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Literature summary extracted from

  • Lipowska, J.; Miks, C.D.; Kwon, K.; Shuvalova, L.; Zheng, H.; Lewinski, K.; Cooper, D.R.; Shabalin, I.G.; Minor, W.
    Pyrimidine biosynthesis in pathogens - structures and analysis of dihydroorotases from Yersinia pestis and Vibrio cholerae (2019), Int. J. Biol. Macromol., 136, 1176-1187 .
    View publication on PubMedView publication on EuropePMC

Application

EC Number Application Comment Organism
3.5.2.3 drug development the substantial difference between bacterial and mammalian DHOs makes the bacterial enzyme a promising drug target for disrupting bacterial growth and thus an important candidate to evaluate as a response to antimicrobial resistance on a molecular level Yersinia pestis
3.5.2.3 drug development the substantial difference between bacterial and mammalian DHOs makes the bacterial enzyme a promising drug target for disrupting bacterial growth and thus an important candidate to evaluate as a response to antimicrobial resistance on a molecular level Vibrio cholerae serotype O1

Cloned(Commentary)

EC Number Cloned (Comment) Organism
3.5.2.3 gene pyrC, sequence comparisons, recombinant expression of His-tagged enzyme in Escherichia coli strain BL21(DE3) Yersinia pestis
3.5.2.3 gene pyrC, sequence comparisons, recombinant expression of His-tagged enzyme in Escherichia coli strain BL21(DE3) Vibrio cholerae serotype O1

Crystallization (Commentary)

EC Number Crystallization (Comment) Organism
3.5.2.3 purified recombinant His-tagged enzyme, enzyme proteolysis before crystallization, sitting drop vapor diffusion technique, mixing of 0.001 ml of 14 mg/ml protein in 20 mM HEPES, pH 7.5, 150 mM NaCl, 10% glycerol, 0.1% sodium azide, 0.5 mM TCEP, and and 20 mM L-citrulline, with 0.0015 ml of crystallization solution containing 133 mM sodium acetate, 67 mM sodium cacodylate-HCl, pH 6.5, 20% w/v PEG 8000, and 2.3% v/v 1-butanol, and equilibration against 0.034 ml of reservoir solution of 1.5 M NaCl, 4-7 days, 16°C, X-ray diffraction structure determination and analysis at 1.95 A resolution, molecular replacement, modelling Vibrio cholerae serotype O1
3.5.2.3 purified recombinant His-tagged enzyme, sitting drop vapor diffusion technique, mixing of 400 nl of 10 mg/ml protein in 20 mM Tris-HCl, pH 7.5, 150 mM NaCl, 10% glycerol, 0.1% sodium azide, and 0.5 mM TCEP, with 400 nl of crystallization solution containing 0.15 M DL-malic acid, pH 7.0, and 20% w/v PEG 3350, equilibration against 0.034 ml of reservoir solution of 1.3 M NaCl, 4-7 days, 16°C, X-ray diffraction structure determination and analysis at 2.4 A resolution, molecular replacement, modelling Yersinia pestis

Inhibitors

EC Number Inhibitors Comment Organism Structure
3.5.2.3 2-oxo-1,2,3,6-tetrahydropyrimidine4,6-dicarboxylate
-
 Vibrio cholerae serotype O1
3.5.2.3 2-oxo-1,2,3,6-tetrahydropyrimidine4,6-dicarboxylate
-
 Yersinia pestis
3.5.2.3 L-6-thiodihydroorotate
-
 Vibrio cholerae serotype O1
3.5.2.3 L-6-thiodihydroorotate
-
 Yersinia pestis
3.5.2.3 additional information malate can bind to the active site Vibrio cholerae serotype O1
3.5.2.3 additional information malate can bind to the active site Yersinia pestis

Metals/Ions

EC Number Metals/Ions Comment Organism Structure
3.5.2.3 Zn2+ the active site of VcDHO contains two zinc ions: Znalpha in trigonal bipyramidal coordination and Znbeta in tetrahedral coordination. Each zinc ion is coordinated by two histidine residues, His13 and His15 for Znalpha, and His135 and His173 for Znbeta in VcDHO, structure analysis, overview Vibrio cholerae serotype O1
3.5.2.3 Zn2+ the active site of YpDHO contains two zinc ions: Znalpha in trigonal bipyramidal coordination and Znbeta in tetrahedral coordination. Each zinc ion is coordinated by two histidine residues, His17 and His19 for Znalpha, and His140 and His178 for Znbeta in YpDHO, structure analysis, overview Yersinia pestis

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
3.5.2.3 (S)-dihydroorotate + H2O Yersinia pestis
-
 N-carbamoyl-L-aspartate
-
 r
3.5.2.3 (S)-dihydroorotate + H2O Vibrio cholerae serotype O1
-
 N-carbamoyl-L-aspartate
-
 r
3.5.2.3 (S)-dihydroorotate + H2O Vibrio cholerae serotype O1 El Tor Inaba N16961
-
 N-carbamoyl-L-aspartate
-
 r
3.5.2.3 (S)-dihydroorotate + H2O Vibrio cholerae serotype O1 ATCC 39315
-
 N-carbamoyl-L-aspartate
-
 r
3.5.2.3 additional information Yersinia pestis N-carbamoyl-L-aspartate is preferred as the physiological substrate ?
-
-
3.5.2.3 additional information Vibrio cholerae serotype O1 N-carbamoyl-L-aspartate is preferred as the physiological substrate ?
-
-
3.5.2.3 additional information Vibrio cholerae serotype O1 El Tor Inaba N16961 N-carbamoyl-L-aspartate is preferred as the physiological substrate ?
-
-
3.5.2.3 additional information Vibrio cholerae serotype O1 ATCC 39315 N-carbamoyl-L-aspartate is preferred as the physiological substrate ?
-
-
3.5.2.3 N-carbamoyl-L-aspartate Yersinia pestis
-
 (S)-dihydroorotate + H2O
-
 r
3.5.2.3 N-carbamoyl-L-aspartate Vibrio cholerae serotype O1
-
 (S)-dihydroorotate + H2O
-
 r
3.5.2.3 N-carbamoyl-L-aspartate Vibrio cholerae serotype O1 El Tor Inaba N16961
-
 (S)-dihydroorotate + H2O
-
 r
3.5.2.3 N-carbamoyl-L-aspartate Vibrio cholerae serotype O1 ATCC 39315
-
 (S)-dihydroorotate + H2O
-
 r

Organism

EC Number Organism UniProt Comment Textmining
3.5.2.3 Vibrio cholerae serotype O1 Q9KL24
-
-
3.5.2.3 Vibrio cholerae serotype O1 ATCC 39315 Q9KL24
-
-
3.5.2.3 Vibrio cholerae serotype O1 El Tor Inaba N16961 Q9KL24
-
-
3.5.2.3 Yersinia pestis Q8ZFU4
-
-

Posttranslational Modification

EC Number Posttranslational Modification Comment Organism
3.5.2.3 additional information VcDHO contains a carboxylated lysine (Kcx) residue in position 96 and two S-oxy cysteine (Csx) residues in positions 259 and 261 Vibrio cholerae serotype O1

Purification (Commentary)

EC Number Purification (Comment) Organism
3.5.2.3 recombinant His-tagged enzyme from Escherichia coli strain BL21(DE3) by nickel affinity chromatography, desalting gel filtration, and ultrafiltration Yersinia pestis
3.5.2.3 recombinant His-tagged enzyme from Escherichia coli strain BL21(DE3) by nickel affinity chromatography, desalting gel filtration, and ultrafiltration Vibrio cholerae serotype O1

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
3.5.2.3 (S)-dihydroorotate + H2O
-
 Yersinia pestis N-carbamoyl-L-aspartate
-
 r
3.5.2.3 (S)-dihydroorotate + H2O
-
 Vibrio cholerae serotype O1 N-carbamoyl-L-aspartate
-
 r
3.5.2.3 (S)-dihydroorotate + H2O
-
 Vibrio cholerae serotype O1 El Tor Inaba N16961 N-carbamoyl-L-aspartate
-
 r
3.5.2.3 (S)-dihydroorotate + H2O
-
 Vibrio cholerae serotype O1 ATCC 39315 N-carbamoyl-L-aspartate
-
 r
3.5.2.3 additional information N-carbamoyl-L-aspartate is preferred as the physiological substrate Yersinia pestis ?
-
-
3.5.2.3 additional information N-carbamoyl-L-aspartate is preferred as the physiological substrate Vibrio cholerae serotype O1 ?
-
-
3.5.2.3 additional information malate can bind to the active site Yersinia pestis ?
-
-
3.5.2.3 additional information malate can bind to the active site Vibrio cholerae serotype O1 ?
-
-
3.5.2.3 additional information N-carbamoyl-L-aspartate is preferred as the physiological substrate Vibrio cholerae serotype O1 El Tor Inaba N16961 ?
-
-
3.5.2.3 additional information malate can bind to the active site Vibrio cholerae serotype O1 El Tor Inaba N16961 ?
-
-
3.5.2.3 additional information N-carbamoyl-L-aspartate is preferred as the physiological substrate Vibrio cholerae serotype O1 ATCC 39315 ?
-
-
3.5.2.3 additional information malate can bind to the active site Vibrio cholerae serotype O1 ATCC 39315 ?
-
-
3.5.2.3 N-carbamoyl-L-aspartate
-
 Yersinia pestis (S)-dihydroorotate + H2O
-
 r
3.5.2.3 N-carbamoyl-L-aspartate
-
 Vibrio cholerae serotype O1 (S)-dihydroorotate + H2O
-
 r
3.5.2.3 N-carbamoyl-L-aspartate
-
 Vibrio cholerae serotype O1 El Tor Inaba N16961 (S)-dihydroorotate + H2O
-
 r
3.5.2.3 N-carbamoyl-L-aspartate
-
 Vibrio cholerae serotype O1 ATCC 39315 (S)-dihydroorotate + H2O
-
 r

Subunits

EC Number Subunits Comment Organism
3.5.2.3 More three-dimensional structure of DHO from Vibrio cholerae, structure analysis and comparison, overview Vibrio cholerae serotype O1
3.5.2.3 More three-dimensional structure of DHO from Yersinia pestis, structure analysis and comparison, overview. Each subunit has a structure based on the (beta/alpha)8-barrel (TIM-barrel) fold, a characteristic of the amidohydrolase superfamily Yersinia pestis

Synonyms

EC Number Synonyms Comment Organism
3.5.2.3 DHO
-
 Yersinia pestis
3.5.2.3 DHO
-
 Vibrio cholerae serotype O1
3.5.2.3 pyrC
-
 Yersinia pestis
3.5.2.3 pyrC
-
 Vibrio cholerae serotype O1
3.5.2.3 type II DHO
-
 Yersinia pestis
3.5.2.3 VcDHO
-
 Vibrio cholerae serotype O1
3.5.2.3 YpDHO
-
 Yersinia pestis

General Information

EC Number General Information Comment Organism
3.5.2.3 evolution the enzyme belongs to the amidohydrolase superfamily Vibrio cholerae serotype O1
3.5.2.3 evolution the structure of YpDHO has essentially the same conformation as the structure of DHO from Escherichia coli (EcDHO), the most thoroughly studied bacterial type II DHO. The enzyme belongs to the amidohydrolase superfamily Yersinia pestis
3.5.2.3 metabolism the de novo pyrimidine biosynthesis pathway is essential for the proliferation of many pathogens. One of the pathway enzymes, dihydroorotase (DHO), catalyzes the reversible interconversion of N-carbamoyl-L-aspartate to 4,5-dihydroorotate. De novo pyrimidine biosynthesis pathway, overview Yersinia pestis
3.5.2.3 metabolism the de novo pyrimidine biosynthesis pathway is essential for the proliferation of many pathogens. One of the pathway enzymes, dihydroorotase (DHO), catalyzes the reversible interconversion of N-carbamoyl-L-aspartate to 4,5-dihydroorotate. De novo pyrimidine biosynthesis pathway, overview Vibrio cholerae serotype O1
3.5.2.3 additional information structure homology modelling using the Plasmodium falciparum enzyme structure as model (PfDHO, UniProtKB ID Q8IKA9) Yersinia pestis
3.5.2.3 additional information structure homology modelling using the Plasmodium falciparum enzyme structure as model (PfDHO,UniProtKB ID Q8IKA9) Vibrio cholerae serotype O1