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Literature summary for 6.3.5.4 extracted from

  • Lomelino, C.L.; Andring, J.T.; McKenna, R.; Kilberg, M.S.
    Asparagine synthetase function, structure, and role in disease (2017), J. Biol. Chem., 292, 19952-19958 .
    View publication on PubMedView publication on EuropePMC
Search for more literature for 6.3.5.4

Cloned(Commentary)

Cloned (Comment) Organism
gene asnB Escherichia coli
gene ASNS, a single copy gene located on chromosome 7 Homo sapiens

Crystallization (Commentary)

Crystallization (Comment) Organism
crystal structure analysis, PDB ID 1CT9 Escherichia coli

Protein Variants

Protein Variants Comment Organism
A380S naturally occuring mutation, homozygous mutation, mutation of a polar residue in the hydrophobic region Homo sapiens
A6E naturally occuring mutation, compound heterozygous, mutation of a charged amino acid in hydrophobic region, causing steric clash with Phe8 Homo sapiens
F362V naturally occuring mutation, homozygous mutation, causes a decrease in van der Waals interactions Homo sapiens
G289A naturally occuring mutation, compound heterozygous, mutation proximal to the ATP-binding site, causing steric hindrance with Ser293 Homo sapiens
L145S naturally occuring mutation, compound heterozygous, mutation of a polar side chain in hydrophobic region Homo sapiens
L247W naturally occuring mutation, causes a decrease in van der Waals interactions Homo sapiens
additional information identification of two naturally occuring nonsense mutations, R407* and W541Cfs*5 (frameshift mutation), leading to truncated enzyme mutants Homo sapiens
R340H naturally occuring mutation, homozygous mutation, causes a loss of hydrogen bonds, and a steric clash with Phe482 Homo sapiens
R49Q naturally occuring mutation, homozygous mutation of the glutamine-binding site, causes loss of hydrogen bonding Homo sapiens
R550C naturally occuring mutation, causes a decrease in side chain length likely to result in loss of interactions Homo sapiens
R550C naturally occuring mutation, homozygous mutation, causes a decrease in side chain length likely to result in loss of interactions Homo sapiens
S480F naturally occuring mutation, compound heterozygous, mutation of a nonpolar residue on protein surface that may decrease solubility Homo sapiens
T337I naturally occuring mutation, Proximal to ATP-binding site, causes a hydrophobic patch on protein that may decrease solubility Homo sapiens
V489D naturally occuring mutation, compound heterozygous, inserts a charged amino acid in hydrophobic region Homo sapiens
Y398C naturally occuring mutation, homozygous mutation, causes a decrease in van der Waals interactions, solvent-accessible thiol group Homo sapiens

Metals/Ions

Metals/Ions Comment Organism Structure
Mg2+ required Homo sapiens
Mg2+ required Escherichia coli

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
ATP + L-aspartate + L-glutamine + H2O Homo sapiens
-
 AMP + diphosphate + L-asparagine + L-glutamate
-
 ?
ATP + L-aspartate + L-glutamine + H2O Escherichia coli
-
 AMP + diphosphate + L-asparagine + L-glutamate
-
 ?
ATP + L-aspartate + NH3 Homo sapiens
-
 AMP + diphosphate + L-asparagine
-
 ?
ATP + L-aspartate + NH3 Escherichia coli
-
 AMP + diphosphate + L-asparagine
-
 ?
L-glutamine + H2O Homo sapiens
-
 L-glutamate + NH3
-
 ?
L-glutamine + H2O Escherichia coli
-
 L-glutamate + NH3
-
 ?

Organism

Organism UniProt Comment Textmining
Escherichia coli P22106
-
-
Homo sapiens P08243
-
-

Reaction

Reaction Comment Organism Reaction ID
ATP + L-aspartate + L-glutamine + H2O = AMP + diphosphate + L-asparagine + L-glutamate reaction mechanism, structure-function relationship Homo sapiens
a
ATP + L-aspartate + L-glutamine + H2O = AMP + diphosphate + L-asparagine + L-glutamate reaction mechanism, structure-function relationship Escherichia coli
a

Source Tissue

Source Tissue Comment Organism Textmining
adenocarcinoma cell
-
 Homo sapiens
-
DLD-1 cell
-
 Homo sapiens
-
fibrosarcoma cell
-
 Homo sapiens
-
HT-1080 cell
-
 Homo sapiens
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
ATP + L-aspartate + L-glutamine + H2O
-
 Homo sapiens AMP + diphosphate + L-asparagine + L-glutamate
-
 ?
ATP + L-aspartate + L-glutamine + H2O
-
 Escherichia coli AMP + diphosphate + L-asparagine + L-glutamate
-
 ?
ATP + L-aspartate + NH3
-
 Homo sapiens AMP + diphosphate + L-asparagine
-
 ?
ATP + L-aspartate + NH3
-
 Escherichia coli AMP + diphosphate + L-asparagine
-
 ?
L-glutamine + H2O
-
 Homo sapiens L-glutamate + NH3
-
 ?
L-glutamine + H2O
-
 Escherichia coli L-glutamate + NH3
-
 ?

Subunits

Subunits Comment Organism
? x * 65000, about, sequence calculation Escherichia coli
More the enzyme contains two functional domains, the N-terminal domain (residues 1-208) consists of a two-layer, antiparallel beta-sheet core surrounded by four alpha-helices, this domain harbors the glutamine-binding pocket, consisting of residues Arg49, Asn75, Glu77, and Asp97. The C-terminal domain (residues 209-561) is composed primarily of alpha-helices, but also encompasses a five-stranded, parallel beta-sheet that contains the ATP-binding site: residues Leu256, Val288, Asp295, Ser363, Gly364, Glu365, and Asp401 Homo sapiens

Synonyms

Synonyms Comment Organism
AS-B
-
 Escherichia coli
ASNS
-
 Homo sapiens
Asparagine synthetase
-
 Homo sapiens
Asparagine synthetase
-
 Escherichia coli

Cofactor

Cofactor Comment Organism Structure
ATP
-
 Homo sapiens
ATP
-
 Escherichia coli

Expression

Organism Comment Expression
Homo sapiens ASNS activity is highly responsive to cellular stress, primarily by increased transcription from the single gene located on chromosome 7. The transcription factor ATF4 binds to an enhancer element within the proximal promoter of the ASNS gene and activates transcription up

General Information

General Information Comment Organism
malfunction asparagine synthetase deficiency, ASD, is a neurological disorder having severe impacts on psychomotor development and mortality at an early age. Children with mutations in the ASNS gene exhibit developmental delays, intellectual disability, microcephaly, intractable seizures, and progressive brain atrophy. Mutations in the ASNS gene have been clinically associated with asparagine synthetase deficiency (ASD), phenotype. Neurologic disorder associated with asparagine synthetase deficiency (ASD). The transcription factor ATF4 binds to an enhancer element within the proximal promoter of the ASNS gene and activates transcription. Role of ATF4 in tumor cell survival and proliferation, ATF4 knockdown causes reduced survival in HT-1080 fibrosarcoma and DLD-1 colorectal adenocarcinoma cells in the absence of nonessential amino acids. Reduced proliferative capacity and increased apoptosis correlate with lower ASNS expression in the ATF4-deficient cells. Supplementation of the tumor cells with asparagine, but not other amino acids, leads to increased cell survival. Role of ASNS activity in modulating tumor growth Homo sapiens
additional information glutamine binds in a manner so that the carboxamide group is oriented toward the interface of the two domains to allow the transfer of an ammonia group from glutamine to aspartate Escherichia coli
additional information glutamine is predicted to bind in a manner so that the carboxamide group is oriented toward the interface of the two domains to allow the transfer of an ammonia group from glutamine to aspartate Homo sapiens
physiological function asparagine synthetase (ASNS) catalyzes the synthesis of asparagine and glutamate from aspartate and glutamine in an ATP-dependent amidotransferase reaction Escherichia coli
physiological function asparagine synthetase (ASNS) catalyzes the synthesis of asparagine and glutamate from aspartate and glutamine in an ATP-dependent amidotransferase reaction. Elevated ASNS protein expression is associated with resistance to asparaginase therapy in childhood acute lymphoblastic leukemia. Regulation of ASNS expression, overview. transcription factor ATF4 binds to an enhancer element within the proximal promoter of the ASNS gene and activates transcription. Asparagine depletion activates the amino acid response, AAR, whereas endoplasmic reticulum stress activates the unfolded protein response, UPR Homo sapiens