2.1.3.2: aspartate carbamoyltransferase
This is an abbreviated version!
For detailed information about aspartate carbamoyltransferase, go to the full flat file.
Word Map on EC 2.1.3.2
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2.1.3.2
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pyrimidine
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dihydroorotase
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ctp
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n-phosphonacetyl-l-aspartate
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trimer
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homotropic
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bisubstrate
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heterotropic
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holoenzyme
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succinate
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orotate
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uridine
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ornithine
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hamster
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uracil
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r-states
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cpsase
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phosphoribosyltransferase
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glutamine-dependent
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carbamylphosphate
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dhoase
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cytidine
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orotidine
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lipscomb
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intersubunit
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changeux
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pyre
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otcase
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syrian
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acivicin
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high-activity
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wheat-germ
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cistron
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unligated
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monod
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trifunctional
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interchain
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dodecameric
- 2.1.3.2
- pyrimidine
- dihydroorotase
- ctp
- n-phosphonacetyl-l-aspartate
- trimer
-
homotropic
-
bisubstrate
-
heterotropic
-
holoenzyme
- succinate
- orotate
- uridine
- ornithine
- hamster
- uracil
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r-states
- cpsase
- phosphoribosyltransferase
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glutamine-dependent
- carbamylphosphate
- dhoase
- cytidine
- orotidine
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lipscomb
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intersubunit
-
changeux
-
pyre
- otcase
-
syrian
- acivicin
-
high-activity
-
wheat-germ
-
cistron
-
unligated
-
monod
-
trifunctional
-
interchain
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dodecameric
Reaction
Synonyms
(S)-2-methyl-3-oxopropanoyl-CoA:pyruvate carboxyltransferase, ACT, aspartate carbamoyltransferase, aspartate carbamyltransferase, aspartate trans carbamoylase, aspartate transcarbamoylase, aspartate transcarbamylase, aspartic acid transcarbamoylase, aspartic carbamyltransferase, aspartic transcarbamylase, ATC, ATC domain of CAD, ATCase, CAD, carbamoylaspartotranskinase, carbamoyltransferase, aspartate, carbamylaspartotranskinase, L-aspartate transcarbamoylase, L-aspartate transcarbamylase, MJ1581, PYRB
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2.1.3.2 aspartate carbamoyltransferaseAdvanced search results
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General Information on EC 2.1.3.2 - aspartate carbamoyltransferase
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GENERAL INFORMATION 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
evolution
malfunction
metabolism
physiological function
additional information
evolution
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2 types of the enzyme occur: a CPSII-DHO-ATC fusion enzyme (CAD) found in animals, fungi, and amoebozoa, where the enzymes carbamoylphosphate synthetase II (CPSII), aspartate transcarbamoylase (ATC), and dihydroorotase (DHO), catalyzing the first three reaction steps of the de novo pyrimidine biosynthetic pathway, form a complex, and (2) stand-alone enzymes found in plants and the protist groups
evolution
in animals, CPSase, ATCase and DHOase are part of a 243 kDa multifunctional polypeptide named CAD
malfunction
analysis of the conformational changes shows that there is a lack of cooperativity in trimeric ATCases that do not possess regulatory subunits
malfunction
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a missense mutation in the carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (cad) gene causes reduced lymphatic vessel development. The mutant also exhibits hyperbranching arteries, reminiscent of Notch pathway mutants. Notch signaling is significantly reduced in cadhu10125 mutants. hu10125 mutants display reduced formation of the thoracic duct and hyperbranched intersegmental arteries, penotype, overview
metabolism
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the aspartate amino-N can be the source of nitrogen for glutamine synthesis by a substrate-channelled pathway which delivers glutamine to carbamoyl phosphate synthetase
metabolism
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the binding of carbamoyl phosphate to the enzymes aspartate and ornithine transcarbamoylase reduces the rate of thermal decomposition of carbamoyl phosphate by a factor of >5000. Both of these transcarbamoylases use an ordered-binding mechanism in which carbamoyl phosphate binds first, allowing the formation of an enzyme-carbamoyl phosphate complex. The critical step in the thermal decomposition of carbamoyl phosphate in aqueous solution, in the absence of enzyme, involves the breaking of the C-O bond facilitated by intramolecular proton transfer from the amine to the phosphate. The binding of carbamoyl phosphate to the active sites of the enzymes significantly inhibits this process by restricting the accessible conformations of the bound ligand to those disfavoring the reactive geometry
metabolism
aspartate transcarbamoylase allosterically regulates pyrimidine nucleotide biosynthesis
metabolism
ATCase catalyzes one of the first reactions in pyrimidine nucleotide biosynthesis
metabolism
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ATCase is an allosteric enzyme that catalyzes the committed step of pyrimidine nucleotide biosynthesis
metabolism
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ATCase regulates the pyrimidine nucleotide biosynthesis by feedback control and by the cooperative binding of the substrate L-aspartate
metabolism
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aspartate transcarbamoylase and dihydroorotase, enzymes that catalyze the second and third step in de novo pyrimidine biosynthesis, are associated in dodecameric complexes in Aquifex aeolicus and many other organisms, intersubunit communication in the dihydroorotase-aspartate transcarbamoylase complex of Aquifex aeolicus, overview. The architecture of the dodecamer is ideally suited to channel the intermediate, carbamoyl aspartate from its site of synthesis on the ATC subunit to the active site of dihydroorotase, which catalyzes the next step in the pathway, because both reactions occur within a large, internal solvent-filled cavity. The apparent second-order rate constant (kcat/Km) of ATC is 7.0fold greater than that of dihydroorotase
metabolism
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the aspartate amino-N can be the source of nitrogen for glutamine synthesis by a substrate-channelled pathway which delivers glutamine to carbamoyl phosphate synthetase
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physiological function
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allosteric transition of ATCase, R-state stabilization by disulfide linkages, overview. Wild-type ATCase displays homotropic cooperativity with respect to the second substrate Asp due a shift from the low-activity, low-affinity T state to the high-activity, high-affinity R state
physiological function
aspartate transcarbamoylase allosterically regulates pyrimidine nucleotide biosynthesis
physiological function
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ATCase catalyzes the committed step, the condensation of carbamoyl phosphate and aspartate to form carbamoyl aspartate and inorganic phosphate and regulates the pyrimidine nucleotide biosynthesis by feedback control and by the cooperative binding of the substrate L-aspartate, catalytic and regulatory mechanisms, overview. Each regulatory chain is also composed of two folding domains: the Zn domain, primarily involved in the binding of the zinc cofactor, and and the Al domain, primarily involved in the binding of allosteric effectors
physiological function
mechanisms of allosteric regulation in aspartate transcarbamoylase, overview
physiological function
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the enzyme controls the rate of pyrimidine nucleotide biosynthesis by feedback inhibition, and helps to balance the pyrimidine and purine pools by competitive allosteric activation by ATP
physiological function
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physically interacting with each other, carbamate kinase and ornithine carbamoyltransferase prevent thermodenaturation of carbamoyl phosphate (a precursor of pyrimidines and arginine, which is an extremely labile and potentially toxic intermediate) in the aqueous cytoplasmic environment. The carbamoyl phosphate channelling complex involves carbamate kinase, ornithine carbamoyltransferase and aspartate carbamoyltransferase
physiological function
the enzyme catalyzes the first step in the pyrimidine biosynthetic pathway
physiological function
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CAD protein, formed by carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase, is a multifunctional enzyme required for the de novo synthesis of pyrimidine nucleotides. Aspartate transcarbamoylase is located at the C-terminal part of CAD, Each activity is coded in a separate domain
physiological function
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carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase form the CAD complex that is essential for UDP biosynthesis, which is necessary for protein glycosylation and de novo biosynthesis of pyrimidine-based nucleotides. CAD is an unappreciated mechanism that regulates Notch/Vegf signaling during angiogenesis
physiological function
enzyme aspartate transcarbamoylase catalyzes the committed step in pyrimidine nucleotide biosynthesis and allosterically regulates the pathway in Escherichia coli
physiological function
upregulation of CAD, comprising CPSase, ATCase and DHOase activities, is essential for normal and tumour cell proliferation
physiological function
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the enzyme catalyzes the first step in the pyrimidine biosynthetic pathway
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physiological function
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physically interacting with each other, carbamate kinase and ornithine carbamoyltransferase prevent thermodenaturation of carbamoyl phosphate (a precursor of pyrimidines and arginine, which is an extremely labile and potentially toxic intermediate) in the aqueous cytoplasmic environment. The carbamoyl phosphate channelling complex involves carbamate kinase, ornithine carbamoyltransferase and aspartate carbamoyltransferase
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additional information
allosteric transition between the T and R enzyme states
additional information
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importance of intradomain and intrachain interactions for the different comformational states, T and R states, active site and allosteric site structure, overview. Important for the stability of the T state are the Glu239c1 interaction with both Lys164c4 and Tyr165c4, the Asp236c1 interaction with Lys143r4, and the Ser238c1 interaction with Asn111r4. In the R state, Glu239c1 forms new interchain interactions with Lys164c1 and Tyr165c1, while Asn111r4 forms a new interaction with Glu109c4
additional information
nucleotide binding site specificity conformational changes due to nucleotide binding, overview
additional information
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nucleotide binding site specificity conformational changes due to nucleotide binding, overview
additional information
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Rheb binds CAD in a GTP- and effector domain-dependent manner. The region of CAD where Rheb binds is located at the C-terminal region of the carbamoyl-phosphate synthetase domain and not in the dihydroorotase and aspartate transcarbamoylase domains. Rheb stimulated carbamoyl-phosphate synthetase activity of CAD in vitro. CAD binding is more pronounced with Rheb2 than with Rheb1
additional information
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the dihydroorotase loop A that binds between the two ATC domains is an allosteric or noncompletive ATC inhibitor with Ki 5 of 0.022 mM, loop A is an important component of the functional linkage between the enzymes. modeling, overview
additional information
three-dimensional enzyme homology structure modeling using the crystal structure of ATCase from Pyrococcus abyssi, PDB ID:1ML4, molecular dynamics simulations and enzyme conformation stability, ligand binding study, overview. The residues Thr53, Arg104, and Gln219 are consistently involved in strong hydrogen-bonding interactions and play a vital role in the TtATCase activity
additional information
Thermus thermophilus HB8 / ATCC 27634 / DSM 579
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three-dimensional enzyme homology structure modeling using the crystal structure of ATCase from Pyrococcus abyssi, PDB ID:1ML4, molecular dynamics simulations and enzyme conformation stability, ligand binding study, overview. The residues Thr53, Arg104, and Gln219 are consistently involved in strong hydrogen-bonding interactions and play a vital role in the TtATCase activity
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