Target Information

Target General Information

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Target ID

T20514 (Former ID: TTDS00342)

Target Name

Delta-aminolevulinic acid dehydratase (ALAD)

Synonyms

Porphobilinogen synthase; Delta-aminolevulinate dehydratase; ALADH; ALAD

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Gene Name

ALAD

Target Type

Successful target

[1]

Disease

[+] 2 Target-related Diseases

Acne vulgaris [ICD-11: ED80]

Epidermal dysplasias [ICD-11: EK90]

Function

Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen.

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BioChemical Class

Alpha-carbonic anhydrase

UniProt ID

HEM2_HUMAN

EC Number

EC 4.2.1.24

Sequence

MQPQSVLHSGYFHPLLRAWQTATTTLNASNLIYPIFVTDVPDDIQPITSLPGVARYGVKR
LEEMLRPLVEEGLRCVLIFGVPSRVPKDERGSAADSEESPAIEAIHLLRKTFPNLLVACD
VCLCPYTSHGHCGLLSENGAFRAEESRQRLAEVALAYAKAGCQVVAPSDMMDGRVEAIKE
ALMAHGLGNRVSVMSYSAKFASCFYGPFRDAAKSSPAFGDRRCYQLPPGARGLALRAVDR
DVREGADMLMVKPGMPYLDIVREVKDKHPDLPLAVYHVSGEFAMLWHGAQAGAFDLKAAV
LEAMTAFRRAGADIIITYYTPQLLQWLKEE

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3D Structure

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PDB

ADReCS ID

BADD_A03510

HIT2.0 ID

T63EKR

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: Porphobilinogen

Ligand Info

Structure Description

Crystal structure of native human erythrocyte 5-aminolaevulinic acid dehydratase

PDB:1E51

Method

X-ray diffraction

Resolution

2.83 Å

Mutation

[5]

PDB Sequence

MQPQSVLHSG

¹⁰

YFHPLLRAWQ

²⁰

TATTTLNASN

³⁰

LIYPIFVTDV

⁴⁰

PDDIQPITSL

⁵⁰

PGVARYGVKR

⁶⁰

LEEMLRPLVE

⁷⁰

EGLRCVLIFG

⁸⁰

VPSRVPKDER

⁹⁰

GSAADSEESP

¹⁰⁰

AIEAIHLLRK

¹¹⁰

TFPNLLVACD

¹²⁰

VCLCPYTSHG

¹³⁰

HCGLLSGAFR

¹⁴²

AEESRQRLAE

¹⁵²

VALAYAKAGC

¹⁶²

QVVAPSDMMD

¹⁷²

GRVEAIKEAL

¹⁸²

MAHGLGNRVS

¹⁹²

VMSYSAKFAS

²⁰²

CFYGPFRDAA

²¹²

KSSPAFGDRR

²²²

CYQLPPGARG

²³²

LALRAVDRDV

²⁴²

REGADMLMVK

²⁵²

PGMPYLDIVR

²⁶²

EVKDKHPDLP

²⁷²

LAVYHVSGEF

²⁸²

AMLWHGAQAG

²⁹²

AFDLKAAVLE

³⁰²

AMTAFRRAGA

³¹²

DIIITYYTPQ

³²²

LLQWLK

Residue

Distance (Å)

PHE79

4.274

ASP120

4.175

CYS122

4.234

CYS124

3.667

CYS132

4.669

SER168

2.875

TYR196

4.065

LYS199

3.071

PHE204

4.034

TYR205

3.417

Residue

Distance (Å)

PHE208

2.979

ARG209

2.526

ARG221

2.700

GLN225

2.912

LYS252

1.632

TYR276

3.882

VAL278

3.691

SER279

2.878

GLY280

4.950

TYR318

2.593

Ligand Name: 3-(2-Aminoethyl)-4-(Aminomethyl)Heptanedioic Acid

Ligand Info

Structure Description

Crystal structure of a low activity F12L mutant of human porphobilinogen synthase

PDB:1PV8

Method

X-ray diffraction

Resolution

2.20 Å

Mutation

Yes

[6]

PDB Sequence

YLHPLLRAWQ

²⁰

TATTTLNASN

³⁰

LIYPIFVTDV

⁴⁰

PDDIQPITSL

⁵⁰

PGVARYGVKR

⁶⁰

LEEMLRPLVE

⁷⁰

EGLRCVLIFG

⁸⁰

VPEESPAIEA

¹⁰⁴

IHLLRKTFPN

¹¹⁴

LLVACDVCLC

¹²⁴

AFRAEESRQR

¹⁴⁹

LAEVALAYAK

¹⁵⁹

AGCQVVAPSD

¹⁶⁹

DGRVEAIKEA

¹⁸¹

LMAHGLGNRV

¹⁹¹

SVMSYSAKFA

²⁰¹

SCFYGPFRDA

²¹¹

ALPPGARGLA

²³⁴

LRAVDRDVRE

²⁴⁴

GADMLMVKPG

²⁵⁴

MPYLDIVREV

²⁶⁴

KDKHPDLPLA

²⁷⁴

VYHVSGEFAM

²⁸⁴

LWHGAQAGAF

²⁹⁴

DLKAAVLEAM

³⁰⁴

TAFRRAGADI

³¹⁴

IITYYTPQLL

³²⁴

QWLKEE

Residue

Distance (Å)

PHE79

3.695

ASP120

4.722

SER168

3.359

TYR196

3.693

LYS199

1.288

PHE204

4.401

TYR205

3.106

Residue

Distance (Å)

PHE208

2.722

ARG209

3.317

LYS252

1.449

TYR276

3.834

VAL278

3.704

SER279

3.082

TYR318

2.791

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
Porphyrin metabolism	hsa00860	Affiliated Target
Class: Metabolism => Metabolism of cofactors and vitamins	Pathway Hierarchy

Degree	6	Degree centrality	6.45E-04	Betweenness centrality	2.03E-04
Closeness centrality	1.33E-01	Radiality	1.12E+01	Clustering coefficient	3.33E-01
Neighborhood connectivity	3.50E+00	Topological coefficient	5.28E-01	Eccentricity	13
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

Target Affiliated Biological Pathways

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BioCyc

[+] 2 BioCyc Pathways

Heme biosynthesis

Tetrapyrrole biosynthesis

KEGG Pathway

[+] 2 KEGG Pathways

Porphyrin and chlorophyll metabolism

Metabolic pathways

Panther Pathway

[+] 1 Panther Pathways

Heme biosynthesis

Pathwhiz Pathway

[+] 1 Pathwhiz Pathways

Porphyrin Metabolism

WikiPathways

[+] 2 WikiPathways

Heme Biosynthesis

Metabolism of porphyrins

References

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REF 1

Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides. Nat Biotechnol. 2003 May;21(5):566-9.

REF 2

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 4784).

REF 3

Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.

REF 4

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

REF 5

The Crystal Structure of Human Ala-Dehydratase

REF 6

Control of tetrapyrrole biosynthesis by alternate quaternary forms of porphobilinogen synthase. Nat Struct Biol. 2003 Sep;10(9):757-63.

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