydroxylase 1; Phylloquinone omega-hydroxylase CYP4F2
• Gene Name: CYP4F2
• UniProt ID: CP4F2_HUMAN
• INTEDE ID: DME0025
• Gene ID: 8529
• EC Number:
  EC: 1.14.13.30
  Oxidoreductase
  Oxygen paired donor oxidoreductase
  NADH/NADPH donor oxidoreductase
  EC: 1.14.13.30
• Lineage:
  Species: Homo sapiens
  Kingdom: Metazoa
  Phylum: Chordata
  Class: Mammalia
  Order: Primates
  Family: Hominidae
  Genus: Homo
  Species: Homo sapiens
• Sequence:
  MSQLSLSWLGLWPVAASPWLLLLLVGASWLLAHVLAWTYAFYDNCRRLRCFPQPPRRNWF
  WGHQGMVNPTEEGMRVLTQLVATYPQGFKVWMGPISPLLSLCHPDIIRSVINASAAIAPK
  DKFFYSFLEPWLGDGLLLSAGDKWSRHRRMLTPAFHFNILKPYMKIFNESVNIMHAKWQL
  LASEGSACLDMFEHISLMTLDSLQKCVFSFDSHCQEKPSEYIAAILELSALVSKRHHEIL
  LHIDFLYYLTPDGQRFRRACRLVHDFTDAVIQERRRTLPSQGVDDFLQAKAKSKTLDFID
  VLLLSKDEDGKKLSDEDIRAEADTFMFEGHDTTASGLSWVLYHLAKHPEYQERCRQEVQE
  LLKDREPKEIEWDDLAHLPFLTMCMKESLRLHPPVPVISRHVTQDIVLPDGRVIPKGIIC
  LISVFGTHHNPAVWPDPEVYDPFRFDPENIKERSPLAFIPFSAGPRNCIGQTFAMAEMKV
  VLALTLLRFRVLPDHTEPRRKPELVLRAEGGLWLRVEPLS
• Function: This enzyme is involved in the metabolism of various endogenous substrates, including fatty acids, eicosanoids and vitamins. It catalyzes predominantly the oxidation of the terminal carbon (omega-oxidation) of long- and very long-chain fatty acids and displays high omega-hydroxylase activity toward polyunsaturated fatty acids (PUFAs). It participates in the conversion of arachidonic acid to omega-hydroxyeicosatetraenoic acid (20-HETE) and plays a role in the oxidative inactivation of eicosanoids. In addition, it catalyzes omega-hydroxylation of 3-hydroxy fatty acids and converts monoepoxides of linoleic acid leukotoxin and isoleukotoxin to omega-hydroxylated metabolites. It also contributes to the degradation of very long-chain fatty acids (VLCFAs) by catalyzing successive omega-oxidations and chain shortening. It plays an important role in vitamin metabolism by chain shortening and catalyzes omega- hydroxylation of the phytyl chain of tocopherols (forms of vitamin E), with preference for gamma-tocopherols over alpha-tocopherols. It also can Omega-hydroxylates and inactivates phylloquinone (vitamin K1), and menaquinone-4 (MK-4, a form of vitamin K2), both acting as cofactors in blood coagulation.
• KEGG Pathway:
  Arachidonic acid metabolism (hsa00590)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Fatty acids (R-HSA-211935)
  Miscellaneous substrates (R-HSA-211958)
  Synthesis of (16-20)-hydroxyeicosatetraenoic acids (HETE) (R-HSA-2142816)
  Synthesis of Leukotrienes (LT) and Eoxins (EX) (R-HSA-2142691)
  Eicosanoids (R-HSA-211979)

Molecular Interaction Atlas (MIA) of This DME

3 Approved Drug(s) Metabolized by This DME

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Dinoprostone	DMTYOPD	Medical abortion	JA00.1Z	Approved	[1]
Fingolimod	DM5JVAN	Multiple sclerosis	8A40	Approved	[2]
Ebastine	DMH21D9	N. A.	N. A.	Phase 4	[3]

3 Clinical Trial Drug(s) Metabolized by This DME

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Pafuramidine	DMFKOR9	Malaria	1F40-1F45	Phase 3	[4]
Tocopherol	DMBIJZ6	N. A.	N. A.	Phase 2	[5]
GSK618334	DMJPXZ4	Drug abuse	6C4G.1Z	Phase 1	[6]

1 Investigative Drug(s) Metabolized by This DME

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Arachidonic Acid	DMUOQZD	Discovery agent	N.A.	Investigative	[7]

Molecular Expression Atlas (MEA) of This DME

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Acute myelocytic leukaemia	2B33.1	Bone marrow	4.69E-45	-1.57E+00	-1.86E+00
Alopecia	ED70	Skin from scalp	9.26E-01	-4.25E-03	-4.96E-03
Alzheimer's disease	8A20	Entorhinal cortex	2.43E-02	2.94E-02	1.61E-01
Ankylosing spondylitis	FA92.0	Pheripheral blood	6.13E-01	-5.27E-02	-3.41E-01
Aortic stenosis	BB70	Calcified aortic valve	9.75E-01	-7.20E-02	-8.68E-02
Apnea	7A40	Hyperplastic tonsil	3.84E-01	-3.78E-01	-8.74E-01
Arthropathy	FA00-FA5Z	Peripheral blood	4.78E-02	2.38E-01	6.21E-01
Asthma	CA23	Nasal and bronchial airway	1.70E-01	2.14E-02	5.91E-02
Atopic dermatitis	EA80	Skin	9.67E-03	-3.47E-01	-4.75E-01
Autism	6A02	Whole blood	6.05E-01	1.86E-02	4.41E-02
Autoimmune uveitis	9A96	Peripheral monocyte	9.74E-01	-3.04E-03	-2.49E-02
Autosomal dominant monocytopenia	4B04	Whole blood	4.64E-02	-4.05E-01	-7.74E-01
Bacterial infection of gingival	1C1H	Gingival tissue	2.09E-01	-4.08E-02	-1.07E-01
Batten disease	5C56.1	Whole blood	2.91E-01	1.41E-01	1.29E+00
Behcet's disease	4A62	Peripheral blood	4.26E-01	1.30E-01	6.44E-01
Bipolar disorder	6A60-6A6Z	Prefrontal cortex	7.73E-01	1.06E-03	6.18E-03
Bladder cancer	2C94	Bladder tissue	1.69E-03	8.12E-01	1.80E+00
Breast cancer	2C60-2C6Z	Breast tissue	5.91E-03	-6.16E-02	-1.85E-01
Cardioembolic stroke	8B11.20	Whole blood	1.19E-05	5.95E-01	1.27E+00
Cervical cancer	2C77	Cervical tissue	8.32E-01	-5.68E-02	-1.88E-01
Childhood onset rheumatic disease	FA20.Z	Peripheral blood	8.77E-01	1.25E-01	5.46E-02
Chronic hepatitis C	1E51.1	Whole blood	4.26E-01	4.73E-02	4.00E-01
Chronic obstructive pulmonary disease	CA22	Lung tissue	7.40E-02	1.06E-01	4.35E-01
Chronic obstructive pulmonary disease	CA22	Small airway epithelium	2.02E-04	2.61E-01	5.68E-01
Chronic rhinosinusitis	CA0A	Sinus mucosa tissue	5.92E-02	1.00E-01	1.03E+00
Colon cancer	2B90	Colon tissue	5.22E-04	-3.36E-01	-4.21E-01
Coronary artery disease	BA80-BA8Z	Peripheral blood	7.88E-01	-5.82E-02	-3.11E-01
Diffuse large B-cell lymphoma	2A81	Tonsil tissue	8.75E-01	4.72E-02	2.34E-01
Endometriosis	GA10	Endometrium tissue	6.66E-02	1.84E-01	5.69E-01
Familial hypercholesterolemia	5C80.00	Peripheral blood	8.81E-01	2.68E-02	1.40E-01
Familial hypercholesterolemia	5C80.00	Whole blood	1.05E-08	-7.43E-01	-1.32E+00
Gastric cancer	2B72	Gastric tissue	1.17E-02	5.41E-01	3.02E+00
Glioblastopma	2A00.00	Nervous tissue	7.23E-03	-1.07E-01	-3.76E-01
Glioma	2A00.0Y-2A00.0Z	Brain stem tissue	6.65E-01	1.14E-02	1.34E-01
Glioma	2A00.0Y-2A00.0Z	White matter tissue	4.91E-02	-4.18E-01	-4.94E-01
Head and neck cancer	2D42	Head and neck tissue	1.81E-02	-2.35E-01	-4.27E-01
HIV-associated neurocognitive impairment	8A2Y-8A2Z	White matter tissue	4.96E-01	-2.58E-02	-1.13E-01
Huntington's disease	8A01.10	Whole blood	2.79E-01	8.25E-03	4.91E-02
Idiopathic pulmonary fibrosis	CB03.4	Lung tissue	1.88E-01	-7.62E-02	-1.28E-01
Immunodeficiency	4A00-4A20	Peripheral blood	8.52E-01	-2.09E-02	-2.56E-01
Influenza	1E30	Whole blood	9.24E-02	1.56E-01	1.77E+00
Interstitial cystitis	GC00.3	Bladder tissue	2.46E-02	-3.39E-01	-1.42E+00
Intracranial aneurysm	8B01.0	Intracranial artery	6.78E-01	-1.03E-01	-3.85E-01
Irritable bowel syndrome	DD91.0	Rectal colon tissue	8.67E-01	1.15E-01	1.26E-01
Ischemic stroke	8B11	Peripheral blood	3.71E-03	1.14E-01	6.64E-01
Juvenile idiopathic arthritis	FA24	Peripheral blood	6.79E-01	1.48E-01	1.33E-01
Lateral sclerosis	8B60.4	Skin	7.39E-01	1.13E-01	4.22E-01
Lateral sclerosis	8B60.4	Cervical spinal cord	8.37E-01	2.61E-02	1.29E-01
Liver cancer	2C12.0	Liver tissue	5.20E-51	-1.55E+00	-3.79E+00
Liver failure	DB99.7-DB99.8	Liver tissue	5.58E-05	-4.45E+00	-1.12E+01
Lung cancer	2C25	Lung tissue	1.39E-18	2.98E-02	1.17E-01
Lupus erythematosus	4A40	Whole blood	3.38E-02	2.15E-01	2.94E-01
Major depressive disorder	6A70-6A7Z	Hippocampus	4.56E-01	5.77E-02	3.59E-01
Major depressive disorder	6A70-6A7Z	Whole blood	7.79E-01	-9.28E-02	-1.99E-01
Melanoma	2C30	Skin	2.52E-04	-1.97E+00	-1.06E+00
Multiple myeloma	2A83.1	Peripheral blood	5.27E-01	-1.18E-01	-5.64E-01
Multiple myeloma	2A83.1	Bone marrow	7.40E-04	-4.31E-01	-2.29E+00
Multiple sclerosis	8A40	Plasmacytoid dendritic cells	2.36E-01	-6.45E-02	-1.81E-01
Myelodysplastic syndrome	2A36-2A3Z	Bone marrow	3.51E-02	-4.11E-03	-1.16E-02
Myelofibrosis	2A20.2	Whole blood	9.41E-01	1.32E-02	5.20E-02
Myocardial infarction	BA41-BA50	Peripheral blood	3.67E-03	1.02E+00	8.40E-01
Myopathy	8C70.6	Muscle tissue	2.17E-01	-4.07E-02	-2.34E-01
Neonatal sepsis	KA60	Whole blood	4.03E-10	4.86E-01	8.90E-01
Neuroectodermal tumour	2A00.11	Brain stem tissue	3.09E-03	-4.41E-01	-1.25E+00
Non-alcoholic fatty liver disease	DB92	Liver tissue	2.15E-02	3.80E-01	1.30E+00
Obesity related type 2 diabetes	5A11	Omental adipose tissue	7.15E-01	-8.86E-02	-4.95E-01
Olive pollen allergy	CA08.00	Peripheral blood	2.64E-01	9.62E-02	5.36E-01
Oral cancer	2B6E	Oral tissue	2.87E-03	-2.55E-01	-5.71E-01
Osteoarthritis	FA00-FA0Z	Synovial tissue	6.84E-02	-2.74E-01	-1.65E+00
Osteoporosis	FB83.1	Bone marrow	1.48E-01	3.43E-02	1.63E-01
Ovarian cancer	2C73	Ovarian tissue	2.33E-01	1.08E-01	2.67E-01
Pancreatic cancer	2C10	Pancreas	6.15E-02	7.98E-02	1.82E-01
Parkinson's disease	8A00.0	Substantia nigra tissue	5.10E-01	-3.24E-02	-1.39E-01
Pediatric respiratory syncytial virus infection	CA40.11	Peripheral blood	1.37E-02	2.76E-01	1.57E+00
Pituitary cancer	2D12	Pituitary tissue	1.77E-01	2.96E-01	8.55E-01
Pituitary gonadotrope tumour	2D12	Pituitary tissue	4.68E-02	1.86E-01	7.93E-01
Polycystic ovary syndrome	5A80.1	Vastus lateralis muscle	1.44E-01	-8.09E-02	-4.93E-01
Polycythemia vera	2A20.4	Whole blood	9.60E-01	-1.27E-04	-4.81E-04
Pompe disease	5C51.3	Biceps muscle	9.65E-01	-6.33E-03	-5.23E-02
Preterm birth	KA21.4Z	Myometrium	6.38E-01	6.47E-04	5.05E-03
Prostate cancer	2C82	Prostate	4.49E-02	-7.84E-01	-4.13E-01
Psoriasis	EA90	Skin	1.56E-07	7.10E-01	8.46E-01
Rectal cancer	2B92	Rectal colon tissue	5.65E-01	-1.36E-01	-2.31E-01
Renal cancer	2C90-2C91	Kidney	3.18E-03	-2.45E+00	-1.73E+00
Retinoblastoma	2D02.2	Uvea	1.21E-02	-1.78E-01	-8.33E-01
Rheumatoid arthritis	FA20	Synovial tissue	6.40E-02	-1.44E-01	-7.62E-01
Rhinovirus infection	CA42.1	Nasal epithelium tissue	1.52E-01	-4.72E-02	-2.41E-01
Schizophrenia	6A20	Prefrontal cortex	4.04E-01	3.74E-02	9.88E-02
Schizophrenia	6A20	Superior temporal cortex	6.40E-01	-4.65E-02	-3.37E-01
Scleroderma	4A42.Z	Whole blood	1.26E-01	2.13E-01	7.41E-01
Seizure	8A60-8A6Z	Whole blood	5.20E-01	1.23E-01	2.10E-01
Sensitive skin	EK0Z	Skin	8.55E-01	5.69E-02	1.42E-01
Sepsis with septic shock	1G41	Whole blood	5.95E-20	5.40E-01	9.30E-01
Shwachman-Diamond syndrome	3A70.0	Bone marrow	4.51E-01	-4.26E-01	-1.03E+00
Sickle cell disease	3A51.0-3A51.3	Peripheral blood	4.70E-02	2.27E-01	9.04E-01
Simpson golabi behmel syndrome	LD2C	Adipose tissue	2.50E-01	-7.31E-02	-1.01E+00
Sjogren's syndrome	4A43.2	Salivary gland tissue	6.62E-01	-9.75E-02	-4.29E-01
Skin cancer	2C30-2C3Z	Skin	1.33E-27	-9.03E-01	-8.35E-01
Thrombocythemia	3B63	Whole blood	9.85E-02	-1.45E-01	-5.83E-01
Thrombocytopenia	3B64	Whole blood	5.63E-01	0.00E+00	0.00E+00
Thyroid cancer	2D10	Thyroid	2.58E-04	8.29E-02	3.11E-01
Tibial muscular dystrophy	8C75	Muscle tissue	5.54E-02	-2.61E-01	-1.07E+00
Tuberous sclerosis complex	LD2D.2	Perituberal tissue	7.20E-01	2.71E-02	1.80E-01
Type 2 diabetes	5A11	Liver tissue	9.92E-01	-8.06E-03	-3.20E-02
Ureter cancer	2C92	Urothelium	2.25E-01	-3.53E-02	-1.92E-01
Uterine cancer	2C78	Endometrium tissue	4.97E-04	1.67E-01	3.63E-01
Vitiligo	ED63.0	Skin	8.43E-01	2.26E-01	1.54E-01

References

• [1] Cloning and characterization of CYP4F21: a prostaglandin E2 20-hydroxylase of ram seminal vesicles. Arch Biochem Biophys. 2001 May 1;389(1):123-9.
• [2] CYP4F enzymes are responsible for the elimination of fingolimod (FTY720), a novel treatment of relapsing multiple sclerosis. Drug Metab Dispos. 2011 Feb;39(2):191-8.
• [3] cDNA cloning and expression of a novel cytochrome p450 (cyp4f12) from human small intestine. Biochem Biophys Res Commun. 2001 Feb 2;280(4):1135-41.
• [4] Human enteric microsomal CYP4F enzymes O-demethylate the antiparasitic prodrug pafuramidine. Drug Metab Dispos. 2007 Nov;35(11):2067-75.
• [5] Discovery, characterization, and significance of the cytochrome P450 omega-hydroxylase pathway of vitamin E catabolism. Ann N Y Acad Sci. 2004 Dec;1031:13-21.
• [6] Product information - Gilenya.
• [7] Role of cytochrome P450 enzymes in the bioactivation of polyunsaturated fatty acids. Biochim Biophys Acta. 2011 Jan;1814(1):210-22.