Product Description: dihydroorotate dehydrogenase
SignalP Peptide: N/A
# Transmembrane Domains: 1
EC Numbers: 1.3.5.2 (Dihydroorotate dehydrogenase (quinone))
Curated GO (PlasmoDB):
| Type | GO Term | Name |
|---|---|---|
| Component | GO:0005743 | mitochondrial inner membrane |
| Component | GO:0005739 | mitochondrion |
| Function | GO:0004152 | dihydroorotate dehydrogenase activity |
| Process | GO:0006207 | 'de novo' pyrimidine nucleobase biosynthetic process |
| Process | GO:0009220 | pyrimidine ribonucleotide biosynthetic process |
| Process | GO:0042493 | response to drug |
| Process | GO:0009410 | response to xenobiotic stimulus |
Expression by stage (LR - Le Roch et al., and MCA - Malaria Cell Atlas):
| Stage | LR class | MCA mean | MCA prop. zeros |
|---|---|---|---|
| Sporozoite | not expressed | N/A | N/A |
| Ring | expressed | 0.20 | 0.90 |
| Trophozoite | expressed | 0.57 | 0.69 |
| Schizont | expressed | 0.07 | 0.96 |
| Gametocyte | possibly expressed | 0.15 | 0.91 |
More info:
Old (Pf3D7v3) Gene ID: PF3D7_0603300
Resistome Missense Mutations: F188I, F227Y, F227L, I263S, C276Y, L531F, L531F
Resistome Compounds with Missense Mutations: DSM265, DSM267, MMV1454442, TCMDC-125334
Resistome # Samples with Disruptive Mutations: 18 (18 missense, 15 "interesting" missense)
Zhang Phenotype: Non - Mutable in CDS
MIS: 0.125 | MFS: -3.099 | #Insertions: 0
PlasmoGEM Phenotype: Slow (Pb ortholog: PBANKA_0102100)
RMgmDB ABS Phenotype: Different from wild type (Pb ortholog: PBANKA_0102100)
Modification: Disrupted | RMgm-1610
More info: PhenoPlasm Link
AlphaFill Uniprot ID: Q08210
"Best" AlphaFill ligand hit: FOT (5-fluoro-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid, Local RMSD=0.04) with 3W1A (Global RMSD=1.41)
BRENDA EC Inhibitors:
| EC # | Name | EC Inhibitors |
|---|---|---|
| 1.3.5.2 | dihydroorotate dehydrogenase (quinone) | HR325OrotatealloxanredoxalLawsoneMNA 279MNA 715A77 1726LapacholA77-1726menadionebrequinar... |
Orthology to BindingDB Entries:
| UniProt | Protein Name | Species | Homology Source | BindingDB Ligands |
|---|---|---|---|---|
| Q08210 | Dihydroorotate dehydrogenase (quinone), mitochondrial | Plasmodium falciparum | HOGENOM, OMA, OrthoDB, OrthoMCL, OrthoMCL BLAST | tricyclic compound 5tricyclic compound 6bicyclic compound 7monocyclic compound 8... |
| Q02127 | Dihydroorotate dehydrogenase (quinone), mitochondrial | Homo sapiens | OMA, OrthoDB, OrthoMCL BLAST | US8536165, 110tricyclic compound 5TERIFLUNOMIDEBiphenquinate... |
| A0A509AEH5 | Dihydroorotate dehydrogenase (quinone), mitochondrial [100-517] | Plasmodium berghei | OMA, OrthoDB, OrthoMCL, OrthoMCL BLAST | JMC521864 Compund DSM1JMC521864 Compund DSM2cid_741601triazolopyrimidine-based compound, DSM98... |
| O35435 | Dihydroorotate dehydrogenase (quinone), mitochondrial | Mus musculus | OMA, OrthoDB, OrthoMCL BLAST | CHEMBL3289670CHEMBL3289672TERIFLUNOMIDECHEMBL3289671... |
| Q54A96 | Dihydroorotate dehydrogenase (quinone), mitochondrial | Plasmodium falciparum | OMA, OrthoMCL, OrthoMCL BLAST | Asinex compound no. 1ChemBridge compound no. 2ChemBridge compound no. 3Asinex compound no. 4... |
| G4VFD7 | Dihydroorotate dehydrogenase (quinone), mitochondrial | OMA, OrthoDB, OrthoMCL, OrthoMCL BLAST | CHEMBL4436314CHEMBL4560384ATOVAQUONECHEMBL2408377... | |
| Q63707 | Dihydroorotate dehydrogenase (quinone), mitochondrial | Rattus norvegicus | OrthoDB, OrthoMCL BLAST | AtovaquoneBiphenquinateAtovaquoneBiphenquinate... |
| A5K1N1 | Dihydroorotate dehydrogenase (quinone), mitochondrial | Plasmodium vivax | OrthoMCL, OrthoMCL BLAST | US8703811, 2US8703811, 3US8703811, 1US8703811, 5... |
Ortholog Group (OrthoMCL): OG6_101797
Most Similar Human Ortholog: Q02127
TM-align score: 0.91 | RMSD: 2.80
Seq Identity: 0.37 | Length: 389 / 569
All Human Orthologs (OrthoMCL):
| Gene ID | Description |
|---|---|
| ENSG00000102967 | dihydroorotate dehydrogenase (quinone) |
Protein Length: 569 | Molecular Weight (kDa): 65.558
PDB ID(s): 1TV5, 3I65, 3I68, 3I6R, 3O8A, 3SFK, 4CQ8, 4CQ9, 4CQA, 4ORM, 4RX0, 5BOO, 5DEL, 5FI8, 5TBO, 6E0B, 6GJG, 6VTY, 7KYK, 7KYV, 7KYY, 7KZ4, 7KZY, 7L01, 7L0K, 7S87
Isoelectric Point: 9.43
Protein Domain Annotations:
| Source | Family ID | Description |
|---|---|---|
| InterPro | IPR001295 | Dihydroorotate dehydrogenase, conserved site |
| InterPro | IPR005719 | Dihydroorotate dehydrogenase, class 2 |
| InterPro | IPR005720 | Dihydroorotate dehydrogenase domain |
| PFam | PF01180 | Dihydroorotate dehydrogenase domain |
| Superfamily | SSF51395 | N/A |
MalariaGEN Pf7 (worldwide samples) # unique SNV/indels:
Homozygous genotype calls only
| variant type | common | rare | doubleton | singleton |
|---|---|---|---|---|
| synonymous | 5 | 25 | 11 | 43 |
| disruptive | 4 | 34 | 26 | 58 |
| missense | 4 | 34 | 26 | 56 |
Any inclusion in genotype call
| variant type | common | rare | doubleton | singleton |
|---|---|---|---|---|
| synonymous | 11 | 52 | 21 | 42 |
| disruptive | 13 | 79 | 52 | 109 |
| missense | 11 | 71 | 45 | 79 |
PlasmoDB Total SNPs: 69
Non-coding: 42 | Synonymous: 15 | Nonsynonymous: 12 | Stop Codon: 0
| PMID | Title | Authors | DOI/Link |
|---|---|---|---|
| 7727509 | Purification, characterization and localization of mitochondrial dihydroorotatedehydrogenase in Plasmodium falciparum, human malaria parasite. | Krungkrai J | 10.1016/0304-4165(94)00158-t |
| 8232427 | The dihydroorotate dehydrogenase gene homologue of Plasmodium falciparum. | LeBlanc SB, Wilson CM | 10.1016/0166-6851(93)90148-q |
| 12368867 | Sequence of Plasmodium falciparum chromosomes 1, 3-9 and 13. | Hall N, Pain A, ..., Barrell BG | 10.1038/nature01095 |
| 18225919 | Analysis of flavin oxidation and electron-transfer inhibition in Plasmodiumfalciparum dihydroorotate dehydrogenase. | Malmquist NA, Gujjar R, Rathod PK, Phillips MA | 10.1021/bi702218c |
| 19640844 | Structural plasticity of malaria dihydroorotate dehydrogenase allows selectivebinding of diverse chemical scaffolds. | Deng X, Gujjar R, ..., Phillips MA | 10.1074/jbc.M109.028589 |
| 20702404 | Novel inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase withanti-malarial activity in the mouse model. | Booker ML, Bastos CM, ..., Sybertz E | 10.1074/jbc.M110.162081 |
| 24073986 | Novel selective and potent inhibitors of malaria parasite dihydroorotatedehydrogenase: discovery and optimization of dihydrothiophenone derivatives. | Xu M, Zhu J, ..., Li H | 10.1021/jm400938g |
| 24782313 | In vitro resistance selections for Plasmodium falciparum dihydroorotatedehydrogenase inhibitors give mutants with multiple point mutations in thedrug-binding site and altered growth. | Ross LS, Gamo FJ, ..., Wirth DF | 10.1074/jbc.M114.558353 |
| 25945708 | The X-ray structure of Plasmodium falciparum dihydroorotate dehydrogenase boundto a potent and selective N-phenylbenzamide inhibitor reveals novel binding-siteinteractions. | Deng X, Matthews D, Rathod PK, Phillips MA | 10.1107/S2053230X15000989 |
| 27874068 | Identification of inhibitors that dually target the new permeability pathway anddihydroorotate dehydrogenase in the blood stage of Plasmodium falciparum. | Dickerman BK, Elsworth B, ..., Gilson PR | 10.1038/srep37502 |
| 28435533 | Discovery of Antimalarial Azetidine-2-carbonitriles That Inhibit P. falciparumDihydroorotate Dehydrogenase. | Maetani M, Kato N, ..., Schreiber SL | 10.1021/acsmedchemlett.7b00030 |
| 32248693 | Lead Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase InhibitorSeries for the Treatment of Malaria. | Kokkonda S, Deng X, ..., Phillips MA | 10.1021/acs.jmedchem.0c00311 |
| 34494883 | A Prioritized and Validated Resource of Mitochondrial Proteins in PlasmodiumIdentifies Unique Biology. | van Esveld SL, Meerstein-Kessel L, ..., Huynen MA | 10.1128/mSphere.00614-21 |