P10632 · CP2C8_HUMAN
- ProteinCytochrome P450 2C8
- GeneCYP2C8
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids490 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697).
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) (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697).
Primarily catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) with a preference for the last double bond (PubMed:15766564, PubMed:19965576, PubMed:7574697).
Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes all trans-retinoic acid toward its 4-hydroxylated form (PubMed:11093772).
Displays 16-alpha hydroxylase activity toward estrogen steroid hormones, 17beta-estradiol (E2) and estrone (E1) (PubMed:14559847).
Plays a role in the oxidative metabolism of xenobiotics. It is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (taxol) (PubMed:26427316).
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) (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697).
Primarily catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) with a preference for the last double bond (PubMed:15766564, PubMed:19965576, PubMed:7574697).
Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes all trans-retinoic acid toward its 4-hydroxylated form (PubMed:11093772).
Displays 16-alpha hydroxylase activity toward estrogen steroid hormones, 17beta-estradiol (E2) and estrone (E1) (PubMed:14559847).
Plays a role in the oxidative metabolism of xenobiotics. It is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (taxol) (PubMed:26427316).
Catalytic activity
- an organic molecule + O2 + reduced [NADPH--hemoprotein reductase] = an alcohol + H+ + H2O + oxidized [NADPH--hemoprotein reductase]This reaction proceeds in the forward direction.
- (5Z,8Z,11Z,14Z)-eicosatetraenoate + O2 + reduced [NADPH--hemoprotein reductase] = (11R,12S)-epoxy-(5Z,8Z,14Z)-eicosatrienoate + H+ + H2O + oxidized [NADPH--hemoprotein reductase]This reaction proceeds in the forward direction.
- (5Z,8Z,11Z,14Z)-eicosatetraenoate + O2 + reduced [NADPH--hemoprotein reductase] = (11S,12R)-epoxy-(5Z,8Z,14Z)-eicosatrienoate + H+ + H2O + oxidized [NADPH--hemoprotein reductase]This reaction proceeds in the forward direction.
- (5Z,8Z,11Z,14Z)-eicosatetraenoate + O2 + reduced [NADPH--hemoprotein reductase] = (14R,15S)-epoxy-(5Z,8Z,11Z)-eicosatrienoate + H+ + H2O + oxidized [NADPH--hemoprotein reductase]This reaction proceeds in the forward direction.
- (5Z,8Z,11Z,14Z)-eicosatetraenoate + O2 + reduced [NADPH--hemoprotein reductase] = (14S,15R)-epoxy-(5Z,8Z,11Z)-eicosatrienoate + H+ + H2O + oxidized [NADPH--hemoprotein reductase]This reaction proceeds in the forward direction.
- (5Z,8Z,11Z,14Z,17Z)-eicosapentaenoate + O2 + reduced [NADPH--hemoprotein reductase] = 11,12-epoxy-(5Z,8Z,14Z,17Z)-eicosatetraenoate + H+ + H2O + oxidized [NADPH--hemoprotein reductase]This reaction proceeds in the forward direction.
- (5Z,8Z,11Z,14Z,17Z)-eicosapentaenoate + O2 + reduced [NADPH--hemoprotein reductase] = 14,15-epoxy-(5Z,8Z,11Z,17Z)-eicosatetraenoate + H+ + H2O + oxidized [NADPH--hemoprotein reductase]This reaction proceeds in the forward direction.
- (5Z,8Z,11Z,14Z,17Z)-eicosapentaenoate + O2 + reduced [NADPH--hemoprotein reductase] = (17R,18S)-epoxy-(5Z,8Z,11Z,14Z)-eicosatetraenoate + H+ + H2O + oxidized [NADPH--hemoprotein reductase]This reaction proceeds in the forward direction.
- (5Z,8Z,11Z,14Z,17Z)-eicosapentaenoate + O2 + reduced [NADPH--hemoprotein reductase] = (17S,18R)-epoxy-(5Z,8Z,11Z,14Z)-eicosatetraenoate + H+ + H2O + oxidized [NADPH--hemoprotein reductase]This reaction proceeds in the forward direction.
- (4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate + O2 + reduced [NADPH--hemoprotein reductase] = (19R,20S)-epoxy-(4Z,7Z,10Z,13Z,16Z)-docosapentaenoate + H+ + H2O + oxidized [NADPH--hemoprotein reductase]This reaction proceeds in the forward direction.
- (4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate + O2 + reduced [NADPH--hemoprotein reductase] = (19S,20R)-epoxy-(4Z,7Z,10Z,13Z,16Z)-docosapentaenoate + H+ + H2O + oxidized [NADPH--hemoprotein reductase]This reaction proceeds in the forward direction.
- all-trans-retinoate + O2 + reduced [NADPH--hemoprotein reductase] = all-trans-4-hydroxyretinoate + H+ + H2O + oxidized [NADPH--hemoprotein reductase]This reaction proceeds in the forward direction.
- 17beta-estradiol + O2 + reduced [NADPH--hemoprotein reductase] = 16alpha,17beta-estriol + H+ + H2O + oxidized [NADPH--hemoprotein reductase]This reaction proceeds in the forward direction.
- estrone + O2 + reduced [NADPH--hemoprotein reductase] = 16alpha-hydroxyestrone + H+ + H2O + oxidized [NADPH--hemoprotein reductase]This reaction proceeds in the forward direction.
Cofactor
Kinetics
KM | SUBSTRATE | pH | TEMPERATURE[C] | NOTES | EVIDENCE | |
---|---|---|---|---|---|---|
50 μM | all-trans-retinoate (4-hydroxylation) | |||||
5.4 μM | (5Z,8Z,11Z,14Z,17Z)-eicosapentaenoate (epoxygenation) | |||||
6 μM | (5Z,8Z,11Z,14Z)-eicosatetraenoate (epoxygenation) | |||||
7.18 μM | paclitaxel | |||||
1.35 μM | amodiaquine |
Vmax | pH | TEMPERATURE[C] | NOTES | EVIDENCE | |
---|---|---|---|---|---|
1211 pmol/min/nmol | toward all-trans-retinoate (4-hydroxylation) | ||||
6.2 nmol/min/nmol | toward (5Z,8Z,11Z,14Z,17Z)-eicosapentaenoate | ||||
4.6 nmol/min/nmol | toward (5Z,8Z,11Z,14Z)-eicosatetraenoate | ||||
2.18 pmol/min/pmol | toward paclitaxel | ||||
11.3 pmol/min/pmol | toward amodiaquine |
Pathway
Steroid metabolism.
Lipid metabolism; arachidonate metabolism.
Cofactor metabolism; retinol metabolism.
Features
Showing features for binding site.
GO annotations
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Chemistry
Names & Taxonomy
Protein names
- Recommended nameCytochrome P450 2C8
- EC number
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionP10632
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Endoplasmic reticulum membrane ; Peripheral membrane protein
Microsome membrane ; Peripheral membrane protein
Keywords
- Cellular component
Disease & Variants
Features
Showing features for natural variant.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Natural variant | VAR_012238 | 139 | in allele CYP2C8*3; reduces enzymatic activity with paclitaxel as substrate; decreases intrinsic clearance of paclitaxel; reduces enzymatic activity with amodiaquine as substrate; dbSNP:rs11572080 | |||
Sequence: R → K | ||||||
Natural variant | VAR_001250 | 154 | ||||
Sequence: E → D | ||||||
Natural variant | VAR_075541 | 171 | in allele CYP2C8*6; no effect on affinity or enzymatic activity with paclitaxel as substrate; decreases affinity for amodiaquine; reduces enzymatic activity with amodiaquine as substrate; decreases intrinsic clearance of amodiaquine; dbSNP:rs142886225 | |||
Sequence: G → S | ||||||
Natural variant | VAR_075542 | 186 | in allele CYP2C8*8; increases affinity for paclitaxel; reduces enzymatic activity with paclitaxel as substrate; decreases intrinsic clearance of paclitaxel; reduces enzymatic activity with amodiaquine as substrate; decreases intrinsic clearance of amodiaquine; dbSNP:rs72558195 | |||
Sequence: R → G | ||||||
Natural variant | VAR_001251 | 193 | ||||
Sequence: N → K | ||||||
Natural variant | VAR_075543 | 223 | in allele CYP2C8*13; reduces enzymatic activity with paclitaxel as substrate; decreases intrinsic clearance of paclitaxel; reduces enzymatic activity with amodiaquine as substrate; decreases intrinsic clearance of amodiaquine; dbSNP:rs2134428602 | |||
Sequence: I → M | ||||||
Natural variant | VAR_075544 | 238 | in allele CYP2C8*14; reduces enzymatic activity with paclitaxel as substrate; decreases intrinsic clearance of paclitaxel; dbSNP:rs188934928 | |||
Sequence: A → P | ||||||
Natural variant | VAR_018958 | 244 | in dbSNP:rs11572102 | |||
Sequence: I → V | ||||||
Natural variant | VAR_075545 | 247 | in allele CYP2C8*9; increases enzymatic activity with paclitaxel as substrate; reduces enzymatic activity with amodiaquine as substrate; decreases intrinsic clearance of amodiaquine; dbSNP:rs769460274 | |||
Sequence: K → R | ||||||
Natural variant | VAR_001252 | 249 | ||||
Sequence: K → R | ||||||
Natural variant | VAR_011754 | 264 | in allele CYP2C8*4; reduces enzymatic activity with paclitaxel as substrate; decreases affinity for amodiaquine; dbSNP:rs1058930 | |||
Sequence: I → M | ||||||
Natural variant | VAR_012239 | 269 | in allele CYP2C8*2; only found in African-Americans; increases intrinsic clearance of paclitaxel; decreases affinity for amodiaquine; increases enzymatic activity with amodiaquine as substrate; dbSNP:rs11572103 | |||
Sequence: I → F | ||||||
Natural variant | VAR_075546 | 383 | in allele CYP2C8*10; reduces enzymatic activity with paclitaxel as substrate; reduces enzymatic activity with amodiaquine as substrate; decreases intrinsic clearance of amodiaquine; dbSNP:rs2134410323 | |||
Sequence: K → N | ||||||
Natural variant | VAR_016947 | 390 | in dbSNP:rs72558194 | |||
Sequence: L → S | ||||||
Natural variant | VAR_012240 | 399 | in allele CYP2C8*3; reduces enzymatic activity with paclitaxel as substrate; decreases intrinsic clearance of paclitaxel; reduces enzymatic activity with amodiaquine as substrate; dbSNP:rs10509681 | |||
Sequence: K → R | ||||||
Natural variant | VAR_001253 | 411 | ||||
Sequence: H → L | ||||||
Natural variant | VAR_075547 | 461 | in allele CYP2C8*12; increases enzymatic activity with paclitaxel as substrate; reduces enzymatic activity with amodiaquine as substrate; decreases intrinsic clearance of amodiaquine | |||
Sequence: Missing |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 688 variants from UniProt as well as other sources including ClinVar and dbSNP.
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for chain, modified residue.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000051699 | 1-490 | Cytochrome P450 2C8 | |||
Sequence: MEPFVVLVLCLSFMLLFSLWRQSCRRRKLPPGPTPLPIIGNMLQIDVKDICKSFTNFSKVYGPVFTVYFGMNPIVVFHGYEAVKEALIDNGEEFSGRGNSPISQRITKGLGIISSNGKRWKEIRRFSLTTLRNFGMGKRSIEDRVQEEAHCLVEELRKTKASPCDPTFILGCAPCNVICSVVFQKRFDYKDQNFLTLMKRFNENFRILNSPWIQVCNNFPLLIDCFPGTHNKVLKNVALTRSYIREKVKEHQASLDVNNPRDFIDCFLIKMEQEKDNQKSEFNIENLVGTVADLFVAGTETTSTTLRYGLLLLLKHPEVTAKVQEEIDHVIGRHRSPCMQDRSHMPYTDAVVHEIQRYSDLVPTGVPHAVTTDTKFRNYLIPKGTTIMALLTSVLHDDKEFPNPNIFDPGHFLDKNGNFKKSDYFMPFSAGKRICAGEGLARMELFLFLTTILQNFNLKSVDDLKNLNTTAVTKGIVSLPPSYQICFIPV | ||||||
Modified residue | 100 | Phosphoserine | ||||
Sequence: S |
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Induction
By phenobarbital.
Gene expression databases
Organism-specific databases
Interaction
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | P10632 | LAMP2 P13473-2 | 3 | EBI-2951522, EBI-21591415 | |
BINARY | P10632 | PRPF40A O75400-2 | 3 | EBI-2951522, EBI-5280197 | |
BINARY | P10632 | SH3GLB1 Q9Y371 | 3 | EBI-2951522, EBI-2623095 |
Protein-protein interaction databases
Chemistry
Miscellaneous
Structure
Sequence & Isoform
- Sequence statusComplete
This entry describes 2 isoforms produced by Alternative splicing.
P10632-1
This isoform has been chosen as the canonical sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
- Name1
- Length490
- Mass (Da)55,825
- Last updated1990-11-01 v2
- ChecksumE920EB2084F477E1
P10632-2
- Name2
Computationally mapped potential isoform sequences
There are 5 potential isoforms mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
G3V188 | G3V188_HUMAN | CYP2C8 | 393 | ||
B7Z1F5 | B7Z1F5_HUMAN | CYP2C8 | 420 | ||
A0A0D9SG51 | A0A0D9SG51_HUMAN | CYP2C8 | 307 | ||
E9PLI9 | E9PLI9_HUMAN | CYP2C8 | 83 | ||
E9PIW6 | E9PIW6_HUMAN | CYP2C8 | 99 |
Features
Showing features for alternative sequence, sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Alternative sequence | VSP_043306 | 1-8 | in isoform 2 | |||
Sequence: MEPFVVLV → MFLQPIAK | ||||||
Alternative sequence | VSP_043307 | 9-110 | in isoform 2 | |||
Sequence: Missing | ||||||
Sequence conflict | 54 | in Ref. 12; no nucleotide entry | ||||
Sequence: F → L | ||||||
Sequence conflict | 67 | in Ref. 12; no nucleotide entry | ||||
Sequence: V → L | ||||||
Sequence conflict | 76 | in Ref. 12; no nucleotide entry | ||||
Sequence: V → C | ||||||
Sequence conflict | 82 | in Ref. 8; AAH20596 | ||||
Sequence: A → S | ||||||
Sequence conflict | 130 | in Ref. 1; AAA35739/AAA35740 and 3; no nucleotide entry | ||||
Sequence: T → N | ||||||
Sequence conflict | 209 | in Ref. 12; no nucleotide entry | ||||
Sequence: N → S | ||||||
Sequence conflict | 384-393 | in Ref. 1; AAA35740 | ||||
Sequence: GTTIMALLTS → SFDNKIMLAA | ||||||
Sequence conflict | 386 | in Ref. 4; BAF85442 | ||||
Sequence: T → A |
Polymorphism
Several alleles are found in the human population, contributing to interindividual variations in the therapeutic efficacy and toxicity of a myriad of drugs such as paclitaxel or amodiaquine. The allele shown here is CYP2C8*1 (PubMed:26427316).
CYP2C8 genetic variations are associated with altered drug metabolism and adverse drug effects including acute rhabdomyolysis after cerivastatin use [MIM:618018]
CYP2C8 genetic variations are associated with altered drug metabolism and adverse drug effects including acute rhabdomyolysis after cerivastatin use [MIM:618018]
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
M17397 EMBL· GenBank· DDBJ | AAA35739.1 EMBL· GenBank· DDBJ | mRNA | ||
M17398 EMBL· GenBank· DDBJ | AAA35740.1 EMBL· GenBank· DDBJ | mRNA | ||
Y00498 EMBL· GenBank· DDBJ | CAA68550.1 EMBL· GenBank· DDBJ | mRNA | ||
AK292753 EMBL· GenBank· DDBJ | BAF85442.1 EMBL· GenBank· DDBJ | mRNA | ||
AK293328 EMBL· GenBank· DDBJ | BAH11492.1 EMBL· GenBank· DDBJ | mRNA | ||
AK315823 EMBL· GenBank· DDBJ | BAF98714.1 EMBL· GenBank· DDBJ | mRNA | ||
AY514490 EMBL· GenBank· DDBJ | AAR89907.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AL359672 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
CH471066 EMBL· GenBank· DDBJ | EAW50018.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC020596 EMBL· GenBank· DDBJ | AAH20596.1 EMBL· GenBank· DDBJ | mRNA | ||
X54807 EMBL· GenBank· DDBJ | CAA38578.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
M21941 EMBL· GenBank· DDBJ | AAA52160.1 EMBL· GenBank· DDBJ | mRNA | ||
M21942 EMBL· GenBank· DDBJ | AAA52161.1 EMBL· GenBank· DDBJ | mRNA | ||
X51535 EMBL· GenBank· DDBJ | CAA35915.1 EMBL· GenBank· DDBJ | mRNA |