Target Information

Target General Information

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Target ID

T50973 (Former ID: TTDI02605)

Target Name

Kynurenine 3-hydroxylase (KMO)

Synonyms

Kynurenine 3monooxygenase; Kynurenine 3-monooxygenase

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Gene Name

KMO

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

Pancreatitis [ICD-11: DC31-DC34]

Function

Required for synthesis of quinolinic acid, a neurotoxic NMDA receptor antagonist and potential endogenous inhibitor of NMDA receptor signaling in axonal targeting, synaptogenesis and apoptosis during brain development. Quinolinic acid may also affect NMDA receptor signaling in pancreatic beta cells, osteoblasts, myocardial cells, and the gastrointestinal tract. Catalyzes the hydroxylation of L-kynurenine (L-Kyn) to form 3-hydroxy-L-kynurenine (L-3OHKyn).

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BioChemical Class

Paired donor oxygen oxidoreductase

UniProt ID

KMO_HUMAN

EC Number

EC 1.14.13.9

Sequence

MDSSVIQRKKVAVIGGGLVGSLQACFLAKRNFQIDVYEAREDTRVATFTRGRSINLALSH
RGRQALKAVGLEDQIVSQGIPMRARMIHSLSGKKSAIPYGTKSQYILSVSRENLNKDLLT
AAEKYPNVKMHFNHRLLKCNPEEGMITVLGSDKVPKDVTCDLIVGCDGAYSTVRSHLMKK
PRFDYSQQYIPHGYMELTIPPKNGDYAMEPNYLHIWPRNTFMMIALPNMNKSFTCTLFMP
FEEFEKLLTSNDVVDFFQKYFPDAIPLIGEKLLVQDFFLLPAQPMISVKCSSFHFKSHCV
LLGDAAHAIVPFFGQGMNAGFEDCLVFDELMDKFSNDLSLCLPVFSRLRIPDDHAISDLS
MYNYIEMRAHVNSSWFIFQKNMERFLHAIMPSTFIPLYTMVTFSRIRYHEAVQRWHWQKK
VINKGLFFLGSLIAISSTYLLIHYMSPRSFLRLRRPWNWIAHFRNTTCFPAKAVDSLEQI
SNLISR

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3D Structure

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AlphaFold

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

GSK065

Drug Info

Phase 1

Pancreatitis

[2]

Preclinical Drug(s)

[+] 5 Preclinical Drugs

CHDI-340246

Drug Info

Preclinical

Huntington disease

[2]

GSK180

Drug Info

Preclinical

Neurodegenerative disorder

[2]

GSK366

Drug Info

Preclinical

Pancreatitis

[2]

Ro 61-8048

Drug Info

Preclinical

Neurodegenerative disorder

[2]

UPF-648

Drug Info

Preclinical

Neurodegenerative disorder

[2]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 42 Inhibitor drugs

GSK065

Drug Info

[3]

Aryl pyrimidine derivative 2

Drug Info

[1]

Aryl pyrimidine derivative 3

Drug Info

[1]

Aryl pyrimidine derivative 4

Drug Info

[1]

Aryl pyrimidine derivative 5

Drug Info

[1]

Aryl pyrimidine derivative 6

Drug Info

[1]

Aryl pyrimidine derivative 7

Drug Info

[1]

Aryl pyrimidine derivative 8

Drug Info

[1]

Aryl pyrimidine derivative 9

Drug Info

[1]

Benzene sulfonamide derivative 1

Drug Info

[1]

Benzene sulfonamide derivative 2

Drug Info

[1]

Benzene sulfonamide derivative 3

Drug Info

[1]

Benzene sulfonamide derivative 4

Drug Info

[1]

Benzene sulfonamide derivative 5

Drug Info

[1]

Benzene sulfonamide derivative 6

Drug Info

[1]

Benzene sulfonamide derivative 7

Drug Info

[1]

Cyclopropane 1-carboxylic acid derivative 1

Drug Info

[1]

Cyclopropane 1-carboxylic acid derivative 10

Drug Info

[1]

Cyclopropane 1-carboxylic acid derivative 2

Drug Info

[1]

Cyclopropane 1-carboxylic acid derivative 3

Drug Info

[1]

Cyclopropane 1-carboxylic acid derivative 4

Drug Info

[1]

Cyclopropane 1-carboxylic acid derivative 5

Drug Info

[1]

Cyclopropane 1-carboxylic acid derivative 6

Drug Info

[1]

Cyclopropane 1-carboxylic acid derivative 7

Drug Info

[1]

Cyclopropane 1-carboxylic acid derivative 8

Drug Info

[1]

Cyclopropane 1-carboxylic acid derivative 9

Drug Info

[1]

Isoxazoles and isoxazoline derivative 1

Drug Info

[1]

Isoxazoles and isoxazoline derivative 2

Drug Info

[1]

Isoxazoles and isoxazoline derivative 3

Drug Info

[1]

Isoxazoles and isoxazoline derivative 4

Drug Info

[1]

Isoxazoles and isoxazoline derivative 5

Drug Info

[1]

Isoxazoles and isoxazoline derivative 6

Drug Info

[1]

PMID27172114-Compound-47

Drug Info

[1]

PMID27172114-Compound-49

Drug Info

[1]

Pyrimidine benzenesulfonamide derivative 1

Drug Info

[1]

Pyrimidine benzenesulfonamide derivative 2

Drug Info

[1]

Pyrimidine benzenesulfonamide derivative 3

Drug Info

[1]

CHDI-340246

Drug Info

[4]

GSK180

Drug Info

[2]

GSK366

Drug Info

[3]

Ro 61-8048

Drug Info

[5]

UPF-648

Drug Info

[6]

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: Flavin-Adenine Dinucleotide

Ligand Info

Structure Description

Crystal Structure of Human KMO

PDB:5X68

Method

X-ray diffraction

Resolution

2.10 Å

Mutation

[7]

PDB Sequence

RKKVAVIGGG

¹⁷

LVGSLQACFL

²⁷

AKRNFQIDVY

³⁷

EAREDTRVAS

⁵³

INLALSHRGR

⁶³

QALKAVGLED

⁷³

QIVSQGIPMR

⁸³

ARMIHSLSGK

⁹³

KSAIPYGTKS

¹⁰³

QYILSVSREN

¹¹³

LNKDLLTAAE

¹²³

KYPNVKMHFN

¹³³

HRLLCNPEEG

¹⁴⁴

MITVLGSDKV

¹⁵⁴

PKDVTCDLIV

¹⁶⁴

GCDGAYSTVR

¹⁷⁴

SHLMKPRFDY

¹⁸⁵

SQQYIPHGYM

¹⁹⁵

ELTIPPKNGD

²⁰⁵

YAMEPNYLHI

²¹⁵

WPRNTFMMIA

²²⁵

LPNMNKSFTC

²³⁵

TLFMPFEEFE

²⁴⁵

KLLTSNDVVD

²⁵⁵

FFQKYFPDAI

²⁶⁵

PLIGEKLLVQ

²⁷⁵

DFFLLPAQPM

²⁸⁵

ISVCSSFHFS

²⁹⁷

HCVLLGDAAH

³⁰⁷

AIVPFFGQGM

³¹⁷

NAGFEDCLVF

³²⁷

DELMDKFSND

³³⁷

LSLCLPVFSR

³⁴⁷

LRIPDDSDLS

³⁶⁰

MYNYIEMRA

Residue

Distance (Å)

ILE14

3.997

GLY15

3.502

GLY16

4.278

GLY17

3.577

LEU18

3.450

VAL19

2.866

GLY20

3.926

TYR37

3.429

GLU38

2.557

ALA39

3.349

ARG40

3.261

SER53

4.134

ASN55

4.658

LEU56

3.488

ALA57

2.761

ARG111

2.209

HIS134

3.579

ARG135

3.676

LEU136

2.961

Residue

Distance (Å)

CYS166

3.666

ASP167

3.388

GLY168

3.564

ALA169

4.766

THR172

2.812

TYR194

3.782

THR236

4.491

PHE238

4.178

MET285

4.706

LEU302

4.360

GLY303

3.437

ASP304

2.544

ALA305

4.642

ILE309

4.548

PRO311

3.698

GLN315

3.338

GLY316

2.985

MET317

2.988

ASN318

2.999

Ligand Name: N(6),N(6)-Dimethyl-L-lysine

Ligand Info

Structure Description

Crystal Structure of Human KMO

PDB:5X68

Method

X-ray diffraction

Resolution

2.10 Å

Mutation

[7]

PDB Sequence

RKKVAVIGGG

¹⁷

LVGSLQACFL

²⁷

AKRNFQIDVY

³⁷

EAREDTRVAS

⁵³

INLALSHRGR

⁶³

QALKAVGLED

⁷³

QIVSQGIPMR

⁸³

ARMIHSLSGK

⁹³

KSAIPYGTKS

¹⁰³

QYILSVSREN

¹¹³

LNKDLLTAAE

¹²³

KYPNVKMHFN

¹³³

HRLLCNPEEG

¹⁴⁴

MITVLGSDKV

¹⁵⁴

PKDVTCDLIV

¹⁶⁴

GCDGAYSTVR

¹⁷⁴

SHLMKPRFDY

¹⁸⁵

SQQYIPHGYM

¹⁹⁵

ELTIPPKNGD

²⁰⁵

YAMEPNYLHI

²¹⁵

WPRNTFMMIA

²²⁵

LPNMNKSFTC

²³⁵

TLFMPFEEFE

²⁴⁵

KLLTSNDVVD

²⁵⁵

FFQKYFPDAI

²⁶⁵

PLIGEKLLVQ

²⁷⁵

DFFLLPAQPM

²⁸⁵

ISVCSSFHFS

²⁹⁷

HCVLLGDAAH

³⁰⁷

AIVPFFGQGM

³¹⁷

NAGFEDCLVF

³²⁷

DELMDKFSND

³³⁷

LSLCLPVFSR

³⁴⁷

LRIPDDSDLS

³⁶⁰

MYNYIEMRA

Residue

Distance (Å)

LEU136

3.185

LEU137

1.330

CYS139

1.329

ASN140

4.708

GLU142

2.703

MET145

4.958

ILE146

3.575

THR147

2.578

VAL148

4.965

THR172

4.647

HIS176

3.593

LEU177

3.925

MET178

1.330

LYS180

1.330

PRO181

3.882

SER287

4.549

Residue

Distance (Å)

VAL288

1.327

CYS290

1.331

SER291

3.957

PHE293

4.982

HIS294

3.425

PHE295

1.329

SER297

1.328

HIS298

3.568

ALA306

3.815

HIS307

4.491

LEU338

4.937

LEU342

3.842

PRO343

4.244

ILE350

4.339

ASP353

3.075

Click to View More Binding Site Information of This Target with Different Ligands

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	Pathway Map
Tryptophan metabolism	hsa00380	Affiliated Target
Class: Metabolism => Amino acid metabolism	Pathway Hierarchy

Degree	6	Degree centrality	6.45E-04	Betweenness centrality	1.93E-04
Closeness centrality	1.36E-01	Radiality	1.14E+01	Clustering coefficient	6.00E-01
Neighborhood connectivity	5.67E+00	Topological coefficient	4.72E-01	Eccentricity	14
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

References

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REF 1

Inhibitors of the kynurenine pathway as neurotherapeutics: a patent review (2012-2015).Expert Opin Ther Pat. 2016 Jul;26(7):815-32.

REF 2

Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond. Nat Rev Drug Discov. 2019 May;18(5):379-401.

REF 3

Structural and mechanistic basis of differentiated inhibitors of the acute pancreatitis target kynurenine-3-monooxygenase. Nat Commun. 2017 Jun 12;8:15827.

REF 4

The novel KMO inhibitor CHDI-340246 leads to a restoration of electrophysiological alterations in mouse models of Huntington's disease. Exp Neurol. 2016 Aug;282:99-118.

REF 5

Modification of kynurenine pathway via inhibition of kynurenine hydroxylase attenuates surgical brain injury complications in a male rat model. J Neurosci Res. 2020 Jan;98(1):155-167.

REF 6

Structural basis of kynurenine 3-monooxygenase inhibition. Nature. 2013 Apr 18;496(7445):382-5.

REF 7

Structural Basis for Inhibitor-Induced Hydrogen Peroxide Production by Kynurenine 3-Monooxygenase. Cell Chem Biol. 2018 Apr 19;25(4):426-438.e4.

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