Target Information
| Target General Information | Top | |||||
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| Target ID |
T42822
(Former ID: TTDS00437)
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| Target Name |
Ferrochelatase (FECH)
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| Synonyms |
Protoheme ferro-lyase; Heme synthetase; FECH
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| Gene Name |
FECH
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 3 Target-related Diseases | + | ||||
| 1 | Acne vulgaris [ICD-11: ED80] | |||||
| 2 | Peroxisomal disease [ICD-11: 5C57] | |||||
| 3 | Synthesis disorder [ICD-11: 5C52-5C59] | |||||
| Function |
Catalyzes the ferrous insertion into protoporphyrin IX.
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| BioChemical Class |
Ferrochelatase
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| UniProt ID | ||||||
| EC Number |
EC 4.99.1.1
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| Sequence |
MRSLGANMAAALRAAGVLLRDPLASSSWRVCQPWRWKSGAAAAAVTTETAQHAQGAKPQV
QPQKRKPKTGILMLNMGGPETLGDVHDFLLRLFLDRDLMTLPIQNKLAPFIAKRRTPKIQ EQYRRIGGGSPIKIWTSKQGEGMVKLLDELSPNTAPHKYYIGFRYVHPLTEEAIEEMERD GLERAIAFTQYPQYSCSTTGSSLNAIYRYYNQVGRKPTMKWSTIDRWPTHHLLIQCFADH ILKELDHFPLEKRSEVVILFSAHSLPMSVVNRGDPYPQEVSATVQKVMERLEYCNPYRLV WQSKVGPMPWLGPQTDESIKGLCERGRKNILLVPIAFTSDHIETLYELDIEYSQVLAKEC GVENIRRAESLNGNPLFSKALADLVHSHIQSNELCSKQLTLSCPLCVNPVCRETKSFFTS QQL Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 2 Approved Drugs | + | ||||
| 1 | Cholic Acid | Drug Info | Approved | Synthesis disorder | [2] | |
| 2 | Methyl aminolevulinate | Drug Info | Approved | Acne vulgaris | [3], [4] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 4 Inhibitor drugs | + | ||||
| 1 | Cholic Acid | Drug Info | [5] | |||
| 2 | Lead acetate | Drug Info | [6] | |||
| 3 | N-Methylmesoporphyrin | Drug Info | [5] | |||
| 4 | N-Methylmesoporphyrin Containing Copper | Drug Info | [5] | |||
| Activator | [+] 1 Activator drugs | + | ||||
| 1 | Methyl aminolevulinate | Drug Info | [1] | |||
| 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: Salicyclic acid | Ligand Info | |||||
| Structure Description | Protein-drug complex | PDB:3W1W | ||||
| Method | X-ray diffraction | Resolution | 2.01 Å | Mutation | Yes | [7] |
| PDB Sequence |
RKPKTGILML
74 NMGGPETLGD84 VHDFLLRLFL94 DRDLMTLPIQ104 NKLAPFIAKR114 LTPKIQEQYR 124 RIGGGSPIKI134 WTSKQGEGMV144 KLLDELSPNT154 APHKYYIGFR164 YVHPLTEEAI 174 EEMERDGLER184 AIAFTQYPQY194 SCSTTGSSLN204 AIYRYYNQVG214 RKPTMKWSTI 224 DRWPTHHLLI234 QCFADHILKE244 LDHFPLEKRS254 EVVILFSAHS264 LPMSVVNRGD 274 PYPQEVSATV284 QKVMERLEYC294 NPYRLVWQSK304 VGPMPWLGPQ314 TDESIKGLCE 324 RGRKNILLVP334 IAFTSDHIET344 LYELDIEYSQ354 VLAKECGVEN364 IRRAESLNGN 374 PLFSKALADL384 VHSHIQSNEL394 CSKQLTLSCP404 LCVNPVCRET414 KSFFTSQQL |
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| Ligand Name: Cholic acid | Ligand Info | |||||
| Structure Description | Hg and protoporphyrin bound Human Ferrochelatase | PDB:3HCN | ||||
| Method | X-ray diffraction | Resolution | 1.60 Å | Mutation | No | [8] |
| PDB Sequence |
RKPKTGILML
74 NMGGPETLGD84 VHDFLLRLFL94 DRDLMTLPIQ104 NKLAPFIAKR114 RTPKIQEQYR 124 RIGGGSPIKI134 WTSKQGEGMV144 KLLDELSPNT154 APHKYYIGFR164 YVHPLTEEAI 174 EEMERDGLER184 AIAFTQYPQY194 SCSTTGSSLN204 AIYRYYNQVG214 RKPTMKWSTI 224 DRWPTHHLLI234 QCFADHILKE244 LDHFPLEKRS254 EVVILFSAHS264 LPMSVVNRGD 274 PYPQEVSATV284 QKVMERLEYC294 NPYRLVWQSK304 VGPMPWLGPQ314 TDESIKGLCE 324 RGRKNILLVP334 IAFTSDHIET344 LYELDIEYSQ354 VLAKECGVEN364 IRRAESLNGN 374 PLFSKALADL384 VHSHIQSNEL394 CSKQLTLSCP404 LCVNPVCRET414 KSFFTSQQL |
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| 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 | 11 | Degree centrality | 1.18E-03 | Betweenness centrality | 2.25E-03 |
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| Closeness centrality | 1.86E-01 | Radiality | 1.31E+01 | Clustering coefficient | 7.27E-02 |
| Neighborhood connectivity | 4.45E+00 | Topological coefficient | 1.30E-01 | Eccentricity | 11 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| 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 Regulators | Top | |||||
|---|---|---|---|---|---|---|
| Target-interacting Proteins | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| BioCyc | [+] 2 BioCyc Pathways | + | ||||
| 1 | Heme biosynthesis | |||||
| 2 | Heme biosynthesis from uroporphyrinogen-III I | |||||
| 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 | |||||
| PID Pathway | [+] 1 PID Pathways | + | ||||
| 1 | HIF-1-alpha transcription factor network | |||||
| WikiPathways | [+] 2 WikiPathways | + | ||||
| 1 | Heme Biosynthesis | |||||
| 2 | Metabolism of porphyrins | |||||
| References | Top | |||||
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| REF 1 | Low-dose methotrexate enhances aminolevulinate-based photodynamic therapy in skin carcinoma cells in vitro and in vivo. Clin Cancer Res. 2009 May 15;15(10):3333-43. | |||||
| 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: 609). | |||||
| REF 3 | FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 021415. | |||||
| REF 4 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
| REF 5 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 6 | Ferrochelatase, a novel target for photodynamic therapy of cancer. Oncol Rep. 1999 Nov-Dec;6(6):1439-42. | |||||
| REF 7 | Salicylic acid induces mitochondrial injury by inhibiting ferrochelatase heme biosynthesis activity. Mol Pharmacol. 2013 Dec;84(6):824-33. | |||||
| REF 8 | Product release rather than chelation determines metal specificity for ferrochelatase. J Mol Biol. 2009 Oct 23;393(2):308-19. | |||||
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