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Information on EC 6.1.1.7 - alanine-tRNA ligase and Organism(s) Homo sapiens and UniProt Accession Q5JTZ9
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6.1.1.7 alanine-tRNA ligaseSpecify your search results
Word Map
- 6.1.1.7
- aminoacylation
- synthetases
- aminoacyl-trna
- leukodystrophy
-
alanylation
-
mischarged
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aarss
- leukoencephalopathy
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mistranslation
- tmrnas
- charcot-marie-tooth
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noncognate
- thrrs
- threonyl-trna
- minihelix
- seryl-trna
-
anti-pl-12
- valrs
-
misactivation
- microhelix
- ilers
-
trans-translation
- molecular biology
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Synonyms
alanyl-trna synthetase, alars, aars2, alanine trna synthetase, ala-trna synthetase, mitochondrial alanyl-trna synthetase, alanyl-transfer rna synthetase, mtalars, alanine-trna ligase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
Ala-tRNA synthetase
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Alanine transfer RNA synthetase
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Alanine translase
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Alanine tRNA synthetase
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Alanine--tRNA ligase
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Alanine-transfer RNA ligase
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Alanyl-transfer ribonucleate synthetase
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Alanyl-transfer ribonucleic acid synthetase
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Alanyl-transfer RNA synthetase
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Alanyl-tRNA synthetase
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AlaRS
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Synthase, alanyl-transfer ribonucleate
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
esterification
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Aminoacylation
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SYSTEMATIC NAME
IUBMB Comments
L-alanine:tRNAAla ligase (AMP-forming)
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CAS REGISTRY NUMBER
COMMENTARY
9031-71-4
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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
additional information
?
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recombinant mutant human appended C-terminal domain (C-Ala) shows strong binding to DNA cellulose, but not to cellulose alone
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?
additional information
?
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recombinant mutant human appended C-terminal domain (C-Ala) shows strong binding to DNA cellulose, but not to cellulose alone
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?
additional information
?
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aminoacylates 9-base pair RNA duplexes whose sequences are based on the acceptor stems of either E. coli or human alanine tRNAs
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?
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
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
additional information
an isolated 23 kDa appended C-terminal domain (C-Ala), consisting of the C-terminal 757968 amino acids, locates in the nucleus
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additional information
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an isolated 23 kDa appended C-terminal domain (C-Ala), consisting of the C-terminal 757968 amino acids, locates in the nucleus
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
the sequence of appended C-terminal domain (C-Ala) of enzyme AlaRS diverged widely in the evolutionary progression to humans. During evolution, 19 aaRSs expanded by acquiring novel noncatalytic appended domains, which are absent from bacteria and many lower eukaryotes but confer extracellular and nuclear functions in higher organisms. AlaRS is the single exception, with an appended C-terminal domain (C-Ala) that is conserved from prokaryotes to humans but with a wide sequence divergence. In human cells, C-Ala is also a splice variant of AlaRS. Crystal structures of two forms of human C-Ala, and small-angle X-ray scattering of AlaRS, show that the large sequence divergence of human C-Ala reshaped C-Ala in a way that changed the global architecture of AlaRS. This reshaping removed the role of C-Ala in prokaryotes for docking tRNA and instead repurposed it to form a dimer interface presenting a DNA-binding groove. This groove cannot form with the bacterial ortholog. Direct DNA binding by human C-Ala, but not by bacterial C-Ala. Instead of acquiring a special appended domain, a new AlaRS architecture has benn created by diversifying a preexisting domain
malfunction
physiological function
the accuracy of mitochondrial protein synthesis is dependent on the coordinated action of nuclear-encoded mitochondrial aminoacyl-tRNA synthetases (mtARSs) and the mitochondrial DNA-encoded tRNAs. The mitochondrial alanyl-tRNA synthetase (mtAlaRS) differs from the other mtARSs because in addition to the aminoacylation domain, it has a conserved editing domain for deacylating tRNAs that have been mischarged within correct amino acids
additional information
malfunction
enzyme mutations are associated with infantile mitochondrial cardiomyopathy
malfunction
importance of the mtARS proteins for mitochondrial pathophysiology since nearly every nuclear gene for mtARS (out of 19) is recognized as a disease gene for mitochondrial disease. Mutations in the AARS2 gene for mitochondrial alanyl-tRNA synthetase (mtAlaRS) is observed both in patients with infantile-onset cardiomyopathy and in patients with childhood to adulthood-onset leukoencephalopathy. The cardiomyopathy phenotype results from a single allele, causing an amino acid change R592W in the editing domain of AARS2, whereas the leukodystrophy mutations are located in other domains of the synthetase. All mutations reduce the aminoacylation activity of the synthetase, because all mtAlaRS domains contribute to tRNA binding for aminoacylation. The cardiomyopathy mutations severely compromise aminoacylation whereas partial activity is retained by the mutation combinations found in the leukodystrophy patients. Molecular basis of the distinct tissue-specific phenotypic outcomes of enzyme mutantions, structure analysis and homology modeling, overview
additional information
enzyme structure modeling, analysis of the contact surface between linker safety belt, and beta-barrel of the editing domain in modeled human mitochondrial AlaRS, overview
additional information
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enzyme structure modeling, analysis of the contact surface between linker safety belt, and beta-barrel of the editing domain in modeled human mitochondrial AlaRS, overview
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). SYAM_HUMAN
985
0
107340
Swiss-Prot
Mitochondrion (Reliability: 1)
PDB
SCOP
CATH
UNIPROT
ORGANISM
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
an isolated appended C-terminal domain (C-Ala), consisting of the C-terminal 757968 amino acids, forms dimers as well as monomers, gel filtration
additional information
-
an isolated appended C-terminal domain (C-Ala), consisting of the C-terminal 757968 amino acids, forms dimers as well as monomers, gel filtration
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
purified recombinant appended C-terminal domain (C-Ala), two different crystal forms, each of which is specific to a particular condition are achieved, one of these crystal forms harbors the monomer and is obtained using 0.1 M Tris, pH 8.5, and 25% w/v PEG 3350, whereas the other captures a dimer using 0.2 M ammonium acetate, 0.1 M Tris, pH 8.5, and 25% w/v PEG 3350, X-ray diffraction structure determination and analysis
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
A77V
naturally occuring mutation of a catalytic residue. the mutant likely affects alanine binding resulting in either totally inactive enzyme or with little aminoacylation activity due to decreased affinity to alanine
E405K
naturally occuring mutation of a structural residue within the tRNA recognition subdomain of the aminoacylation domain, the mutation leads to a partly reduced rate of tRNA aminoacylation due to structural instability in the tRNA recognition fold
F50C
naturally occuring mutation, leads to reduced rate of aminoacylation due to instability of alanine- and ATP-binding sites and impaired alanyl-adenylate formation
G965R
naturally occuring mutation predicted to impair protein folding and stability resulting in loss of aminoacylation activity
L155R
the mutation is associated with infantile mitochondrial cardiomyopathy
R199C
naturally occuring mutation of a catalytic residue involved in ATP binding, the mutantion leads to reduced rate of tRNA aminoacylation due to affected ATP-binding and impaired alanyl-adenylate formation
R592W
R592W/A961V
naturally occuring lethal mutation R592W in gene AARS2 causing infantile cardiomyopathy, mutation A961V is predicted to impair protein folding and stability resulting in loss of aminoacylation activity
R592W/C218L
naturally occuring lethal mutation R592W in gene AARS2 causing infantile cardiomyopathy, truncated mutant
R592W/L155R
naturally occuring lethal mutation R592W in gene AARS2 causing infantile cardiomyopathy, mutation L155R is predicted to impair protein folding and stability resulting in loss of aminoacylation activity
R592W/R329H
naturally occuring lethal mutation R592W in gene AARS2 causing infantile cardiomyopathy, mutation R329H is predicted to impair protein folding and stability resulting in loss of aminoacylation activity
R592W/Y539C
naturally occuring lethal mutation R592W in gene AARS2 causing infantile cardiomyopathy. The Y539C mutation causes a dramatic decrease of aminoacylation rate due to impaired tRNA binding and positioning of the 3'-end within the active site
additional information
R592W
the mutation is associated with infantile mitochondrial cardiomyopathy
R592W
a naturally occuring lethal mutation in the editing domain of AARS2 causing a cardiomyopathy phenotype, homology modeling of the AARS2 missense mutant, overview. The AARS2 cardiomyopathy mutation R592W is a common founder mutation and carried by all the identified patients with the severe infantile-onset phenotype
additional information
construction of an isolated appended C-terminal domain (C-Ala) consisting of the C-terminal 757968 amino acids, the 23 kDa protein forms dimers as well as monomers, and locates in the nucleus
additional information
-
construction of an isolated appended C-terminal domain (C-Ala) consisting of the C-terminal 757968 amino acids, the 23 kDa protein forms dimers as well as monomers, and locates in the nucleus
additional information
patient haplotypes around the AARS2 mutation, some patients show heterozygous mutations R592W/L155R, R592W/R329H, R592W/A961V, R592W/C218L, or R592W/Y539C, but the same pehnotype as homozygous R592W mutants. Mapping and function predictions of AARS2 mutations associated with cardiomyopathy and leukodystrophy
additional information
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patient haplotypes around the AARS2 mutation, some patients show heterozygous mutations R592W/L155R, R592W/R329H, R592W/A961V, R592W/C218L, or R592W/Y539C, but the same pehnotype as homozygous R592W mutants. Mapping and function predictions of AARS2 mutations associated with cardiomyopathy and leukodystrophy
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene alaS, sequence comparisons, recombinant expression of a C-Ala construct consisting of the C-terminal 757-968 amino acids
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Shiba, K.; Ripmaster, T.; Suzuki, N.; Nichols, R.; Plotz, P.; Noda, T.; Schimmel, P.
Human alanyl-tRNA synthetase. Conservation in evolution of catalytic core and microhelix recognition
Biochemistry
34
10340-10349
1995
Escherichia coli, Homo sapiens
Goetz, A.; Tyynismaa, H.; Euro, L.; Ellonen, P.; Hyoetylaeinen, T.; Ojala, T.; Haemaelaeinen, R.H.; Tommiska, J.; Raivio, T.; Oresic, M.; Karikoski, R.; Tammela, O.; Simola, K.O.; Paetau, A.; Tyni, T.; Suomalainen, A.
Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy
Am. J. Hum. Genet.
88
635-642
2011
Homo sapiens (Q5JTZ9), Homo sapiens
Euro, L.; Konovalova, S.; Asin-Cayuela, J.; Tulinius, M.; Griffin, H.; Horvath, R.; Taylor, R.W.; Chinnery, P.F.; Schara, U.; Thorburn, D.R.; Suomalainen, A.; Chihade, J.; Tyynismaa, H.
Structural modeling of tissue-specific mitochondrial alanyl-tRNA synthetase (AARS2) defects predicts differential effects on aminoacylation
Front. Genet.
6
21
2015
Homo sapiens (Q5JTZ9), Homo sapiens
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