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Information on EC 6.1.1.10 - methionine-tRNA ligase and Organism(s) Homo sapiens
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6.1.1.10 methionine-tRNA ligaseIUBMB Comments
In those organisms producing N-formylmethionyl-tRNAfMet for translation initiation, this enzyme also recognizes the initiator tRNAfMet and catalyses the formation of L-methionyl-tRNAfMet, the substrate for EC 2.1.2.9, methionyl-tRNA formyltransferase.
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Word Map
- 6.1.1.10
- synthetases
- aminoacyl-trna
- aminoacylation
-
anticodons
- homocysteine
- trnafmet
-
thiolactone
-
aarss
-
isoleucyl-trna
-
trypsin-modified
-
isoleucylation
-
noncognate
- tyrosyl-trna
- arc1p
-
atp-ppi
- formylmethionine
- medicine
- leucyl-trna
-
kmsks
-
misacylation
-
hcy-thiolactone
- ilers
- lysyl-trna
-
trna-binding
- valrs
- valyl-trna
-
cysteinyl-trna
- drug development
- pharmacology
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
methionyl-trna synthetase, metrs, methionyl trna synthetase, mars-1, metrs2, metrs1, hcmetrs, methionyl-trna-synthetase, let-65, methionine-trna ligase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
Methionine translase
Methionine--tRNA ligase
Methionyl tRNA synthetase
Methionyl-transfer ribonucleate synthetase
Methionyl-transfer ribonucleic acid synthetase
Methionyl-transfer RNA synthetase
methionyl-tRNA synthetase
MetRS
Synthetase, methionyl-transfer ribonucleate
Methionine translase
-
-
-
-
Methionine--tRNA ligase
-
-
-
-
Methionyl tRNA synthetase
-
-
-
-
Methionyl-transfer ribonucleate synthetase
-
-
-
-
Methionyl-transfer ribonucleic acid synthetase
-
-
-
-
Methionyl-transfer RNA synthetase
-
-
-
-
MetRS
-
-
-
-
Synthetase, methionyl-transfer ribonucleate
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
ATP + L-methionine + tRNAMet = AMP + diphosphate + L-methionyl-tRNAMet
mechanism, catalytic domain is formed by amino acid residues A215-K823
-
ATP + L-methionine + tRNAMet = AMP + diphosphate + L-methionyl-tRNAMet
two-step reaction process via anenzyme-L-Met-AMP intermediate
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Aminoacylation
esterification
Aminoacylation
-
-
-
-
esterification
-
-
-
-
PATHWAY SOURCE
PATHWAYS
BRENDA
-
-
SYSTEMATIC NAME
IUBMB Comments
L-methionine:tRNAMet ligase (AMP-forming)
In those organisms producing N-formylmethionyl-tRNAfMet for translation initiation, this enzyme also recognizes the initiator tRNAfMet and catalyses the formation of L-methionyl-tRNAfMet, the substrate for EC 2.1.2.9, methionyl-tRNA formyltransferase.
CAS REGISTRY NUMBER
COMMENTARY
9033-22-1
-
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
ATP + L-methionine + tRNAMet
AMP + diphosphate + L-methionyl-tRNAMet
-
-
-
?
ATP + L-methionine + tRNAMet
AMP + diphosphate + L-methionyl-tRNAMet
-
-
-
-
?
ATP + L-methionine + tRNAMet
AMP + diphosphate + L-methionyl-tRNAMet
-
-
-
r
ATP + L-methionine + tRNAMet
AMP + diphosphate + L-methionyl-tRNAMet
-
-
-
?
ATP + L-methionine + tRNAMet
AMP + diphosphate + L-methionyl-tRNAMet
-
-
-
r
ATP + L-methionine + tRNAMet
AMP + diphosphate + L-methionyl-tRNAMet
-
the C-terminal ancillary RNA-binding domain is important for activity and has dual function provided by 2 structural motifs: 1. the helix-turn-helix HTH motif, which confers rate-limiting dissociation of the aminoaclyted tRNA from the enzyme, and 2. the KGKKKK lysine-rich cluster LRC, which is probably involved in accelerating the association step of deacylated tRNA
-
r
ATP + L-methionine + tRNAMet
AMP + diphosphate + L-methionyl-tRNAMet
-
the nucleolar located enzyme is related to rRNA synthesis, the cytoplasmic enzyme is involved in protein biosynthesis
-
?
ATP + L-methionine + tRNAMet
AMP + diphosphate + L-methionyl-tRNAMet
human mitochondrial wild-type and mutant mtRNAs: T5048 deletion, and T5052C or T5012A point mutations, initiator tRNA from Escherichia coli, tRNAMet from Bos taurus
-
-
r
additional information
?
-
-
homocysteine thiolactone is formed as a product of an error-editing reaction, which prevents incorporation of homocysteine into tRNA and protein (not enzyme from temperature-sensitive mutant of CHO-cells, at non-permissive temperature)
-
-
?
additional information
?
-
the enzyme performs ATP/diphosphate exchange in absence of substrates
-
-
?
additional information
?
-
-
the enzyme performs ATP/diphosphate exchange in absence of substrates
-
-
?
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
ATP + L-methionine + tRNAMet
AMP + diphosphate + L-methionyl-tRNAMet
-
-
-
-
?
ATP + L-methionine + tRNAMet
AMP + diphosphate + L-methionyl-tRNAMet
-
-
-
r
ATP + L-methionine + tRNAMet
AMP + diphosphate + L-methionyl-tRNAMet
-
-
-
?
ATP + L-methionine + tRNAMet
AMP + diphosphate + L-methionyl-tRNAMet
-
-
-
r
ATP + L-methionine + tRNAMet
AMP + diphosphate + L-methionyl-tRNAMet
-
the nucleolar located enzyme is related to rRNA synthesis, the cytoplasmic enzyme is involved in protein biosynthesis
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
2-(2-butyl-4-chloro-1-(4-nitrobenzyl)-1H-imidazol-5-yl)-2,4-dihydro-1Hbenzo[d][1,3]oxazine
-
-
2-(2-butyl-4-chloro-1-(4-phenoxybenzyl)-1H-imidazol-5-yl)-5-(4-methoxyphenyl)-1-oxa-3-azaspiro[5.5]undecane
-
-
2-(2-butyl-4-chloro-1H-imidazol-5-yl)-5-(4-methoxyphenyl)-1-oxa-3-azaspiro[5.5]undecane
-
-
4'-((2-butyl-4-chloro-5-(5-(4-methoxyphenyl)-1-oxa-3-azaspiro[5.5]undecan-2-yl)-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile
-
-
4'-[(3-[5-[4-(hydroxymethyl)phenyl]-1-oxa-3-azaspiro[5.5]undecan-2-yl]-2,3-dihydro-1H-indol-1-yl)methyl][1,1'-biphenyl]-2-carbonitrile
-
-
4'-[[3-(1,4-dihydro-2H-3,1-benzoxazin-2-yl)-1H-indol-1-yl]methyl][1,1'-biphenyl]-2-carbonitrile
-
-
4-(5-(4-methoxyphenyl)-1-oxa-3-azaspiro[5.5]undecan-2-yl)-N,Ndimethylaniline
-
-
5-(4-methoxyphenyl)-2-(2-methyl-1H-indol-3-yl)-1-oxa-3-azaspiro[5.5]undecane
-
-
5-(4-methoxyphenyl)-2-(2-phenyl-1H-indol-3-yl)-1-oxa-3-azaspiro[5.5]undecane
-
-
actinomycin D
-
inhibits the nucleolar located enzyme due to dependence on polymerase I
alpha-Amanitin
-
inhibits the nucleolar located enzyme due to dependence on polymerase I
cisplatin
-
inhibits the nucleolar located enzyme due to dependence on polymerase I
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
elongation factor EF-1alpha
-
activates, assists in dissociation of Met-tRNAMet from the enzyme, the aminoacylated tRNA is transfered from to the enzyme to the elongation factor
-
spermine
slight stimulation, additionally spermine increases the enzyme activity by stabilizing conformation of negatively charged DNA
additional information
bovine serum albumin has no effect on the enzyme
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
-
dissociation constants for wild-type and mutant enzymes
-
0.00015
tRNAMet
pH 8.2, 37°C, mitochondrial tRNAMet from Bos taurus, recombinant enzyme
0.00016
tRNAMet
pH 8.2, 37°C, human mitochondrial wild-type tRNAMet, recombinant enzyme
0.0021
tRNAMet
pH 8.2, 37°C, initiator tRNA from Escherichia coli, recombinant enzyme
0.0039
tRNAMet
-
wild-type enzyme in the multi-enzyme complex and mutant K866A, pH 7.5, 25°C
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.019
tRNAMet
pH 8.2, 37°C, mitochondrial tRNAMet from Bos taurus, recombinant enzyme
0.021
tRNAMet
pH 8.2, 37°C, human mitochondrial wild-type tRNAMet, recombinant enzyme
11
tRNAMet
pH 8.2, 37°C, initiator tRNA from Escherichia coli, recombinant enzyme
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
22
-
tRNA aminoacylation assay at room temperature for 30 min for IC50 determinations
30
-
tRNA aminoacylation assay at 30°C for 1 to 7.5 min for initial rate determination
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
translocation from the cytoplasm is triggered by insulin, epidermal growth factor, translocation by a proliferation signal, the enzyme is part of the multi-aminoacyl-tRNA synthetase complex in the nucleolus
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
physiological function
-
the enzyme also provides a cytosolic anchoring site for aminoacyl-tRNA synthetase-interacting multifunctional protein-3 (AIMP3)/p18, a potent tumor suppressor that is translocated to the nucleus for DNA repair upon DNA damage which is released from the enzyme by UV irradiation-induced stress. The enzyme plays a role as a coregulator with eukaryotic initiation factor-2 subunit-alpha for general control nonrepressed-2-mediated translational inhibition and as a coupler of translational inhibition and DNA repair following DNA damage by releasing bound tumor suppressor AIMP3 for its nuclear translocation
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). SYMM_HUMAN
593
0
66591
Swiss-Prot
Mitochondrion (Reliability: 2)
SYMC_HUMAN
900
0
101116
Swiss-Prot
Secretory Pathway (Reliability: 5)
B4DF61_HUMAN
635
0
71801
TrEMBL
other Location (Reliability: 2)
B4DVV7_HUMAN
520
0
58479
TrEMBL
Mitochondrion (Reliability: 2)
A8K492_HUMAN
900
0
101144
TrEMBL
Secretory Pathway (Reliability: 5)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
domain structure, structure modeling based on crystal structures of Escherichia coli with PDB code 1QQR, overview, the enzyme contains the consensus motifs of class I aminoacyl-tRNA, but lacks the Zn2+ binding motif and the C-terminal dimerization region
additional information
-
domain structure, structure modeling based on crystal structures of Escherichia coli with PDB code 1QQR, overview, the enzyme contains the consensus motifs of class I aminoacyl-tRNA, but lacks the Zn2+ binding motif and the C-terminal dimerization region
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
S662D
-
the mutation induces a conformational change in methionyl-tRNAsynthetase and significantly reduces its interaction with aminoacyl-tRNA synthetase-interacting multifunctional protein-3. This mutant possesses significantly reduced catalytic activity because of loss of tRNAMet binding, resulting in down-regulation of global translation
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant His-tagged mature enzyme form from Escherichia coli by ion exchange chromatography
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
DNA sequence determination and analysis, expression in Escherichia coli BL21(DE3) of the wild-type enzyme as His-tagged enzyme
-
expression of the wild-type, and exchange mutant enzymes in Escherichia coli BL21(DE3), cloning and expression of the catalytic domain, amino acid residues A215-K823, and the C-terminal extension in Escherichia coli BL21(DE3)
-
mature enzyme form, DNA and amino acid sequence determination and analysis, expression of His-tagged enzyme in Escherichia coli
plasmid pcDNA3.1MRS, containing a gene encoding hcMetRS, and plasmid pcDNA3.1MRSce2, containing a gene encoding full-length hmMetRS, are used, genes are inserted into pET100/D-TOPO vectors
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
-
REP3123 represents a promising narrow spectrum, new mode-of-action agent with an excellent microbiological profile that warrants its further evaluation as a novel drug
medicine
-
REP8839 is a selective inhibitor of methionyl-tRNA synthetase with antibacterial activity against a variety of gram-positive organisms
medicine
-
methionyl-tRNA synthetase overexpression is associated with poor clinical outcomes in non-small cell lung cancer
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Jakubowski, H.; Goldman, E.
Synthesis of homocysteine thiolactone by methionyl-tRNA synthetase in cultured mammalian cells
FEBS Lett.
317
237-240
1993
Saccharomyces cerevisiae, Cricetulus griseus, Escherichia coli, Homo sapiens, Mus musculus
Kaminska, M.; Shalak, V.; Mirande, M.
The appended C-domain of human methionyl-tRNA synthetase has a tRNA-sequestering function
Biochemistry
40
14309-14316
2001
Homo sapiens
Ko, Y.G.; Kang, Y.S.; Kim, E.K.; Park, S.G.; Kim, S.
Nucleolar localization of human methionyl-tRNA synthetase and its role in ribosomal RNA synthesis
J. Cell Biol.
149
567-574
2000
Homo sapiens
Spencer, A.C.; Heck, A.; Takeuchi, N.; Watanabe, K.; Spremulli, L.L.
Characterization of the human mitochondrial methionyl-tRNA synthetase
Biochemistry
43
9743-9754
2004
Homo sapiens (P56192), Homo sapiens
Green, L.; Bullard, J.; Ribble, W.; Dean, F.; Ayers, D.; Ochsner, U.; Janjic, N.; Jarvis, T.
Inhibition of methionyl-tRNA synthetase by REP8839 and effects of resistance mutations on enzyme activity
Antimicrob. Agents Chemother.
53
86-94
2009
Streptococcus pneumoniae, Escherichia coli, Haemophilus influenzae, Homo sapiens, Staphylococcus aureus
Critchley, I.A.; Green, L.S.; Young, C.L.; Bullard, J.M.; Evans, R.J.; Price, M.; Jarvis, T.C.; Guiles, J.W.; Janjic, N.; Ochsner, U.A.
Spectrum of activity and mode of action of REP3123, a new antibiotic to treat Clostridium difficile infections
J. Antimicrob. Chemother.
63
954-963
2009
Clostridioides difficile, Streptococcus pneumoniae, Escherichia coli, Haemophilus influenzae, Homo sapiens, Staphylococcus aureus
van Meel, E.; Wegner, D.J.; Cliften, P.; Willing, M.C.; White, F.V.; Kornfeld, S.; Cole, F.S.
Rare recessive loss-of-function methionyl-tRNA synthetase mutations presenting as a multi-organ phenotype
BMC Med. Genet.
14
106
2013
Homo sapiens (P56192)
Kwon, N.H.; Kang, T.; Lee, J.Y.; Kim, H.H.; Kim, H.R.; Hong, J.; Oh, Y.S.; Han, J.M.; Ku, M.J.; Lee, S.Y.; Kim, S.
Dual role of methionyl-tRNA synthetase in the regulation of translation and tumor suppressor activity of aminoacyl-tRNA synthetase-interacting multifunctional protein-3
Proc. Natl. Acad. Sci. USA
108
19635-19640
2011
Homo sapiens
Kim, E.Y.; Jung, J.Y.; Kim, A.; Kim, K.; Chang, Y.S.
Methionyl-tRNA synthetase overexpression is associated with poor clinical outcomes in non-small cell lung cancer
BMC Cancer
17
467
2017
Homo sapiens, Mus musculus
Bharathkumar, H.; Mohan, C.D.; Rangappa, S.; Kang, T.; Keerthy, H.K.; Fuchs, J.E.; Kwon, N.H.; Bender, A.; Kim, S.; Basappa, S.; Rangappa, K.S.
Screening of quinoline, 1,3-benzoxazine, and 1,3-oxazine-based small molecules against isolated methionyl-tRNA synthetase and A549 and HCT116 cancer cells including an in silico binding mode analysis
Org. Biomol. Chem.
13
9381-9387
2015
Homo sapiens
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