Target Information

Target General Information

Target ID

T59720 (Former ID: TTDR00659)

Target Name

Fragile histidine triad protein (FHIT)

Synonyms

Fragile histidinetriad protein; Fragile histidinetriad (FHIT) gene; Dinucleosidetriphosphatase; Diadenosine 5',5'''-P1,P3-triphosphate hydrolase; Bis(5'-adenosyl)-triphosphatase; AP3AASE; AP3A hydrolase

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Gene Name

FHIT

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

Nausea/vomiting [ICD-11: MD90]

Function

Can also hydrolyze P(1)-P(4)-bis(5'-adenosyl) tetraphosphate (Ap4A), but has extremely low activity with ATP. Modulates transcriptional activation by CTNNB1 and thereby contributes to regulate the expression of genes essential for cell proliferation and survival, such as CCND1 and BIRC5. Plays a role in the induction of apoptosis via SRC and AKT1 signaling pathways. Inhibits MDM2-mediated proteasomal degradation of p53/TP53 and thereby plays a role in p53/TP53-mediated apoptosis. Induction of apoptosis depends on the ability of FHIT to bind P(1)-P(3)-bis(5'-adenosyl) triphosphate or related compounds, but does not require its catalytic activity, it may in part come from the mitochondrial form, which sensitizes the low-affinity Ca(2+) transporters, enhancing mitochondrial calcium uptake. Functions as tumor suppressor. Cleaves P(1)-P(3)-bis(5'-adenosyl) triphosphate (Ap3A) to yield AMP and ADP.

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BioChemical Class

Acid anhydride hydrolase

UniProt ID

FHIT_HUMAN

EC Number

EC 3.6.1.29

Sequence

MSFRFGQHLIKPSVVFLKTELSFALVNRKPVVPGHVLVCPLRPVERFHDLRPDEVADLFQ
TTQRVGTVVEKHFHGTSLTFSMQDGPEAGQTVKHVHVHVLPRKAGDFHRNDSIYEELQKH
DKEDFPASWRSEEEMAAEAAALRVYFQ

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3D Structure

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PDB

Drugs and Modes of Action

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Approved Drug(s)

[+] 1 Approved Drugs

Fructose

Drug Info

Approved

Vomiting

[2]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 3 Inhibitor drugs

Fructose

Drug Info

[1]

Adenosine Monotungstate

Drug Info

[1]

Ado-P-Ch2-P-Ps-Ado

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: Adenosine monophosphate

Ligand Info

Structure Description

FHIT (FRAGILE HISTIDINE TRIAD PROTEIN) IN COMPLEX WITH ADENOSINE/SULFATE AMP ANALOG

PDB:3FIT

Method

X-ray diffraction

Resolution

2.40 Å

Mutation

Yes

[3]

PDB Sequence

MSFRFGQHLI

¹⁰

KPSVVFLKTE

²⁰

LSFALVNRKP

³⁰

VVPGHVLVCP

⁴⁰

LRPVERFHDL

⁵⁰

RPDEVADLFQ

⁶⁰

TTQRVGTVVE

⁷⁰

KHFHGTSLTF

⁸⁰

SQDGPEAGQT

⁹¹

VKHVHVHVLP

¹⁰¹

RKAGDWRSEE

¹³³

EAAEAAALRV

¹⁴⁴

Residue

Distance (Å)

PHE5

3.838

HIS8

3.098

ILE10

3.063

LEU25

4.185

VAL26

4.048

ASN27

3.080

ARG28

3.679

Residue

Distance (Å)

LYS29

4.359

HIS35

3.966

LEU37

3.347

THR91

2.781

VAL92

4.088

HIS96

4.245

HIS98

4.415

Ligand Name: alphabeta-methyleneADP

Ligand Info

Structure Description

FHIT-SUBSTRATE ANALOG

PDB:5FIT

Method

X-ray diffraction

Resolution

2.30 Å

Mutation

Yes

[4]

PDB Sequence

SFRFGQHLIK

¹¹

PSVVFLKTEL

²¹

SFALVNRKPV

³¹

VPGHVLVCPL

⁴¹

RPVERFHDLR

⁵¹

PDEVADLFQT

⁶¹

TQRVGTVVEK

⁷¹

HFHGTSLTFS

⁸¹

QDGPEAGQTV

⁹²

KHVHVHVLPR

¹⁰²

KAGDASWRSE

¹³²

EEAAEAAALR

¹⁴³

VYFQ

Residue

Distance (Å)

PHE5

3.892

HIS8

3.328

ILE10

4.213

LEU25

3.655

VAL26

3.680

ASN27

2.776

ARG28

3.656

LYS29

3.651

HIS35

3.511

Residue

Distance (Å)

LEU37

3.588

GLN83

2.536

GLY89

3.140

GLN90

3.828

THR91

3.157

VAL92

3.321

HIS96

2.807

HIS98

2.913

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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	Pathway Map
Purine metabolism	hsa00230	Affiliated Target
Class: Metabolism => Nucleotide metabolism	Pathway Hierarchy

Degree	1	Degree centrality	1.07E-04	Betweenness centrality	0.00E+00
Closeness centrality	1.37E-01	Radiality	1.14E+01	Clustering coefficient	0.00E+00
Neighborhood connectivity	4.00E+00	Topological coefficient	1.00E+00	Eccentricity	12
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 Regulators

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Target-regulating microRNAs

Target-regulating microRNAs Info

References

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REF 1

How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.

REF 2

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

REF 3

MAD analysis of FHIT, a putative human tumor suppressor from the HIT protein family. Structure. 1997 Jun 15;5(6):763-74.

REF 4

Structure-based analysis of catalysis and substrate definition in the HIT protein family. Science. 1997 Oct 10;278(5336):286-90.

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