Target Information

Target General Information

Target ID

T19244

Target Name

S-mephenytoin 4-hydroxylase (CYP2C9)

Synonyms

Cytochrome P450 PB-1; Cytochrome P450 MP-8; Cytochrome P450 MP-4; Cytochrome P450 2C9; Cytochrome P-450MP; Cholesterol 25-hydroxylase; CYPIIC9; CYP2C10; (S)-limonene 7-monooxygenase; (S)-limonene 6-monooxygenase; (R)-limonene 6-monooxygenase

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Gene Name

CYP2C9

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

Bacterial infection [ICD-11: 1A00-1C4Z]

Function

In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan. Cytochromes P450 are a group of heme-thiolate monooxygenases.

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BioChemical Class

Paired donor oxygen oxidoreductase

UniProt ID

CP2C9_HUMAN

EC Number

EC 1.14.14.-

Sequence

MDSLVVLVLCLSCLLLLSLWRQSSGRGKLPPGPTPLPVIGNILQIGIKDISKSLTNLSKV
YGPVFTLYFGLKPIVVLHGYEAVKEALIDLGEEFSGRGIFPLAERANRGFGIVFSNGKKW
KEIRRFSLMTLRNFGMGKRSIEDRVQEEARCLVEELRKTKASPCDPTFILGCAPCNVICS
IIFHKRFDYKDQQFLNLMEKLNENIKILSSPWIQICNNFSPIIDYFPGTHNKLLKNVAFM
KSYILEKVKEHQESMDMNNPQDFIDCFLMKMEKEKHNQPSEFTIESLENTAVDLFGAGTE
TTSTTLRYALLLLLKHPEVTAKVQEEIERVIGRNRSPCMQDRSHMPYTDAVVHEVQRYID
LLPTSLPHAVTCDIKFRNYLIPKGTTILISLTSVLHDNKEFPNPEMFDPHHFLDEGGNFK
KSKYFMPFSAGKRICVGEALAGMELFLFLTSILQNFNLKSLVDPKNLDTTPVVNGFASVP
PFYQLCFIPV

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3D Structure

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PDB

ADReCS ID

BADD_A01337 ; BADD_A02053 ; BADD_A02189 ; BADD_A05391 ; BADD_A05554 ; BADD_A06627

HIT2.0 ID

T69RXK

Drugs and Modes of Action

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Approved Drug(s)

[+] 1 Approved Drugs

Sulfaphenazole

Drug Info

Approved

Bacterial infection

[2]

Mode of Action

[+] 1 Modes of Action

Modulator

[+] 1 Modulator drugs

Sulfaphenazole

Drug Info

[1]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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Ligand Name: Flurbiprofen

Ligand Info

Structure Description

Crystal Structure of P4502C9 with Flurbiprofen bound

PDB:1R9O

Method

X-ray diffraction

Resolution

2.00 Å

Mutation

Yes

[3]

PDB Sequence

RGKLPPGPTP

³⁵

LPLQIGIKDI

⁵⁰

SKSLTNLSKV

⁶⁰

YGPVFTLYFG

⁷⁰

LKPIVVLHGY

⁸⁰

EAVKEALIDL

⁹⁰

GEEFSGRGIF

¹⁰⁰

PLAERANRGF

¹¹⁰

GIVFSNGKKW

¹²⁰

KEIRRFSLMT

¹³⁰

LRNFGMGKRS

¹⁴⁰

IEDRVQEEAR

¹⁵⁰

CLVEELRKTK

¹⁶⁰

ASPCDPTFIL

¹⁷⁰

GCAPCNVICS

¹⁸⁰

IIFHKRFDYK

¹⁹⁰

DQQFLNLMEK

²⁰⁰

LNENIKILSS

²¹⁰

PWIPIIDYFP

²²⁷

GTHNKLLKNV

²³⁷

AFMKSYILEK

²⁴⁷

VKEHQESMDM

²⁵⁷

NNPQDFIDCF

²⁶⁷

LMKMEKEKHN

²⁷⁷

QPSEFTIESL

²⁸⁷

ENTAVDLFGA

²⁹⁷

GTETTSTTLR

³⁰⁷

YALLLLLKHP

³¹⁷

EVTAKVQEEI

³²⁷

ERVIGRNRSP

³³⁷

CMQDRSHMPY

³⁴⁷

TDAVVHEVQR

³⁵⁷

YIDLLPTSLP

³⁶⁷

HAVTCDIKFR

³⁷⁷

NYLIPKGTTI

³⁸⁷

LISLTSVLHD

³⁹⁷

NKEFPNPEMF

⁴⁰⁷

DPHHFLDEGG

⁴¹⁷

NFKKSKYFMP

⁴²⁷

FSAGKRICVG

⁴³⁷

EALAGMELFL

⁴⁴⁷

FLTSILQNFN

⁴⁵⁷

LKSLVDPKNL

⁴⁶⁷

DTTPVVNGFA

⁴⁷⁷

SVPPFYQLCF

⁴⁸⁷

IPIHH

Residue

Distance (Å)

ARG108

2.693

VAL113

3.722

PHE114

3.810

LEU201

4.123

ASN204

3.223

ILE205

3.565

LEU208

3.584

LEU233

4.917

VAL237

3.720

Residue

Distance (Å)

MET240

3.667

VAL292

3.850

ASP293

3.645

GLY296

3.539

ALA297

3.354

THR301

3.829

LEU362

4.351

LEU366

3.762

Ligand Name: Losartan

Ligand Info

Structure Description

Crystal structure of CYP2C9 genetic variant A477T (*30) in complex with multiple losartan molecules

PDB:5X23

Method

X-ray diffraction

Resolution

2.00 Å

Mutation

Yes

[4]

PDB Sequence

KLPPGPTPLP

³⁷

VIGNILQIGI

⁴⁷

KDISKSLTNL

⁵⁷

SKVYGPVFTL

⁶⁷

YFGLKPIVVL

⁷⁷

HGYEAVKEAL

⁸⁷

IDLGEEFSGR

⁹⁷

GIFPLAERAN

¹⁰⁷

RGFGIVFSNG

¹¹⁷

KKWKEIRRFS

¹²⁷

LMTLRNFGMG

¹³⁷

KRSIEDRVQE

¹⁴⁷

EARCLVEELR

¹⁵⁷

KTKASPCDPT

¹⁶⁷

FILGCAPCNV

¹⁷⁷

ICSIIFHKRF

¹⁸⁷

DYKDQQFLNL

¹⁹⁷

MEKLNENIKI

²⁰⁷

LSSPWIQICN

²¹⁷

NFSPIIDYFP

²²⁷

GTHNKLLKNV

²³⁷

AFMKSYILEK

²⁴⁷

VKEHQESMDM

²⁵⁷

NNPQDFIDCF

²⁶⁷

LMKMEKEKHN

²⁷⁷

QPSEFTIESL

²⁸⁷

ENTAVDLFGA

²⁹⁷

GTETTSTTLR

³⁰⁷

YALLLLLKHP

³¹⁷

EVTAKVQEEI

³²⁷

ERVIGRNRSP

³³⁷

CMQDRSHMPY

³⁴⁷

TDAVVHEVQR

³⁵⁷

YIDLLPTSLP

³⁶⁷

HAVTCDIKFR

³⁷⁷

NYLIPKGTTI

³⁸⁷

LISLTSVLHD

³⁹⁷

NKEFPNPEMF

⁴⁰⁷

DPHHFLDEGG

⁴¹⁷

NFKKSKYFMP

⁴²⁷

FSAGKRICVG

⁴³⁷

EALAGMELFL

⁴⁴⁷

FLTSILQNFN

⁴⁵⁷

LKSLVDPKNL

⁴⁶⁷

DTTPVVNGFT

⁴⁷⁷

SVPPFYQLCF

⁴⁸⁷

IPI

Residue

Distance (Å)

PHE69

3.824

ILE74

4.556

GLY98

4.833

ILE99

4.940

PHE100

3.539

LEU102

4.151

ALA103

3.842

ALA106

3.591

ASN107

4.640

ARG108

2.147

VAL113

3.843

PHE114

3.982

LYS200

4.301

LEU201

2.739

ASN204

3.174

ILE205

4.170

LEU208

3.668

ILE213

4.795

GLN214

2.791

ILE215

4.861

ASN218

2.371

TYR225

4.225

PHE226

3.368

PRO227

3.410

Residue

Distance (Å)

GLY228

3.012

THR229

3.079

ASN231

3.436

LYS232

3.188

LEU233

4.046

LYS235

4.554

ASN236

3.530

VAL237

3.614

MET240

2.957

VAL292

3.689

ASP293

3.180

GLY296

3.580

ALA297

3.412

THR301

4.717

LEU361

4.658

LEU362

3.774

PRO363

3.078

THR364

2.867

SER365

2.214

LEU366

3.840

PRO367

3.324

LEU388

4.091

PHE476

2.286

THR477

4.255

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Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues. The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Human Tissue Distribution Human Pathway Affiliation Biological Network Descriptors

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.

The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Human Tissue Distribution

Human Pathway Affiliation

Biological Network Descriptors

There is no similarity protein (E value < 0.005) for this target


Note: If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.

KEGG Pathway	Pathway ID	Affiliated Target
Arachidonic acid metabolism	hsa00590	Affiliated Target
Class: Metabolism => Lipid metabolism	Pathway Hierarchy
Linoleic acid metabolism	hsa00591	Affiliated Target
Class: Metabolism => Lipid metabolism	Pathway Hierarchy
Retinol metabolism	hsa00830	Affiliated Target
Class: Metabolism => Metabolism of cofactors and vitamins	Pathway Hierarchy
Metabolism of xenobiotics by cytochrome P450	hsa00980	Affiliated Target
Class: Metabolism => Xenobiotics biodegradation and metabolism	Pathway Hierarchy
Drug metabolism - cytochrome P450	hsa00982	Affiliated Target
Class: Metabolism => Xenobiotics biodegradation and metabolism	Pathway Hierarchy
Serotonergic synapse	hsa04726	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy
Click to Show/Hide the Information of Affiliated Human Pathways

Degree	8	Degree centrality	8.59E-04	Betweenness centrality	6.59E-04
Closeness centrality	1.71E-01	Radiality	1.27E+01	Clustering coefficient	3.57E-02
Neighborhood connectivity	6.38E+00	Topological coefficient	2.16E-01	Eccentricity	12
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

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Target-regulating microRNAs

Target-regulating microRNAs Info

References

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REF 1

Identification of amino acid substitutions that confer a high affinity for sulfaphenazole binding and a high catalytic efficiency for warfarin meta... Biochemistry. 1998 Nov 17;37(46):16270-9.

REF 2

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

REF 3

The structure of human cytochrome P450 2C9 complexed with flurbiprofen at 2.0-A resolution. J Biol Chem. 2004 Aug 20;279(34):35630-7.

REF 4

Structural Basis of Single-Nucleotide Polymorphisms in Cytochrome P450 2C9. Biochemistry. 2017 Oct 17;56(41):5476-5480.

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