P9WJF1 · DPRE1_MYCTU
- ProteinDecaprenylphosphoryl-beta-D-ribose oxidase
- GenedprE1
- StatusUniProtKB reviewed (Swiss-Prot)
- Amino acids461 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Component of the DprE1-DprE2 complex that catalyzes the 2-step epimerization of decaprenyl-phospho-ribose (DPR) to decaprenyl-phospho-arabinose (DPA), a key precursor that serves as the arabinose donor required for the synthesis of cell-wall arabinans (PubMed:16291675, PubMed:19299584).
DprE1 catalyzes the first step of epimerization, namely FAD-dependent oxidation of the C2' hydroxyl of DPR to yield the keto intermediate decaprenyl-phospho-2'-keto-D-arabinose (DPX) (PubMed:22733761).
The intermediate DPX is then transferred to DprE2 subunit of the epimerase complex, most probably through a 'substrate channel' at the interface of DprE1-DprE2 complex (PubMed:25789990).
Can also use farnesyl-phosphoryl-beta-D-ribofuranose (FPR) as substrate in vitro (PubMed:25427196).
Appears to be essential for the growth and survival of M.tuberculosis (PubMed:12657046, PubMed:24517327).
DprE1 catalyzes the first step of epimerization, namely FAD-dependent oxidation of the C2' hydroxyl of DPR to yield the keto intermediate decaprenyl-phospho-2'-keto-D-arabinose (DPX) (PubMed:22733761).
The intermediate DPX is then transferred to DprE2 subunit of the epimerase complex, most probably through a 'substrate channel' at the interface of DprE1-DprE2 complex (PubMed:25789990).
Can also use farnesyl-phosphoryl-beta-D-ribofuranose (FPR) as substrate in vitro (PubMed:25427196).
Appears to be essential for the growth and survival of M.tuberculosis (PubMed:12657046, PubMed:24517327).
DprE1 is a highly vulnerable and fully validated tuberculosis drug target.
Miscellaneous
Was identified as a high-confidence drug target.
Catalytic activity
- FAD + H+ + trans,octa-cis-decaprenylphospho-beta-D-ribofuranose = FADH2 + trans,octa-cis-decaprenylphospho-beta-D-erythro-pentofuranosid-2-ulose
Activity regulation
Is inhibited by 8-nitro-benzothiazinones (BTZs) such as BTZ043 and PBTZ169; BTZs are a new class of antimycobacterial agents that kill M.tuberculosis in vitro, ex vivo, and in mouse models of tuberculosis (PubMed:19299584, PubMed:20828197, PubMed:22733761, PubMed:24500695).
Is also inhibited by dinitrobenzamide derivatives (DNBs), which thus block formation of both cell-wall lipoarabinomannan and arabinogalactan via inhibition of decaprenyl-phospho-arabinose (DPA) synthesis; DNBs show high activity against intracellular growth of M.tuberculosis inside macrophages, including extensively drug resistant (XDR) strains (PubMed:19876393).
BTZs and DNBs are suicide inhibitors that act via covalent modification of DprE1; the essential nitro group of these compounds is reduced by DprE1 to a nitroso group, which then specifically reacts with Cys-387 of DprE1 to form an irreversible semimercaptal adduct (PubMed:20828197, PubMed:22733761, PubMed:24500695).
Many other compounds with diverse scaffolds were found to act as either covalent (e.g. nitroquinoxalines, nitroimidazoles) or non-covalent (e.g. the benzothiazole derivative TCA1, the 2-carboxyquinoxaline Ty38C, 8-pyrrole-benzothiazinones, 1,4-azaindoles, pyrazolopyridones, 4-aminoquinolone piperidine amides) DprE1 inhibitors (PubMed:23776209, PubMed:24215368, PubMed:24818517, PubMed:25427196, PubMed:25987616, PubMed:27666194).
Is also inhibited by dinitrobenzamide derivatives (DNBs), which thus block formation of both cell-wall lipoarabinomannan and arabinogalactan via inhibition of decaprenyl-phospho-arabinose (DPA) synthesis; DNBs show high activity against intracellular growth of M.tuberculosis inside macrophages, including extensively drug resistant (XDR) strains (PubMed:19876393).
BTZs and DNBs are suicide inhibitors that act via covalent modification of DprE1; the essential nitro group of these compounds is reduced by DprE1 to a nitroso group, which then specifically reacts with Cys-387 of DprE1 to form an irreversible semimercaptal adduct (PubMed:20828197, PubMed:22733761, PubMed:24500695).
Many other compounds with diverse scaffolds were found to act as either covalent (e.g. nitroquinoxalines, nitroimidazoles) or non-covalent (e.g. the benzothiazole derivative TCA1, the 2-carboxyquinoxaline Ty38C, 8-pyrrole-benzothiazinones, 1,4-azaindoles, pyrazolopyridones, 4-aminoquinolone piperidine amides) DprE1 inhibitors (PubMed:23776209, PubMed:24215368, PubMed:24818517, PubMed:25427196, PubMed:25987616, PubMed:27666194).
Kinetics
kcat is 4.1 min-1 with farnesyl-phosphoryl-beta-D-ribofuranose as substrate (at pH 8 and 30 degrees Celsius).
Pathway
Cell wall biogenesis; cell wall polysaccharide biosynthesis.
Features
Showing features for binding site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Binding site | 53-63 | FAD (UniProtKB | ChEBI) | ||||
Sequence: ARGLGRSYGDN | ||||||
Binding site | 117 | FAD (UniProtKB | ChEBI) | ||||
Sequence: G | ||||||
Binding site | 122-125 | FAD (UniProtKB | ChEBI) | ||||
Sequence: TVGG | ||||||
Binding site | 129-132 | FAD (UniProtKB | ChEBI) | ||||
Sequence: CDIH | ||||||
Binding site | 184 | FAD (UniProtKB | ChEBI) | ||||
Sequence: I | ||||||
Binding site | 415 | FAD (UniProtKB | ChEBI) | ||||
Sequence: Y |
GO annotations
Aspect | Term | |
---|---|---|
Cellular Component | periplasmic space | |
Cellular Component | plasma membrane | |
Molecular Function | D-arabinono-1,4-lactone oxidase activity | |
Molecular Function | FAD binding | |
Molecular Function | oxidoreductase activity | |
Biological Process | arabinan biosynthetic process | |
Biological Process | capsule polysaccharide biosynthetic process | |
Biological Process | cell wall organization | |
Biological Process | cell wall polysaccharide biosynthetic process | |
Biological Process | response to antibiotic |
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameDecaprenylphosphoryl-beta-D-ribose oxidase
- EC number
- Alternative names
Gene names
Organism names
- Strain
- Taxonomic lineageBacteria > Actinomycetota > Actinomycetes > Mycobacteriales > Mycobacteriaceae > Mycobacterium > Mycobacterium tuberculosis complex
Accessions
- Primary accessionP9WJF1
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
Phenotypes & Variants
Disruption phenotype
Traditional knockout mutant with dprE1 disruption could not be achieved, suggesting this gene is essential (PubMed:24517327).
Conditional knock-down mutant of dprE1 show that down-regulation of DprE1 results in rapid in vitro growth arrest, swelling of the bacteria, cell wall damage, stop of cell division or lysis, decreased survival in macrophages and virulence attenuation (PubMed:24517327).
Cells lacking this gene display impaired growth (PubMed:12657046).
Conditional knock-down mutant of dprE1 show that down-regulation of DprE1 results in rapid in vitro growth arrest, swelling of the bacteria, cell wall damage, stop of cell division or lysis, decreased survival in macrophages and virulence attenuation (PubMed:24517327).
Cells lacking this gene display impaired growth (PubMed:12657046).
Features
Showing features for natural variant, mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Natural variant | 17 | in strain: TRC11; Ty38c-resistant mutant strain lacking Rv3406, but sensitive to moxifloxacin | ||||
Sequence: G → C | ||||||
Mutagenesis | 17 | Significantly less susceptible to Ty38c inhibition. 34-fold reduction in catalytic activity. | ||||
Sequence: G → C | ||||||
Natural variant | 314 | in a spontaneous TCA1-resistant mutant strain, but sensitive to BTZ | ||||
Sequence: Y → C | ||||||
Natural variant | 368 | in strain: TRC12; Ty38c-resistant mutant strain lacking Rv3406, but sensitive to moxifloxacin | ||||
Sequence: L → P | ||||||
Mutagenesis | 368 | Significantly less susceptible to Ty38c inhibition. 7-fold reduction in catalytic activity. | ||||
Sequence: L → P | ||||||
Natural variant | 387 | in strain: NTB9; BTZ043-resistant | ||||
Sequence: C → G | ||||||
Natural variant | 387 | in strain: NTB1; BTZ043-resistant | ||||
Sequence: C → S | ||||||
Mutagenesis | 387 | Confers resistance to BTZ043 and PBTZ169. Decreases M.tuberculosis cytotoxicity in macrophages. Does not affect binding affinity of the substrate to the enzyme, and only slightly affects catalytic efficiency. Is only partially inhibited by PBTZ169 at high concentrations, while totally inhibited by the non-covalent inhibitor Ty38c. | ||||
Sequence: C → A, S, or T | ||||||
Mutagenesis | 387 | Confers resistance to BTZ043 and PBTZ169. Loss of covalent modification with BTZ043. Decreases M.tuberculosis cytotoxicity in macrophages. Does not affect binding affinity of the substrate to the enzyme, but reduces catalytic efficiency by 4-fold. Is only partially inhibited by PBTZ169 at high concentrations, while nearly totally inhibited by the non-covalent inhibitor Ty38c. | ||||
Sequence: C → G | ||||||
Mutagenesis | 387 | Confers resistance to BTZ043 and PBTZ169. Decreases M.tuberculosis cytotoxicity in macrophages. Does not affect binding affinity of the substrate to the enzyme, but reduces catalytic efficiency by 4-fold. Is only partially inhibited by PBTZ169 at high concentrations, while totally inhibited by the non-covalent inhibitor Ty38c. | ||||
Sequence: C → N |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 5 variants from UniProt as well as other sources including ClinVar and dbSNP.
Chemistry
PTM/Processing
Features
Showing features for chain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000390891 | 1-461 | Decaprenylphosphoryl-beta-D-ribose oxidase | |||
Sequence: MLSVGATTTATRLTGWGRTAPSVANVLRTPDAEMIVKAVARVAESGGGRGAIARGLGRSYGDNAQNGGGLVIDMTPLNTIHSIDADTKLVDIDAGVNLDQLMKAALPFGLWVPVLPGTRQVTVGGAIACDIHGKNHHSAGSFGNHVRSMDLLTADGEIRHLTPTGEDAELFWATVGGNGLTGIIMRATIEMTPTSTAYFIADGDVTASLDETIALHSDGSEARYTYSSAWFDAISAPPKLGRAAVSRGRLATVEQLPAKLRSEPLKFDAPQLLTLPDVFPNGLANKYTFGPIGELWYRKSGTYRGKVQNLTQFYHPLDMFGEWNRAYGPAGFLQYQFVIPTEAVDEFKKIIGVIQASGHYSFLNVFKLFGPRNQAPLSFPIPGWNICVDFPIKDGLGKFVSELDRRVLEFGGRLYTAKDSRTTAETFHAMYPRVDEWISVRRKVDPLRVFASDMARRLELL |
Proteomic databases
Structure
Family & Domains
Features
Showing features for domain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Domain | 19-194 | FAD-binding PCMH-type | ||||
Sequence: TAPSVANVLRTPDAEMIVKAVARVAESGGGRGAIARGLGRSYGDNAQNGGGLVIDMTPLNTIHSIDADTKLVDIDAGVNLDQLMKAALPFGLWVPVLPGTRQVTVGGAIACDIHGKNHHSAGSFGNHVRSMDLLTADGEIRHLTPTGEDAELFWATVGGNGLTGIIMRATIEMTPT |
Sequence similarities
Belongs to the DprE1 family.
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length461
- Mass (Da)50,163
- Last updated2014-04-16 v1
- ChecksumB9B770002E5FE81C
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AL123456 EMBL· GenBank· DDBJ | CCP46619.1 EMBL· GenBank· DDBJ | Genomic DNA |