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Information on EC 2.1.1.228 - tRNA (guanine37-N1)-methyltransferase and Organism(s) Homo sapiens and UniProt Accession Q32P41
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2.1.1.228 tRNA (guanine37-N1)-methyltransferaseIUBMB Comments
This enzyme is important for the maintenance of the correct reading frame during translation. Unlike TrmD from Escherichia coli, which recognizes the G36pG37 motif preferentially, the human enzyme (encoded by TRMT5) also methylates inosine at position 37 .
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Word Map
- 2.1.1.228
- methyltransferases
-
anticodon
- adomet
- 1-methylguanosine
- drug development
-
n2-guanine
- trmt10a
- 1-methyladenine
-
adomet-dependent
- 5-methyluridine
- trmfo
-
n1-methylation
-
methyl-deficient
- 7-methylguanine
-
spout
-
epitranscriptome
-
nsun2-mediated
- 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
Reaction Schemes
+
guanine37 in tRNA
=
+
N1-methylguanine37 in tRNA
Synonyms
trna methyltransferase, trna(m1g37)methyltransferase, patrmd, trm5p, patrm5a, trna(m(1)g37)methyltransferase, trmt5, attrm5a, trna (m1g37) methyltransferase, patrm5b, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
S-adenosyl-L-methionine + guanine37 in tRNA = S-adenosyl-L-homocysteine + N1-methylguanine37 in tRNA
a highly conserved aspartate residue, D275 in Homo sapiens Trm5, in the flexible loop preceding the proposed general base E288 may be involved in the induced-fit movement of the catalytic process
PATHWAY SOURCE
PATHWAYS
-
-, -, -
SYSTEMATIC NAME
IUBMB Comments
S-adenosyl-L-methionine:tRNA (guanine37-N1)-methyltransferase
This enzyme is important for the maintenance of the correct reading frame during translation. Unlike TrmD from Escherichia coli, which recognizes the G36pG37 motif preferentially, the human enzyme (encoded by TRMT5) also methylates inosine at position 37 [4].
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
S-adenosyl-L-methionine + guanine37 in Escherichia coli tRNA1Leu
S-adenosyl-L-homocysteine + N1-methylguanine37 in Escherichia coli tRNA1Leu
-
-
-
?
S-adenosyl-L-methionine + guanine37 in human mitochondrial tRNAPro
S-adenosyl-L-homocysteine + N1-methylguanine37 in human mitochondrial tRNAPro
-
-
-
?
S-adenosyl-L-methionine + guanine37 in human mitochondrial tRNAPro possessing an A36G37 sequence
S-adenosyl-L-homocysteine + N1-methylguanine37 in human mitochondrial tRNAPro possessing an A36G37 sequence
-
-
-
?
S-adenosyl-L-methionine + guanine37 in tRNA
S-adenosyl-L-homocysteine + N1-methylguanine37 in tRNA
S-adenosyl-L-methionine + guanine37 in tRNACys
S-adenosyl-L-homocysteine + N1-methylguanine37 in tRNACys
-
-
-
?
S-adenosyl-L-methionine + guanine37 in yeast tRNA(Asp) possessing a G36G37 sequence
S-adenosyl-L-homocysteine + N1-methylguanine37 in yeast tRNA(Asp) possessing a G36G37 sequence
-
-
-
?
S-adenosyl-L-methionine + guanine37 in yeast tRNAAsp possessing a C36G37 sequence
S-adenosyl-L-homocysteine + N1-methylguanine37 in yeast tRNAAsp possessing a C36G37 sequence
-
-
-
?
S-adenosyl-L-methionine + guanine37 in yeast tRNAAsp possessing a G36G37 sequence
S-adenosyl-L-homocysteine + N1-methylguanine37 in yeast tRNAAsp possessing a G36G37 sequence
-
-
-
?
S-adenosyl-L-methionine + guanine37 in yeast tRNAAsp possessing an A36G37 sequence
S-adenosyl-L-homocysteine + N1-methylguanine37 in yeast tRNA(Asp) possessing an A36G37 sequence
-
-
-
?
S-adenosyl-L-methionine + guanine37 in yeast tRNAAsp possessing an U36G37 sequence
S-adenosyl-L-homocysteine + N1-methylguanine37 in yeast tRNAAsp possessing an U36G37 sequence
-
-
-
?
S-adenosyl-L-methionine + guanine37 in yeast tRNAPhe possessing an A36G37 sequence
S-adenosyl-L-homocysteine + N1-methylguanine37 in yeast tRNAPhe possessing an A36G37 sequence
-
-
-
?
S-adenosyl-L-methionine + inosine37 in yeast tRNAAsp possessing a G36I37 sequence
S-adenosyl-L-homocysteine + N1-methylinosine37 in yeast tRNAAsp possessing a G36I37 sequence
-
-
-
?
S-adenosyl-L-methionine + guanine37 in tRNA
S-adenosyl-L-homocysteine + N1-methylguanine37 in tRNA
-
-
-
-
?
S-adenosyl-L-methionine + guanine37 in tRNA
S-adenosyl-L-homocysteine + N1-methylguanine37 in tRNA
-
-
-
?
S-adenosyl-L-methionine + guanine37 in tRNA
S-adenosyl-L-homocysteine + N1-methylguanine37 in tRNA
-
-
-
-
?
S-adenosyl-L-methionine + guanine37 in tRNA
S-adenosyl-L-homocysteine + N1-methylguanine37 in tRNA
-
-
-
?
S-adenosyl-L-methionine + guanine37 in tRNA
S-adenosyl-L-homocysteine + N1-methylguanine37 in tRNA
methylates the N1 position of guanosine 37 (G37) in selected tRNA transcripts
-
-
?
additional information
?
-
guanosine37-methylation by TRM5 occurs regardless of the nature of the nucleotide at position 36. TRM5 also methylates inosine at position 37. The TRM5 enzyme is sensitive to subtle changes in the tRNA-protein tertiary interaction leading to loss of activity. The enzyme does not methylate adenosine37, cytosine37 or uridine37 in tRNA. The TRM5 enzyme is sensitive to subtle changes in the tRNA-protein tertiary interaction leading to loss of activity
-
-
?
additional information
?
-
-
guanosine37-methylation by TRM5 occurs regardless of the nature of the nucleotide at position 36. TRM5 also methylates inosine at position 37. The TRM5 enzyme is sensitive to subtle changes in the tRNA-protein tertiary interaction leading to loss of activity. The enzyme does not methylate adenosine37, cytosine37 or uridine37 in tRNA. The TRM5 enzyme is sensitive to subtle changes in the tRNA-protein tertiary interaction leading to loss of activity
-
-
?
additional information
?
-
radioactive assay method development and evaluation using labeled S-adenosyl-L-methionine and unlabeled tRNA, detailed overview. The slow step of the Trm5 reaction is after methyl transfer and is associated with release of the m1G37-tRNA product
-
-
-
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
S-adenosyl-L-methionine + guanine37 in tRNA
S-adenosyl-L-homocysteine + N1-methylguanine37 in tRNA
S-adenosyl-L-methionine + guanine37 in tRNA
S-adenosyl-L-homocysteine + N1-methylguanine37 in tRNA
-
-
-
-
?
S-adenosyl-L-methionine + guanine37 in tRNA
S-adenosyl-L-homocysteine + N1-methylguanine37 in tRNA
-
-
-
?
S-adenosyl-L-methionine + guanine37 in tRNA
S-adenosyl-L-homocysteine + N1-methylguanine37 in tRNA
-
-
-
-
?
S-adenosyl-L-methionine + guanine37 in tRNA
S-adenosyl-L-homocysteine + N1-methylguanine37 in tRNA
-
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
KCl
TRM5 enzyme is stimulated 4fold by 100 mM KCl. TRM5 tends to lose all activity in 600 mM KCl
additional information
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
DTT
TRM5 displays maximal activity above 1 mM DTT and loses 20% of its activity below that value
KCl
TRM5 enzyme is stimulated 4fold by 100 mM KCl. TRM5 tends to lose all activity in 600 mM KCl
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
glycerol
TRM5 performs best between 25 and 30% glycerol, and is less active at lower concentrations. The enzyme retains 45% of its activity in the presence of 50% glycerol
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.018
guanine37 in human mitochondrial tRNAPro possessing an A36G37 sequence
pH 8.0, 37°C
-
0.000075
guanine37 in yeast tRNAAsp possessing a C36G37 sequence
pH 8.0, 37°C
-
0.000244
guanine37 in yeast tRNAAsp possessing a G36G37 sequence
pH 8.0, 37°C
-
0.00059
guanine37 in yeast tRNAAsp possessing an A36G37 sequence
pH 8.0, 37°C
-
0.00058
guanine37 in yeast tRNAAsp possessing an U36G37 sequence
pH 8.0, 37°C
-
0.0000457
guanine37 in yeast tRNAPhe possessing an A36G37 sequence
pH 8.0, 37°C
-
0.00123
inosine37 in yeast tRNAAsp possessing a G36I37 sequence
below 0.00123 pH 8.0, 37°C
-
additional information
additional information
pre-steady-state and steady-state kinetic analysis of wild-type and mutant enzymes, the rate-determining step is product release from the enzyme, kinetic isotope effect, overview
-
additional information
additional information
-
pre-steady-state and steady-state kinetic analysis of wild-type and mutant enzymes, the rate-determining step is product release from the enzyme, kinetic isotope effect, overview
-
additional information
additional information
pre-steady-state and steady-state Michaelis-Menten kinetics, single turnover assays
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
at least 5 classes (class I-V) of structurally distinct AdoMet-dependent methyltransferases have been identified. Trm5 belongs to the class I tRNA methyl transferases. Trm5 is an active monomer that uses the class I-fold. Methanococcus jannaschii MjTrm5 is homologous to human Trm5
malfunction
structure-guided mutational analysis of HsTrm5 in comparison to the archaeal enzyme from Methanococcus jannaschii, MjTrm5, overview. Validation of the MjTrm5 ternary structure as a useful model for HsTrm5
physiological function
methylation is to the G37 base on the 3' side of the anticodon to generate m1G37-tRNA suppresses frameshift errors during protein synthesis and is therefore essential for cell growth in all three domains of life. This methylation is catalyzed by TrmD in bacteria and by Trm5 in eukaryotes and archaea. Although TrmD and Trm5 catalyze the same methylation reaction, kinetic analysis reveal that these two enzymes are unrelated to each other and are distinct in their reaction mechanism. Both TrmD and Trm5 are essential for cell growth, because their reaction product m1G37 occurring on the 3' side of the tRNA anticodon is necessary to suppress +1-frameshift errors on the ribosome
evolution
-
the enzyme shows strong homology to members of the class I-like methyltransferase superfamily
malfunction
-
mutations in TRMT5 are associated with the hypomodification of a guanosine residue at position 37 (G37) of mitochondrial tRNA, this hypomodification is particularly prominent in skeletal muscle. The patients show lactic acidosis and evidence of multiple mitochondrial respiratory-chain-complex deficiencies in skeletal muscle
physiological function
-
methylation of G37 to form m1G acts to sterically block Watson-Crick base pairing and thereby both maintain an open loop conformation, by blocking base pairing with nucleotides elsewhere in the anticodon loop, and protect against frame shifting by preventing its interaction with the mRNA
additional information
additional information
active-site structure and overall structure analysis, molecular modeling using structure PdB ID 2ZZN, overview
additional information
-
active-site structure and overall structure analysis, molecular modeling using structure PdB ID 2ZZN, overview
additional information
evaluation of the kinetic assays that are used to reveal the distinction between TrmD and Trm5, 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). TRM5_HUMAN
509
0
58246
Swiss-Prot
Mitochondrion (Reliability: 4)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
D275A
site-directed mutagenesis, the mutation leads to significantly reduced activity
E288A
site-directed mutagenesis, the mutation at the general base position leads to highly reduced activity
E394K
site-directed mutagenesis, the mutation facilitates enzyme expression in Escherichia coli
H289A
site-directed mutagenesis, the mutation C-terminally adjacent to the general base does not affect the enzyme activity
H289R
site-directed mutagenesis, the mutation C-terminally adjacent to the general base does not affect the enzyme activity
M261L
site-directed mutagenesis, the single M261L substitution that recapitulates the archaeal residue minimizes the 27-kDa protease product upon enzyme expression in Escherichia coli, indicating improved stability
M261L/T261I
site-directed mutagenesis, the double M261L substitution also shows improved stability
M386V
-
naturally occuring TRMT5 mutation, the mutant shows diminished G37 modification of a mitochondrial tRNA and a pathogenic phenotype
R291H
-
naturally occuring TRMT5 mutation, the mutant shows diminished G37 modification of a mitochondrial tRNA and a pathogenic phenotype
additional information
additional information
structure-guided mutational analysis of HsTrm5 in comparison to the archaeal enzyme from Methanococcus jannaschii, MjTrm5, overview. Validation of the MjTrm5 ternary structure as a useful model for HsTrm5
additional information
-
structure-guided mutational analysis of HsTrm5 in comparison to the archaeal enzyme from Methanococcus jannaschii, MjTrm5, overview. Validation of the MjTrm5 ternary structure as a useful model for HsTrm5
additional information
-
identification of TRMT5 enzyme mutants in patients, the loss of m1G37 does not appear to impact tRNA stability, phenotype, overview
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant C-terminally His-tagged enzyme, lacking the N-terminal peptide V2LWILWRP9, from Escherichia coli by metal ion affinity chromatography and anion exchange chromatography
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene TRM5, recombinant expression of C-terminally His-tagged enzyme, lacking the N-terminal peptide V2LWILWRP9, in Escherichia coli
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Brule, H.; Elliott, M.; Redlak, M.; Zehner, Z.E.; Holmes, W.M.
Isolation and characterization of the human tRNA-(N1G37) methyltransferase (TRM5) and comparison to the Escherichia coli TrmD protein
Biochemistry
43
9243-9255
2004
Escherichia coli (P0A873), Escherichia coli, Homo sapiens (Q32P41), Homo sapiens
Powell, C.A.; Kopajtich, R.; DSouza, A.R.; Rorbach, J.; Kremer, L.S.; Husain, R.A.; Dallabona, C.; Donnini, C.; Alston, C.L.; Griffin, H.; Pyle, A.; Chinnery, P.F.; Strom, T.M.; Meitinger, T.; Rodenburg, R.J.; Schottmann, G.; Schuelke, M.; Romain, N.; Haller, R.G.; Ferrero, I.; Haack, T.B.; Taylor, R.W.; Pr, P.r.o.
TRMT5 mutations cause a defect in post-transcriptional modification of mitochondrial tRNA associated with multiple respiratory-chain deficiencies
Am. J. Hum. Genet.
97
319-328
2015
Homo sapiens
Christian, T.; Gamper, H.; Hou, Y.M.
Conservation of structure and mechanism by Trm5 enzymes
RNA
19
1192-1199
2013
Homo sapiens (Q32P41), Homo sapiens
Hou, Y.M.; Masuda, I.
Kinetic analysis of tRNA methyltransferases
Methods Enzymol.
560
91-116
2015
Escherichia coli (P0A873), Haemophilus influenzae (P43912), Haemophilus influenzae ATCC 51907 (P43912), Haemophilus influenzae DSM 11121 (P43912), Haemophilus influenzae KW20 (P43912), Haemophilus influenzae RD (P43912), Homo sapiens (Q32P41), Methanocaldococcus jannaschii (Q58293), Methanocaldococcus jannaschii ATCC 43067 (Q58293), Methanocaldococcus jannaschii DSM 2661 (Q58293), Methanocaldococcus jannaschii JAL-1 (Q58293), Methanocaldococcus jannaschii JCM 10045 (Q58293), Methanocaldococcus jannaschii NBRC 100440 (Q58293)
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