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Information on EC 3.5.1.6 - beta-ureidopropionase and Organism(s) Homo sapiens and UniProt Accession Q9UBR1
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3.5.1.6 beta-ureidopropionaseIUBMB Comments
The animal enzyme also acts on beta-ureidoisobutyrate.
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Word Map
- 3.5.1.6
- pyrimidine
- uracil
- dihydropyrimidinase
- thymine
- dihydrouracil
- kluyveri
- nitrilase
-
amidohydrolases
-
beta-aminoisobutyric
- beta-ureidoisobutyrate
- medicine
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Synonyms
beta-ureidopropionase, beta-alanine synthase, betaas, 3-ureidopropionase, betaupase, beta-up, bup-1, n-carbamoyl-beta-alanine amidohydrolase, betaup, 
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topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
N-carbamoyl-beta-alanine amidohydrolase
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of linear amides
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-
-
-
PATHWAY SOURCE
PATHWAYS
KEGG
-
-, -
SYSTEMATIC NAME
IUBMB Comments
N-carbamoyl-beta-alanine amidohydrolase
The animal enzyme also acts on beta-ureidoisobutyrate.
CAS REGISTRY NUMBER
COMMENTARY
9027-27-4
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
N-carbamoyl-beta-aminoisobutyrate + H2O
beta-aminoisobutyrate + CO2 + NH3
-
-
-
-
?
3-ureidopropanoate + H2O
beta-alanine + CO2 + NH3
3-ureidopropanoate i.e. N-carbamoyl-beta-alanine
-
-
?
N-carbamoyl-beta-alanine + H2O
beta-alanine + CO2 + NH3
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L enantiomer specific hydrolysis
-
-
ir
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
beta-Alanine
causes dissociation to inactive dimers, competitive inhibition
iodoacetamide
30 min preincubation with 50 mM iodoacetamide renders the enzyme completely inactive, probably due to covalent modification of the active-site cysteine (C233)
Zn2+
5.5% residual activity is measured after preincubation with 50 mM ZnCl2
additional information
preincubation of the enzyme with 1 mM EDTA has no influence on activity
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
N-Carbamoyl-beta-alanine
causes association to more active higher molecular mass species
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
0.0167
purified recombinant detagged mutant L13S, pH and temperature not specified in the publication
0.0558
purified recombinant detagged mutant S264R, pH and temperature not specified in the publication
0.282
purified recombinant detagged wild-type enzyme, pH and temperature not specified in the publication
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
metabolism
additional information
malfunction
beta-ureidopropionase deficiency is a rare inborn error of metabolism (IEM) affecting pyrimidine metabolism. Enzyme deficiency, due to enzyme mutation, R326Q, and Dravet syndrome, combine cause intractable and recurrent convulsions, global developmental delay and microcephaly. Excessive amount of beta-ureidopropionic acid and beta-ureidoisobutyric acid, the two disease-specific markers for beta-ureidopropionase deficiency. Differentiation between Dravet syndrome and beta-ureidopropionase deficiency is clinically challenging since both conditions share overlapping clinical features, usage of NMR or GC-MS is helpful in laboratory diagnosis
malfunction
beta-ureidopropionase deficient patients show neurological abnormalities (intellectual disabilities, seizures, abnormal tonus regulation, microcephaly, and malformations on neuro-imaging) and markedly elevated levels of N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid in urine and plasma, phenotypes of six missense and one splice-site mutants, overview
malfunction
enzyme mutational analysis: association between the c.-80C>G (rs2070474) genetic enzyme variant and gastrointestinal toxicity, strong positive correlation between the carriers of the c.-80GG genotype and the development of severe (grade 3-4) mucositis. Gene UPB1 variants may contribute to the development of 5-fluorouracil-related toxicity in some fluoropyrimidine-treated patients, but with less importance that the alterations in the dihydropyrimidine dehydrogenase (EC 1.3.1.2) gene
metabolism
beta-ureidopropionase is the third enzyme of the pyrimidine degradation pathway
metabolism
beta-ureidopropionase is the third enzyme of the pyrimidine degradation pathway and it catalyzes the conversion of N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid to beta-alanine and beta-aminoisobutyric acid, respectively, and ammonia and CO2
metabolism
the beta-ureidopropionase enzyme catalyzes the final step in the 5-fluorouracil catabolic pathway
metabolism
the enzyme catalyzes the third step of the reductive pyrimidine catabolic pathway responsible for breakdown of uracil-, thymine- and pyrimidine-based antimetabolites such as 5-fluorouracil
additional information
the catalytically crucial cysteine C233 performs the nucleophilic attack on the substrate resulting in the covalent acyl-enzyme complex. Residue R236 is part of the active site and has a putative role in binding the carboxyl group of the substrate. Analysis of a homology model of human beta-ureidopropionase generated using the crystal structure of the enzyme from Drosophila melanogaster indicated that the point mutations p.G235R, p.R236W and p.S264R lead to amino acid exchanges in the active site and therefore affect substrate binding and catalysis
additional information
-
screening for genetic deficiency in betaUPase, GC/MS analysis of urine metabolome. Patients 1, 2, 3 and 4 are asymptomatic and patients 5 and 6 have autism and West syndrome, respectively. In the disorders in the first and second steps of pyrimidine degradation, the clinical presentation and disease severity varies considerably, even among patients in the same family
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). BUP1_HUMAN
384
0
43166
Swiss-Prot
other Location (Reliability: 1)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
43158
4 * 43158, sequence calculation, structure analysis by dynamic light scattering and circular dichroism spectroscopy, and modeling, overview
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
homodimer
homodimer at pH 9, the enzyme increasingly associates to form octamers and larger oligomers with decreasing pH. Native PAGE analysis of wild-type enzyme indicates coexistence in at least five different oligomeric states, of which the smallest is most probably the dimer
oligomer
homodimer at pH 9, the enzyme increasingly associates to form octamers and larger oligomers with decreasing pH. Native PAGE analysis of wild-type enzyme indicates coexistence in at least five different oligomeric states, of which the smallest is most probably the dimer
tetramer
4 * 43158, sequence calculation, structure analysis by dynamic light scattering and circular dichroism spectroscopy, and modeling, overview
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
T299C is crystallized by the hanging-drop vapor diffusion method at 20°C. The T299C mutant enzyme crystallizes in space group C2221 with one polypeptide chain per asymmetric unit. The structure is determined to 2.08 A by molecular replacement
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
G235R
naturally occuring mutation and site-directed mutagenesis, inactive mutant. Mutation G235R introduces a large amino acid side chain for which there is no space available at this location. The larger structural rearrangements in the active site cavity required to prevent clashes with surrounding residues are expected to lead to enzyme inactivity and misfolding and defects in oligomerization, inability to obtain significant expression of soluble protein for this mutant
L13S
R130D/S208R
inactive mutant enzyme, the mutant enzyme is exclusively dimeric
R130I
inactive mutant enzyme, a significant monomer proportion is detected
R236W
naturally occuring mutation and site-directed mutagenesis, the mutant shows highly reduced activity compared to the wild-type enzyme
R326Q
S208A
inactive mutant enzyme, a significant monomer proportion is detected
S264R
naturally occuring mutation and site-directed mutagenesis,mutation S264R abolishes the hydrogen bond to Y314, which may be important for structural fixation of a residue stretch that is involved in shaping the entrance to the active site, the mutant shows reduced activity compared to the wild-type enzyme
T359M
A85E
-
expression of the A85E plasmid results in severely reduced BUP-1 enzyme activity, with only 2.7% activity relative to the wild-type UPB1 plasmid
additional information
L13S
naturally occuring mutation and site-directed mutagenesis, the mutation results in folding defects and oligomer assembly impairment, the mutant shows reduced activity compared to the wild-type enzyme
L13S
inactive mutant enzyme, the mutation is identified in beta-ureidopropionase-deficient patients
R326Q
naturally occuring mutation and site-directed mutagenesis, the mutation results in folding defects and oligomer assembly impairment, inactive mutant
R326Q
naturally occuring mutation in exon 9 affecting pre-mRNA splicing, analysis using a minigel approach
T359M
naturally occuring mutation and site-directed mutagenesis, the mutation results in folding defects and oligomer assembly impairment, the mutant shows highly reduced activity compared to the wild-type enzyme
additional information
missense mutations and intronic mutations that lead to aberrant splicing, overview
additional information
disruption of dimer-dimer interfaces by site-directed mutagenesis generated dimeric, inactive enzyme variants
additional information
-
screening for genetic deficiency in betaUPase, genotyping and phenotypes, overview
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant wild-type and mutant enzymes from Escherichia coli strain C41(DE3)pRARE2 by nickel affinity chromatography, desalting gel filtration, and cleavage of the tag by His-tagged 3C protease, followed by gel filtration and anion exchange chromatography
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
cDNA encoding human beta-ureidopropionase gene, BUP-1 cloned, plasmid yc28d10.r1 sequenced and expressed in Escherichia coli BL21, eukaryotic expression vector pCR3 transfected to COS-7-cells
gene UPB1, DNA and amino acid sequence determination and analysis, genotyping, reverse transcription and quantitative real-time PCR enzyme expression analysis, overview
gene UPB1, located on chromosome 22q11.2, DNA and amino acid sequence determination and analysis, expression of wild-type and mutant enzymes in HEK293 cells
gene UPB1, located on chromosome 22q11.2, DNA and amino acid sequence determination and analysis, sequence comparisons and genomic organization analysis, genotyping of beta-ureidopropionase deficient patients as well as the analysis of the mutations in a three-dimensional framework, PCR enzyme expression analysis, overview. Recombinant heterologous expression of wild-type and mutant enzymes in Escherichia coli strain C41(DE3)pRARE2, all mutations yield mutant beta-ureidopropionase proteins with significantly decreased activity
mutation A85E is introduced into the wild-type UPB1 plasmid using site-directed mutagenesis. The mutated plasmid is then transfected into the RKO cell line
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
-
analysis of putative enzyme defects in patients with neurological disfunctions
medicine
pharmacogenetic studies in patients receiving fluoropyrimidine-based chemotherapy should include genetic variants in dihydropyrimidinase (DPYS) and beta-ureidopropionase (UPB1), in addition to DPYD, to improve the understanding of their contribution to severe toxicity from fluoropyrimidine-based chemotherapy. Potential unknown underlying causal variants linked to the associated dihydropyrimidinase and beta-ureidopropionase variants may have a clinically relevant effect on fluoropyrimidine toxicity and should be investigated
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Matthews, M.M.; Traut, T.W.
Regulation of N-carbamoyl-beta-alanine amidohydrolase, the terminal enzyme in pyrimidine catabolism, by ligand-induced change in polymerization
J. Biol. Chem.
262
7232-7237
1987
Clostridium uracilicum, Clostridium uracilicum M5-2, Euglena gracilis, Homo sapiens, Mus musculus, Rattus rattus
Van Kuilenburg, A.B.P.; Van Lenthe, H.; Van Gennip, A.H.
A radiochemical assay for beta-ureidopropionase using radiolabeled N-carbamyl-beta-alanine obtained via hydrolysis of [2-14C]5,6-dihydrouracil
Anal. Biochem.
272
250-253
1999
Homo sapiens, Rattus rattus
Vreken, P.; van Kuilenburg, A.B.P.; Hamajima, N.; Meinsma, R.; van Lenthe, H.; Goehlich-Ratmann, G.; Assmann, B.E.; Wevers, R.A.; van Gennip, A.H.
cDNA cloning, genomic structure and chromosomal localization of the human BUP-1 gene encoding beta-ureidopropionase
Biochim. Biophys. Acta
1447
251-257
1999
Homo sapiens (Q9UBR1), Homo sapiens, Rattus rattus
Schnackerz, K.D.; Dobritzsch, D.
Amidohydrolases of the reductive pyrimidine catabolic pathway: Purification, characterization, structure, reaction mechanisms and enzyme deficiency
Biochim. Biophys. Acta
1784
431-444
2008
Arabidopsis thaliana, Bos taurus, Caenorhabditis elegans, Dictyostelium discoideum, Drosophila melanogaster, Euglena gracilis, Homo sapiens, Lachancea kluyveri, Pseudomonas putida, Rattus norvegicus, Zea mays
van Kuilenburg, A.B.; van Lenthe, H.; van Gennip, A.H.
Activity of pyrimidine degradation enzymes in normal tissues
Nucleosides Nucleotides Nucleic Acids
25
1211-1214
2006
Homo sapiens
Thomas, H.R.; Ezzeldin, H.H.; Guarcello, V.; Mattison, L.K.; Fridley, B.L.; Diasio, R.B.
Genetic regulation of beta-ureidopropionase and its possible implication in altered uracil catabolism
Pharmacogenet. Genomics
18
25-35
2008
Homo sapiens
Kuhara, T.; Ohse, M.; Inoue, Y.; Shinka, T.
Five cases of beta-ureidopropionase deficiency detected by GC/MS analysis of urine metabolome
J. Mass Spectrom.
44
214-221
2009
Homo sapiens
Van Kuilenburg, A.; Dobritzsch, D.; Meijer, J.; Krumpel, M.; Selim, L.; Rashed, M.; Assmann, B.; Meinsma, R.; Lohkamp, B.; Ito, T.; Abeling, N.; Saito, K.; Eto, K.; Smitka, M.; Engvall, M.; Zhang, C.; Xu, W.; Zoetekouw, L.; Hennekam, R.
beta-Ureidopropionase deficiency: phenotype, genotype and protein structural consequences in 16 patients
Biochim. Biophys. Acta
1822
1096-1108
2012
Homo sapiens (Q9UBR1)
Lam, C.W.; Law, C.Y.; Leung, K.F.; Lai, C.K.; Pak-lam Chen, S.; Chan, B.; Chan, K.Y.; Yuen, Y.P.; Mak, C.M.; Yan-wo Chan, A.
NMR-based urinalysis for rapid diagnosis of beta-ureidopropionase deficiency in a patient with Dravet syndrome
Clin. Chim. Acta
440
201-204
2015
Homo sapiens (Q9UBR1), Homo sapiens
Meijer, J.; Nakajima, Y.; Zhang, C.; Meinsma, R.; Ito, T.; Van Kuilenburg, A.B.
Publishers note. Identification of a novel synonymous mutation in the human beta-ureidopropionase gene UPB1 affecting pre-mRNA splicing
Nucleosides Nucleotides Nucleic Acids
33
639-645
2014
Homo sapiens (Q9UBR1)
Fidlerova, J.; Kleiblova, P.; Kormunda, S.; Novotny, J.; Kleibl, Z.
Contribution of the beta-ureidopropionase (UPB1) gene alterations to the development of fluoropyrimidine-related toxicity
Pharmacol. Rep.
64
1234-1242
2012
Homo sapiens (Q9UBR1)
Maurer, D.; Lohkamp, B.; Krumpel, M.; Widersten, M.; Dobritzsch, D.
Crystal structure and pH-dependent allosteric regulation of human beta-ureidopropionase, an enzyme involved in anticancer drug metabolism
Biochem. J.
475
2395-2416
2018
Homo sapiens (Q9UBR1)
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