Target Information
Target General Information | Top | |||||
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Target ID |
T20514
(Former ID: TTDS00342)
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Target Name |
Delta-aminolevulinic acid dehydratase (ALAD)
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Synonyms |
Porphobilinogen synthase; Delta-aminolevulinate dehydratase; ALADH; ALAD
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Gene Name |
ALAD
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Target Type |
Successful target
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[1] | ||||
Disease | [+] 2 Target-related Diseases | + | ||||
1 | Acne vulgaris [ICD-11: ED80] | |||||
2 | 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
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UniProt ID | ||||||
EC Number |
EC 4.2.1.24
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Sequence |
MQPQSVLHSGYFHPLLRAWQTATTTLNASNLIYPIFVTDVPDDIQPITSLPGVARYGVKR
LEEMLRPLVEEGLRCVLIFGVPSRVPKDERGSAADSEESPAIEAIHLLRKTFPNLLVACD VCLCPYTSHGHCGLLSENGAFRAEESRQRLAEVALAYAKAGCQVVAPSDMMDGRVEAIKE ALMAHGLGNRVSVMSYSAKFASCFYGPFRDAAKSSPAFGDRRCYQLPPGARGLALRAVDR DVREGADMLMVKPGMPYLDIVREVKDKHPDLPLAVYHVSGEFAMLWHGAQAGAFDLKAAV LEAMTAFRRAGADIIITYYTPQLLQWLKEE Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
ADReCS ID | BADD_A03510 | |||||
HIT2.0 ID | T63EKR |
Drugs and Modes of Action | Top | |||||
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Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
1 | Aminolevulinic acid hci | Drug Info | Approved | Acne vulgaris | [2], [3] | |
Mode of Action | [+] 1 Modes of Action | + | ||||
Inhibitor | [+] 12 Inhibitor drugs | + | ||||
1 | Aminolevulinic acid hci | Drug Info | [1], [4], [5] | |||
2 | Porphobilinogen | Drug Info | [6] | |||
3 | 2-Sulfhydryl-Ethanol | Drug Info | [6] | |||
4 | 3-(2-Aminoethyl)-4-(Aminomethyl)Heptanedioic Acid | Drug Info | [6] | |||
5 | 4,7-Dioxosebacic Acid | Drug Info | [6] | |||
6 | 4-Oxosebacic Acid | Drug Info | [6] | |||
7 | 5-Fluorolevulinic Acid | Drug Info | [6] | |||
8 | 5-hydroxyvaleric acid | Drug Info | [7] | |||
9 | Delta-Amino Valeric Acid | Drug Info | [6] | |||
10 | Formic Acid | Drug Info | [6] | |||
11 | Laevulinic Acid | Drug Info | [6] | |||
12 | S,S-(2-Hydroxyethyl)Thiocysteine | Drug Info | [6] |
Cell-based Target Expression Variations | Top | |||||
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Cell-based Target Expression Variations |
Drug Binding Sites of Target | Top | |||||
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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 | No | [8] |
PDB Sequence |
MQPQSVLHSG
10 YFHPLLRAWQ20 TATTTLNASN30 LIYPIFVTDV40 PDDIQPITSL50 PGVARYGVKR 60 LEEMLRPLVE70 EGLRCVLIFG80 VPSRVPKDER90 GSAADSEESP100 AIEAIHLLRK 110 TFPNLLVACD120 VCLCPYTSHG130 HCGLLSGAFR142 AEESRQRLAE152 VALAYAKAGC 162 QVVAPSDMMD172 GRVEAIKEAL182 MAHGLGNRVS192 VMSYSAKFAS202 CFYGPFRDAA 212 KSSPAFGDRR222 CYQLPPGARG232 LALRAVDRDV242 REGADMLMVK252 PGMPYLDIVR 262 EVKDKHPDLP272 LAVYHVSGEF282 AMLWHGAQAG292 AFDLKAAVLE302 AMTAFRRAGA 312 DIIITYYTPQ322 LLQWLK
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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
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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 | [9] |
PDB Sequence |
YLHPLLRAWQ
20 TATTTLNASN30 LIYPIFVTDV40 PDDIQPITSL50 PGVARYGVKR60 LEEMLRPLVE 70 EGLRCVLIFG80 VPEESPAIEA104 IHLLRKTFPN114 LLVACDVCLC124 AFRAEESRQR 149 LAEVALAYAK159 AGCQVVAPSD169 DGRVEAIKEA181 LMAHGLGNRV191 SVMSYSAKFA 201 SCFYGPFRDA211 ALPPGARGLA234 LRAVDRDVRE244 GADMLMVKPG254 MPYLDIVREV 264 KDKHPDLPLA274 VYHVSGEFAM284 LWHGAQAGAF294 DLKAAVLEAM304 TAFRRAGADI 314 IITYYTPQLL324 QWLKEE
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Click to View More Binding Site Information of This Target with Different Ligands |
Different Human System Profiles of Target | Top |
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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
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There is no similarity protein (E value < 0.005) for this target
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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.
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KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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Porphyrin metabolism | hsa00860 | Affiliated Target |
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Class: Metabolism => Metabolism of cofactors and vitamins | Pathway Hierarchy |
Degree | 6 | Degree centrality | 6.45E-04 | Betweenness centrality | 2.03E-04 |
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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 | Top |
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Drug Property Profile of Target | Top | |
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(1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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(5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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"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 | Top | |||||
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Target Poor or Non Binders |
Target Affiliated Biological Pathways | Top | |||||
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BioCyc | [+] 2 BioCyc Pathways | + | ||||
1 | Heme biosynthesis | |||||
2 | Tetrapyrrole biosynthesis | |||||
KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
1 | Porphyrin and chlorophyll metabolism | |||||
2 | Metabolic pathways | |||||
Panther Pathway | [+] 1 Panther Pathways | + | ||||
1 | Heme biosynthesis | |||||
Pathwhiz Pathway | [+] 1 Pathwhiz Pathways | + | ||||
1 | Porphyrin Metabolism | |||||
WikiPathways | [+] 2 WikiPathways | + | ||||
1 | Heme Biosynthesis | |||||
2 | Metabolism of porphyrins |
References | Top | |||||
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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 | Melatonin protects against delta-aminolevulinic acid-induced oxidative damage in male Syrian hamster Harderian glands. Int J Biochem Cell Biol. 2002 May;34(5):544-53. | |||||
REF 5 | A novel mutation of delta-aminolaevulinate dehydratase in a healthy child with 12% erythrocyte enzyme activity. Br J Haematol. 1999 Sep;106(4):931-7. | |||||
REF 6 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
REF 7 | Structure of yeast 5-aminolaevulinic acid dehydratase complexed with the inhibitor 5-hydroxylaevulinic acid. Acta Crystallogr D Biol Crystallogr. 2005 Sep;61(Pt 9):1222-6. | |||||
REF 8 | The Crystal Structure of Human Ala-Dehydratase | |||||
REF 9 | Control of tetrapyrrole biosynthesis by alternate quaternary forms of porphobilinogen synthase. Nat Struct Biol. 2003 Sep;10(9):757-63. |
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