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UniProtKB - P08684 (CP3A4_HUMAN)

Entry version 232 (29 Sep 2021)
Sequence version 4 (23 Jan 2007)
Previous versions | rss
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Protein

Cytochrome P450 3A4

Gene

CYP3A4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score:

Annotation score:5 out of 5

<p>The annotation score provides a heuristic measure of the annotation content of a UniProtKB entry or proteome. This score <strong>cannot</strong> be used as a measure of the accuracy of the annotation as we cannot define the 'correct annotation' for any given protein.<p><a href='/help/annotation_score' target='_top'>More...</a></p>-Experimental evidence at protein leveli <p>This indicates the type of evidence that supports the existence of the protein. Note that the 'protein existence' evidence does not give information on the accuracy or correctness of the sequence(s) displayed.<p><a href='/help/protein_existence' target='_top'>More...</a></p>

<p>This section provides any useful information about the protein, mostly biological knowledge.<p><a href='/help/function_section' target='_top'>More...</a></p>Functioni

A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:14559847, PubMed:12865317, PubMed:15373842, PubMed:15764715, PubMed:20702771, PubMed:19965576, PubMed:21490593, PubMed:21576599).

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 hydroxylation of carbon-hydrogen bonds (PubMed:2732228, PubMed:14559847, PubMed:12865317, PubMed:15373842, PubMed:15764715, PubMed:21576599, PubMed:21490593).

Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:14559847, PubMed:12865317).

Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:2732228, PubMed:15373842, PubMed:15764715, PubMed:22773874).

Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:2732228, PubMed:15373842, PubMed:15764715).

Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599).

Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160).

Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576).

Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771).

Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376).

Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772).

Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812).

Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686).

Hydroxylates antimalarial drug quinine (PubMed:8968357).

Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850).

Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D3) (PubMed:29461981).

19 Publications

Miscellaneous

Chimeric transcripts, characterized by CYP3A43 exon 1 joined at canonical splice sites to distinct sets of CYP3A4 exons, have been detected. All are possibly produced by trans-splicing. The chimeric transcripts exist in 3 different combinations: CYP3A43 exon 1 joined in frame to CYP3A4 exons 2-13, CYP3A43 exon 1 joined in frame to CYP3A4 exons 4-13 and CYP3A43 exon 1 joined in frame to CYP3A4 exon 7-13. The longest chimeric isoform (CYP3A43 exon 1 joined to CYP3A4 exons 2-13) exhibits 6-beta-hydroxylase activity, while a shorter isoform (CYP3A43 exon 1 joined to CYP3A4 exons 4-13) does not. All chimeric transcripts are expressed at very low levels in the liver (PubMed:11726664).1 Publication

<p>This subsection of the <a href="http://www.uniprot.org/help/function_section">Function</a> section describes the catalytic activity of an enzyme, i.e. a chemical reaction that the enzyme catalyzes.<p><a href='/help/catalytic_activity' target='_top'>More...</a></p>Catalytic activityi

<p>This subsection of the 'Function' section provides information relevant to cofactors. A cofactor is any non-protein substance required for a protein to be catalytically active. Some cofactors are inorganic, such as the metal atoms zinc, iron, and copper in various oxidation states. Others, such as most vitamins, are organic.<p><a href='/help/cofactor' target='_top'>More...</a></p>Cofactori

heme2 Publications

<p>This subsection of the <a href="http://www.uniprot.org/help/function_section">Function</a> section describes regulatory mechanisms for enzymes, transporters or microbial transcription factors, and reports the components which regulate (by activation or inhibition) the reaction.<p><a href='/help/activity_regulation' target='_top'>More...</a></p>Activity regulationi

Activated by cytochrome b5.2 Publications

<p>This subsection of the 'Function' section describes biophysical and chemical properties, such as maximal absorption, kinetic parameters, pH dependence, redox potentials and temperature dependence.<p><a href='/help/biophysicochemical_properties' target='_top'>More...</a></p>Kineticsi

  1. KM=52.16 µM for 17beta-estradiol (2-hydroxylation)1 Publication
  2. KM=53.88 µM for 17beta-estradiol (4-hydroxylation)1 Publication
  3. KM=7.69 µM for estrone (2-hydroxylation)1 Publication
  4. KM=7.18 µM for estrone (4-hydroxylation)1 Publication
  5. KM=17 µM for testosterone (1beta-hydroxylation)1 Publication
  6. KM=44 µM for testosterone (2beta-hydroxylation)1 Publication
  7. KM=23 µM for testosterone (6beta-hydroxylation)1 Publication
  8. KM=32 µM for testosterone (15beta-hydroxylation)1 Publication
  9. KM=182 µM for cholesterol (25-hydroxylation)1 Publication
  10. KM=62 µM for cholesterol (4beta-hydroxylation)1 Publication
  11. KM=37 µM for cholesterol (22R-hydroxylation)1 Publication
  12. KM=161 µM for cholesterol (24R-hydroxylation)1 Publication
  13. KM=15 µM for cholesterol (24S-hydroxylation)1 Publication
  14. KM=80 µM for cholesterol (26-hydroxylation)1 Publication
  15. KM=118 µM for anandamide (epoxidation across positions 5 and 6)1 Publication
  16. KM=48 µM for anandamide (epoxidation across positions 8 and 9)1 Publication
  17. KM=118 µM for anandamide (epoxidation across positions 11 and 12)1 Publication
  18. KM=80 µM for anandamide (epoxidation across positions 14 and 15)1 Publication
  19. KM=25 µM for all-trans retinol1 Publication
  20. KM=34 µM for all-trans-retinoate (4-hydroxylation)1 Publication
  21. KM=89 µM for cortisone (6beta-hydroxylation)1 Publication
  22. KM=148 µM for cortisol (6beta-hydroxylation)1 Publication
  23. KM=114.4 µM for quinine1 Publication
  24. KM=450 µM for 1,4-cineole1 Publication
  1. Vmax=1020 pmol/min/nmol enzyme toward 17beta-estradiol (2-hydroxylation)1 Publication
  2. Vmax=448.5 pmol/min/nmol enzyme toward 17beta-estradiol (4-hydroxylation)1 Publication
  3. Vmax=167.5 pmol/min/nmol enzyme toward estrone (2-hydroxylation)1 Publication
  4. Vmax=79.5 pmol/min/nmol enzyme toward estrone (4-hydroxylation)1 Publication
  5. Vmax=42 pmol/min/nmol enzyme toward cholesterol (25-hydroxylation)1 Publication
  6. Vmax=12 pmol/min/nmol enzyme toward cholesterol (4beta-hydroxylation)1 Publication
  7. Vmax=3.42 pmol/min/nmol enzyme toward cholesterol (22R-hydroxylation)1 Publication
  8. Vmax=3.48 pmol/min/nmol enzyme toward cholesterol (24R-hydroxylation)1 Publication
  9. Vmax=0.2 pmol/min/nmol enzyme toward cholesterol (24S-hydroxylation)1 Publication
  10. Vmax=3.18 pmol/min/nmol enzyme toward cholesterol (26-hydroxylation)1 Publication
  11. Vmax=225 pmol/min/nmol enzyme toward all-trans retinol1 Publication
  12. Vmax=195 pmol/min/nmol enzyme toward all-trans-retinoate (4-hydroxylation)1 Publication
  13. Vmax=15 pmol/min/pmol enzyme toward cortisone (6beta-hydroxylation)1 Publication
  14. Vmax=27 pmol/min/pmol enzyme toward cortisol (6beta-hydroxylation)1 Publication
  15. Vmax=7.49 pmol/min/pmol enzyme toward quinine1 Publication
  16. Vmax=7.5 nmol/min/nmol enzyme toward 1,4-cineole1 Publication

<p>This subsection of the <a href="http://www.uniprot.org/help/function_section">'Function'</a> section describes the metabolic pathway(s) associated with a protein.<p><a href='/help/pathway' target='_top'>More...</a></p>Pathwayi: Steroid hormone biosynthesis

This protein is involved in Steroid hormone biosynthesis.2 Publications
View all proteins of this organism that are known to be involved in Steroid hormone biosynthesis.

Pathwayi: retinol metabolism

This protein is involved in the pathway retinol metabolism, which is part of Cofactor metabolism.1 Publication
View all proteins of this organism that are known to be involved in the pathway retinol metabolism and in Cofactor metabolism.

Pathwayi: cholesterol metabolism

This protein is involved in the pathway cholesterol metabolism, which is part of Steroid metabolism.1 Publication
View all proteins of this organism that are known to be involved in the pathway cholesterol metabolism and in Steroid metabolism.

Pathwayi: fatty acid metabolism

This protein is involved in the pathway fatty acid metabolism, which is part of Lipid metabolism.1 Publication
View all proteins of this organism that are known to be involved in the pathway fatty acid metabolism and in Lipid metabolism.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the <a href="http://www.uniprot.org/help/function_section">Function</a> section indicates at which position the protein binds a given metal ion. The nature of the metal is indicated in the 'Description' field.<p><a href='/help/metal' target='_top'>More...</a></p>Metal bindingi442Iron (heme axial ligand)Combined sources1

<p>The <a href="http://www.geneontology.org/">Gene Ontology (GO)</a> project provides a set of hierarchical controlled vocabulary split into 3 categories:<p><a href='/help/gene_ontology' target='_top'>More...</a></p>GO - Molecular functioni

Complete GO annotation on QuickGO ...

GO - Biological processi

Complete GO annotation on QuickGO ...

<p>UniProtKB Keywords constitute a <a href="http://www.uniprot.org/keywords">controlled vocabulary</a> with a hierarchical structure. Keywords summarise the content of a UniProtKB entry and facilitate the search for proteins of interest.<p><a href='/help/keywords' target='_top'>More...</a></p>Keywordsi

Molecular functionMonooxygenase, Oxidoreductase
Biological processFatty acid metabolism, Lipid biosynthesis, Lipid metabolism, Steroid biosynthesis, Steroid metabolism, Sterol metabolism
LigandHeme, Iron, Metal-binding

Enzyme and pathway databases

BioCyc Collection of Pathway/Genome Databases

More...BioCyci		MetaCyc:HS08544-MONOMER

BRENDA Comprehensive Enzyme Information System

More...BRENDAi		1.14.14.55, 2681
1.14.14.73, 2681
1.14.99.38, 2681

Pathway Commons web resource for biological pathway data

More...PathwayCommonsi		P08684

Reactome - a knowledgebase of biological pathways and processes

More...Reactomei		R-HSA-211981, Xenobiotics
R-HSA-5423646, Aflatoxin activation and detoxification
R-HSA-9027307, Biosynthesis of maresin-like SPMs

SABIO-RK: Biochemical Reaction Kinetics Database

More...SABIO-RKi		P08684

SIGNOR Signaling Network Open Resource

More...SIGNORi		P08684

UniPathway: a resource for the exploration and annotation of metabolic pathways

More...UniPathwayi		UPA00199
UPA00296
UPA00912

Chemistry databases

SwissLipids knowledge resource for lipid biology

More...SwissLipidsi		SLP:000001201

<p>This section provides information about the protein and gene name(s) and synonym(s) and about the organism that is the source of the protein sequence.<p><a href='/help/names_and_taxonomy_section' target='_top'>More...</a></p>Names & Taxonomyi

<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section provides an exhaustive list of all names of the protein, from commonly used to obsolete, to allow unambiguous identification of a protein.<p><a href='/help/protein_names' target='_top'>More...</a></p>Protein namesi
Recommended name:
Cytochrome P450 3A41 Publication (EC:1.14.14.14 Publications)
Alternative name(s):
1,4-cineole 2-exo-monooxygenase1 Publication
1,8-cineole 2-exo-monooxygenase (EC:1.14.14.561 Publication)
Albendazole monooxygenase (sulfoxide-forming) (EC:1.14.14.731 Publication)
Albendazole sulfoxidase
CYPIIIA3
CYPIIIA4
Cholesterol 25-hydroxylase1 Publication