Cytochrome P450 2D6

Function

A cytochrome P450 monooxygenase involved in the metabolism of fatty acids, steroids and retinoids. Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 20-hydroxyeicosatetraenoic acid ethanolamide (20-HETE-EA) and 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling. Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis. Catalyzes the oxidative transformations of all-trans retinol to all-trans retinal, a precursor for the active form all-trans-retinoic acid. Also involved in the oxidative metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants.

Classification

Family (Pfam)

PF00067 p450

InterPro

Cyt_P450, Cyt_P450_CS, Cyt_P450_E_grp-I, Cyt_P450_E_grp-I_CYP2D-like, Cyt_P450_sf, Cytochrome_P450_fam2

Functional cluster

Cytochrome P450 & Heme Enzymes

Experimental structures · PDB · 14

• 2F9Q X-ray 3.00A
• 3QM4 X-ray 2.85A
• 3TBG X-ray 2.10A
• 3TDA X-ray 2.67A
• 4WNT X-ray 2.60A
• 4WNU X-ray 2.26A
• 4WNV X-ray 2.35A
• 4WNW X-ray 3.30A
• 4XRY X-ray 2.50A
• 4XRZ X-ray 2.40A
• 5TFT X-ray 2.71A
• 5TFU X-ray 2.75A
• … and 2 more

A predicted model is available from AlphaFold.

Gene Ontology · 27

• GO:0005737 cytoplasm
• GO:0005783 endoplasmic reticulum
• GO:0005789 endoplasmic reticulum membrane
• GO:0005739 mitochondrion
• GO:0062188 anandamide 11,12 epoxidase activity
• GO:0062189 anandamide 14,15 epoxidase activity
• GO:0062187 anandamide 8,9 epoxidase activity
• GO:0020037 heme binding
• GO:0005506 iron ion binding
• GO:0004497 monooxygenase activity
• GO:0016491 oxidoreductase activity
• GO:0016712 oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
• GO:0009822 alkaloid catabolic process
• GO:0009820 alkaloid metabolic process
• GO:0019369 arachidonate metabolic process
• GO:0008203 cholesterol metabolic process
• GO:0009804 coumarin metabolic process
• GO:0008210 estrogen metabolic process
• GO:0033076 isoquinoline alkaloid metabolic process
• GO:0042759 long-chain fatty acid biosynthetic process
• GO:0016098 monoterpenoid metabolic process
• GO:0090350 negative regulation of organofluorine metabolic process
• GO:0070989 oxidative demethylation
• GO:0042572 retinol metabolic process
• GO:0008202 steroid metabolic process
• GO:0042178 xenobiotic catabolic process
• GO:0006805 xenobiotic metabolic process

Disease associations

• obsolete drug metabolism, poor, CYP2D6-related MONDO:0012148

Neighborhood · nearest proteins

Related proteins · sequence + function similarity

• Cytochrome P450 2D6 1.00
• Cytochrome P450 2D6 1.00
• Cytochrome P450 2D17 1.00
• Cytochrome P450 2D19 0.99
• Cytochrome P450 2D14 0.99
• Cytochrome P450 2D15 0.98
• Cytochrome P450 2D7 0.98
• Cytochrome P450 2D4 0.97
• Vitamin D(3) 25-hydroxylase 0.97
• Cytochrome P450 2D16 0.97
• Cytochrome P450 2D28 0.96
• Cytochrome P450 2D20 0.95

Co-cited proteins · studied together in the literature

• Cytochrome P450 2B6 2 shared papers
• Cytochrome P450 1A2 4 shared papers
• Cytochrome P450 1A1 4 shared papers
• Cytochrome P450 3A4 4 shared papers
• Cytochrome P450 2C9 3 shared papers
• Cytochrome P450 2C19 3 shared papers
• Cytochrome P450 1B1 1 shared papers
• Cytochrome P450 1B1 2 shared papers
• Cytochrome P450 3A5 2 shared papers
• Cytochrome P450 2J2 1 shared papers
• Cytochrome P450 1A1 1 shared papers
• Cytochrome P450 2C8 2 shared papers

Literature · 24 cited papers

• In vitro functional assessment of 22 newly identified CYP2D6 allelic variants in the Chinese population. Basic Clin. Pharmacol. Toxicol. · 2015
• An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J. Proteomics · 2014
• Cholesterol 25-hydroxylation activity of CYP3A. J. Lipid Res. · 2011
• Anandamide oxidation by wild-type and polymorphically expressed CYP2B6 and CYP2D6. Drug Metab. Dispos. · 2011
• Analysis of epoxyeicosatrienoic acids by chiral liquid chromatography/electron capture atmospheric pressure chemical ionization mass spectrometry using [13C]-analog internal standards. Rapid Commun. Mass Spectrom. · 2010
• Stereoselective epoxidation of the last double bond of polyunsaturated fatty acids by human cytochromes P450. J. Lipid Res. · 2010
• The endocannabinoid anandamide is a substrate for the human polymorphic cytochrome P450 2D6. J. Pharmacol. Exp. Ther. · 2008
• Crystal structure of human cytochrome P450 2D6. J. Biol. Chem. · 2006
• Identification and characterization of novel sequence variations in the cytochrome P4502D6 (CYP2D6) gene in African Americans. Pharmacogenomics J. · 2005
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. · 2004
• Genetic variation in eleven phase I drug metabolism genes in an ethnically diverse population. Pharmacogenomics · 2004
• Biosynthesis of all-trans-retinoic acid from all-trans-retinol: catalysis of all-trans-retinol oxidation by human P-450 cytochromes. Drug Metab. Dispos. · 2000
• … and 12 more in the literature graph