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Information on EC 2.1.1.202 - multisite-specific tRNA:(cytosine-C5)-methyltransferase and Organism(s) Homo sapiens and UniProt Accession Q8TEA1
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2.1.1.202 multisite-specific tRNA:(cytosine-C5)-methyltransferaseIUBMB Comments
The enzyme from Saccharomyces cerevisiae is responsible for complete 5-methylcytosine methylations of yeast tRNA. The incidence of modification depends on the cytosine position in tRNA. At positions 34 and 40, 5-methylcytosine is found only in two yeast tRNAs (tRNALeu(CUA) and tRNAPhe(GAA), respectively), whereas most other elongator yeast tRNAs bear either 5-methylcytosine48 or 5-methylcytosine49, but never both in the same tRNA molecule . The formation of 5-methylcytosine34 and 5-methylcytosine40 is a strictly intron-dependent process, whereas the formation of 5-methylcytosine48 and 5-methylcytosine49 is an intron-independent process [2,3].
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Word Map
- 2.1.1.202
- methyltransferases
- mtases
-
methylome
-
williams-beuren
-
anticodon
-
transcriptome-wide
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Archaea
The expected taxonomic range for this enzyme is: Eukaryota, Archaea
Reaction Schemes
hide(3 overall reactions are displayed. Show all (4)>>)
+
=
+
+
cytosine34 in tRNA precursor
=
+
5-methylcytosine34 in tRNA precursor
+
=
+
+
cytosine40 in tRNA precursor
=
+
5-methylcytosine40 in tRNA precursor
+
cytosine48 in tRNA
=
+
5-methylcytosine48 in tRNA
Synonyms
trdmt1, nsun6, trm4p, cytosine-5 rna methyltransferase, trm4b, rna:m5c methyltransferase, phnsun6, nop2/sun rna methyltransferase 2, trm4a, m5c rna methyltransferase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
NSUN2
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
S-adenosyl-L-methionine + cytosine34 in tRNA precursor = S-adenosyl-L-homocysteine + 5-methylcytosine34 in tRNA precursor
the enzyme forms a covalent enzyme-substrate intermediate with its target
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S-adenosyl-L-methionine + cytosine40 in tRNA precursor = S-adenosyl-L-homocysteine + 5-methylcytosine40 in tRNA precursor
the enzyme forms a covalent enzyme-substrate intermediate with its target
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S-adenosyl-L-methionine + cytosine48 in tRNA = S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNA
the enzyme forms a covalent enzyme-substrate intermediate with its target
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S-adenosyl-L-methionine + cytosine49 in tRNA = S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNA
the enzyme forms a covalent enzyme-substrate intermediate with its target
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PATHWAY SOURCE
PATHWAYS
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SYSTEMATIC NAME
IUBMB Comments
S-adenosyl-L-methionine:tRNA (multisite-cytosine-C5)-methyltransferase
The enzyme from Saccharomyces cerevisiae is responsible for complete 5-methylcytosine methylations of yeast tRNA. The incidence of modification depends on the cytosine position in tRNA. At positions 34 and 40, 5-methylcytosine is found only in two yeast tRNAs (tRNALeu(CUA) and tRNAPhe(GAA), respectively), whereas most other elongator yeast tRNAs bear either 5-methylcytosine48 or 5-methylcytosine49, but never both in the same tRNA molecule [1]. The formation of 5-methylcytosine34 and 5-methylcytosine40 is a strictly intron-dependent process, whereas the formation of 5-methylcytosine48 and 5-methylcytosine49 is an intron-independent process [2,3].
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 + cytosine72 in tRNACys
S-adenosyl-L-homocysteine + 5-methylcytosine72 in tRNACys
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-
-
?
S-adenosyl-L-methionine + cytosine72 in tRNACys(GCA)
S-adenosyl-L-homocysteine + 5-methylcytosine72 in tRNACys(GCA)
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-
-
?
S-adenosyl-L-methionine + cytosine72 in tRNACys(GCA)-G2A:C71U
S-adenosyl-L-homocysteine + 5-methylcytosine72 in tRNACys(GCA)-G2A:C71U
-
-
-
?
S-adenosyl-L-methionine + cytosine72 in tRNAThr
S-adenosyl-L-homocysteine + 5-methylcytosine72 in tRNAThr
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-
-
?
S-adenosyl-L-methionine + CpG-rich ssRNA (5'-CGCGCGCGCGCG-3')
?
m5C methylation directly alters the phosphate backbone in CpG RNA duplex, leading to a C3'-endo to C2'-endo sugar pucker switch of the terminal residues under physiologically-relevant conditions. m5C triggers a B-to-Z DNA, but not A-to-Z, transformation in CpG DNA duplex. The m5C-probe has the sensitivity to detect a single m5C mark change
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-
?
S-adenosyl-L-methionine + cytosine in tRNALeu(CAA)
S-adenosyl-L-homocysteine + 5-methylcytosine in tRNALeu(CAA)
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-
-
?
S-adenosyl-L-methionine + cytosine15 in vtRNA1.3
S-adenosyl-L-homocysteine + 5-methylcytosine15 in vtRNA1.3
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-
-
?
S-adenosyl-L-methionine + cytosine27 in vtRNA1.2
S-adenosyl-L-homocysteine + 5-methylcytosine27 in vtRNA1.2
-
-
-
?
S-adenosyl-L-methionine + cytosine27 in vtRNA1.3
S-adenosyl-L-homocysteine + 5-methylcytosine27 in vtRNA1.3
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-
-
?
S-adenosyl-L-methionine + cytosine34 in tRNA
S-adenosyl-L-homocysteine + 5-methylcytosine34 in tRNA
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-
-
?
S-adenosyl-L-methionine + cytosine34 in tRNALeu precursor
S-adenosyl-L-homocysteine + 5-methylcytosine34 in tRNALeu precursor
-
-
-
-
?
S-adenosyl-L-methionine + cytosine4( in tRNAPro(AGG)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAPro(AGG)
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-
-
?
S-adenosyl-L-methionine + cytosine40 in tRNA
S-adenosyl-L-homocysteine + 5-methylcytosine40 in tRNA
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-
-
?
S-adenosyl-L-methionine + cytosine40 in tRNAGly precursor
S-adenosyl-L-homocysteine + 5-methylcytosine40 in tRNAGly precursor
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-
-
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?
S-adenosyl-L-methionine + cytosine48 in tRNAAla(AGC)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAAla(AGC)
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-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNAAla(CGC)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAAla(CGC)
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-
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?
S-adenosyl-L-methionine + cytosine48 in tRNAAla(UGC)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAAla(UGC)
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-
?
S-adenosyl-L-methionine + cytosine48 in tRNAAsp precursor
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAAsp precursor
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-
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?
S-adenosyl-L-methionine + cytosine48 in tRNAAsp(GUC)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAAsp(GUC)
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-
?
S-adenosyl-L-methionine + cytosine48 in tRNAAspGTC
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAAspGTC
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-
?
S-adenosyl-L-methionine + cytosine48 in tRNAGln(CUG)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAGln(CUG)
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?
S-adenosyl-L-methionine + cytosine48 in tRNAGln(UUG)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAGln(UUG)
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-
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?
S-adenosyl-L-methionine + cytosine48 in tRNAGlu(CUC)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAGlu(CUC)
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?
S-adenosyl-L-methionine + cytosine48 in tRNAGlu(UUC)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAGlu(UUC)
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?
S-adenosyl-L-methionine + cytosine48 in tRNAGly precursor
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAGly precursor
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?
S-adenosyl-L-methionine + cytosine48 in tRNAGly(CCC)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAGly(CCC)
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?
S-adenosyl-L-methionine + cytosine48 in tRNAGly(GCC)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAGly(GCC)
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?
S-adenosyl-L-methionine + cytosine48 in tRNAGly(UCC)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAGly(UCC)
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?
S-adenosyl-L-methionine + cytosine48 in tRNAGlyGCC
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAGlyGCC
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-
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?
S-adenosyl-L-methionine + cytosine48 in tRNAHis(GUG)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAHis(GUG)
-
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?
S-adenosyl-L-methionine + cytosine48 in tRNAIle(AAU)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAIle(AAU)
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?
S-adenosyl-L-methionine + cytosine48 in tRNALeu(AAG)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNALeu(AAG)
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?
S-adenosyl-L-methionine + cytosine48 in tRNALeu(CAA) precursor
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNALeu(CAA) precursor
NSUN2-mediated methylation of C34 of tRNALeu(CAA) has been shown to occur exclusively on intron-containing tRNA precursors
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-
?
S-adenosyl-L-methionine + cytosine48 in tRNALeu(CAG)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNALeu(CAG)
-
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?
S-adenosyl-L-methionine + cytosine48 in tRNALeu(UAA)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNALeu(UAA)
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-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNALeu(UAG)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNALeu(UAG)
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?
S-adenosyl-L-methionine + cytosine48 in tRNALeuCAA
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNALeuCAA
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-
-
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?
S-adenosyl-L-methionine + cytosine48 in tRNALys(CUU)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNALys(CUU)
-
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?
S-adenosyl-L-methionine + cytosine48 in tRNALys(UUU)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNALys(UUU)
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?
S-adenosyl-L-methionine + cytosine48 in tRNAMet(CAU)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAMet(CAU)
-
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?
S-adenosyl-L-methionine + cytosine48 in tRNAPhe(GAA)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAPhe(GAA)
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?
S-adenosyl-L-methionine + cytosine48 in tRNAPro(CGG)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAPro(CGG)
-
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?
S-adenosyl-L-methionine + cytosine48 in tRNAPro(UGG)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAPro(UGG)
-
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?
S-adenosyl-L-methionine + cytosine48 in tRNASer(AGA)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNASer(AGA)
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?
S-adenosyl-L-methionine + cytosine48 in tRNASer(CGA)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNASer(CGA)
-
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?
S-adenosyl-L-methionine + cytosine48 in tRNASer(GCU)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNASer(GCU)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNASer(UGA)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNASer(UGA)
-
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-
?
S-adenosyl-L-methionine + cytosine48 in tRNAThr(AGU)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAThr(AGU)
-
-
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?
S-adenosyl-L-methionine + cytosine48 in tRNAThr(CGT)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAThr(CGT)
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?
S-adenosyl-L-methionine + cytosine48 in tRNAThr(UGU)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAThr(UGU)
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?
S-adenosyl-L-methionine + cytosine48 in tRNATyr(GUA)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNATyr(GUA)
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?
S-adenosyl-L-methionine + cytosine48 in tRNAVal(AAC)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAVal(AAC)
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?
S-adenosyl-L-methionine + cytosine48 in tRNAVal(CAC)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAVal(CAC)
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?
S-adenosyl-L-methionine + cytosine48 in tRNAVal(UAC)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAVal(UAC)
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?
S-adenosyl-L-methionine + cytosine49 in tRNAasp precursor
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAAsp precursor
-
-
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?
S-adenosyl-L-methionine + cytosine49 in tRNAAsp(GUC)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAAsp(GUC)
-
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?
S-adenosyl-L-methionine + cytosine49 in tRNAAspGTC
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAAspGTC
-
-
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?
S-adenosyl-L-methionine + cytosine49 in tRNAGln(CUG)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAGln(CUG)
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?
S-adenosyl-L-methionine + cytosine49 in tRNAGln(UUG)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAGln(UUG)
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?
S-adenosyl-L-methionine + cytosine49 in tRNAGlu(CUC)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAGlu(CUC)
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?
S-adenosyl-L-methionine + cytosine49 in tRNAGlu(UUC)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAGlu(UUC)
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?
S-adenosyl-L-methionine + cytosine49 in tRNAGly precursor
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAGly precursor
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?
S-adenosyl-L-methionine + cytosine49 in tRNAGly(CCC)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAGly(CCC)
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?
S-adenosyl-L-methionine + cytosine49 in tRNAGly(GCC)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAGly(GCC)
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?
S-adenosyl-L-methionine + cytosine49 in tRNAGly(UCC)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAGly(UCC)
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?
S-adenosyl-L-methionine + cytosine49 in tRNAGlyGCC
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAGlyGCC
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?
S-adenosyl-L-methionine + cytosine49 in tRNALeuCAA
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNALeuCAA
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?
S-adenosyl-L-methionine + cytosine49 in tRNALys(UUU)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNALys(UUU)
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?
S-adenosyl-L-methionine + cytosine49 in tRNAPhe(GAA)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAPhe(GAA)
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?
S-adenosyl-L-methionine + cytosine49 in tRNAPro(AGG)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAPro(AGG)
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?
S-adenosyl-L-methionine + cytosine49 in tRNAPro(CGG)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAPro(CGG)
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?
S-adenosyl-L-methionine + cytosine49 in tRNAPro(UGG)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAPro(UGG)
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?
S-adenosyl-L-methionine + cytosine49 in tRNAThr(AGU)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAThr(AGU)
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?
S-adenosyl-L-methionine + cytosine49 in tRNAVal(AAC)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAVal(AAC)
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?
S-adenosyl-L-methionine + cytosine49 in tRNAVal(CAC)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAVal(CAC)
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?
S-adenosyl-L-methionine + cytosine49 in tRNAVal(UAC)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAVal(UAC)
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?
S-adenosyl-L-methionine + cytosine50 in tRNAAspGTC
S-adenosyl-L-homocysteine + 5-methylcytosine50 in tRNAAspGTC
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?
S-adenosyl-L-methionine + cytosine50 in tRNAGlu(CUC)
S-adenosyl-L-homocysteine + 5-methylcytosine50 in tRNAGlu(CUC)
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?
S-adenosyl-L-methionine + cytosine50 in tRNAGlu(UUC)
S-adenosyl-L-homocysteine + 5-methylcytosine50 in tRNAGlu(UUC)
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?
S-adenosyl-L-methionine + cytosine50 in tRNAGly precursor
S-adenosyl-L-homocysteine + 5-methylcytosine50 in tRNAGly precursor
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?
S-adenosyl-L-methionine + cytosine50 in tRNAGly(CCC)
S-adenosyl-L-homocysteine + 5-methylcytosine50 in tRNAGly(CCC)
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?
S-adenosyl-L-methionine + cytosine50 in tRNAGly(GCC)
S-adenosyl-L-homocysteine + 5-methylcytosine50 in tRNAGly(GCC)
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?
S-adenosyl-L-methionine + cytosine50 in tRNAGly(UCC)
S-adenosyl-L-homocysteine + 5-methylcytosine50 in tRNAGly(UCC)
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?
S-adenosyl-L-methionine + cytosine50 in tRNAGlyGCC
S-adenosyl-L-homocysteine + 5-methylcytosine50 in tRNAGlyGCC
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?
S-adenosyl-L-methionine + cytosine50 in tRNALeuCAA
S-adenosyl-L-homocysteine + 5-methylcytosine50 in tRNALeuCAA
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-
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?
S-adenosyl-L-methionine + cytosine50 in tRNAPro(AGG)
S-adenosyl-L-homocysteine + 5-methylcytosine50 in tRNAPro(AGG)
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?
S-adenosyl-L-methionine + cytosine50 in tRNAPro(CGG)
S-adenosyl-L-homocysteine + 5-methylcytosine50 in tRNAPro(CGG)
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?
S-adenosyl-L-methionine + cytosine50 in tRNAPro(UGG)
S-adenosyl-L-homocysteine + 5-methylcytosine50 in tRNAPro(UGG)
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?
S-adenosyl-L-methionine + cytosine59 in vtRNA1.2
S-adenosyl-L-homocysteine + 5-methylcytosine59 in vtRNA1.2
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?
S-adenosyl-L-methionine + cytosine59 in vtRNA1.3
S-adenosyl-L-homocysteine + 5-methylcytosine59 in vtRNA1.3
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?
S-adenosyl-L-methionine + cytosine69 in vtRNA1.1
S-adenosyl-L-homocysteine + 5-methylcytosine69 in vtRNA1.1
-
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-
?
additional information
?
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susbtrate specificity of NSUN6, overview. Three-dimensional L-shape structure of a tRNA with the positions of m5C modifications and the cognate methyltransferases responsible for installing them marked. The m5C modifications in cytoplasmic and mitochondrial tRNAs. Schematic secondary structure and three-dimensional L-shape structure of a tRNA with the positions of m5C modifications, determination of the interaction sites of NSUN6 with the discriminator base and additional base pairs in the acceptor stem and the D-loop, as observed by X-ray crystallography, overview. m5C72 modifications installed by NSUN6 lie within the acceptor stem of tRNA. NSUN6 forms extensive contacts with its substrate tRNAs. Binding of NSUN6 disrupts base pairing within the tRNA acceptor stem and promotes base-flipping of C71 to make the C5 atom of the C72 nucleotide, which is normally base paired with G1, accessible for methylation. NSUN6 also has a PUA domain that binds to the D-stem region of substrate tRNAs, as well as the non-genomically encoded CCA 3' end. Consistent with this binding mode, the presence of the CCA is found to be an essential pre-requisite for methylation of tRNACys and tRNAThr by NUSN6
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additional information
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susbtrate specificity of NSUN6, overview. Three-dimensional L-shape structure of a tRNA with the positions of m5C modifications and the cognate methyltransferases responsible for installing them marked. The m5C modifications in cytoplasmic and mitochondrial tRNAs. Schematic secondary structure and three-dimensional L-shape structure of a tRNA with the positions of m5C modifications, determination of the interaction sites of NSUN6 with the discriminator base and additional base pairs in the acceptor stem and the D-loop, as observed by X-ray crystallography, overview. m5C72 modifications installed by NSUN6 lie within the acceptor stem of tRNA. NSUN6 forms extensive contacts with its substrate tRNAs. Binding of NSUN6 disrupts base pairing within the tRNA acceptor stem and promotes base-flipping of C71 to make the C5 atom of the C72 nucleotide, which is normally base paired with G1, accessible for methylation. NSUN6 also has a PUA domain that binds to the D-stem region of substrate tRNAs, as well as the non-genomically encoded CCA 3' end. Consistent with this binding mode, the presence of the CCA is found to be an essential pre-requisite for methylation of tRNACys and tRNAThr by NUSN6
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additional information
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the CCA end is precisely recognized by hNSun6 primarily through the PUA domain, overview. The main chains of the residues (Arg126, Pro206 and Asp209) recognizes C74. Recognition for C75 comes from the main chain residues (Lys192 and Gly193) and the side chain residues (Lys192 and Asp209). The base moiety of C75 is stacked with the Tyr131 residue. Recognition for A76 is achieved mostly by the main chain of His129 and the side chain of Lys 192. Hydrophobic interactions with ambient aa residues, including Cys120, facilitate localization of the A76 base moiety. The discriminator base U73 binds to the RRM motif. C72 is recognized by the catalytic core. Multiple roles of the PUA domain in tRNA binding
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additional information
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the CCA end is precisely recognized by hNSun6 primarily through the PUA domain, overview. The main chains of the residues (Arg126, Pro206 and Asp209) recognizes C74. Recognition for C75 comes from the main chain residues (Lys192 and Gly193) and the side chain residues (Lys192 and Asp209). The base moiety of C75 is stacked with the Tyr131 residue. Recognition for A76 is achieved mostly by the main chain of His129 and the side chain of Lys 192. Hydrophobic interactions with ambient aa residues, including Cys120, facilitate localization of the A76 base moiety. The discriminator base U73 binds to the RRM motif. C72 is recognized by the catalytic core. Multiple roles of the PUA domain in tRNA binding
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additional information
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NSUN2 candidate ncRNA targets identified include RNAs with central functions in the processing, folding and modification of other ncRNAs (RPPH1, Y RNA, SCARNA2), RNAs important for protein synthesis and trafficking (5S rRNA and 7SL RNA) and RNAs involved in multidrug resistance and other processes (Vault RNAs). Notably, all of the NSUN2 targets revealed by 5-azacytidine-mediated RNA immunoprecipitation are either transcribed by RNA Pol III in the nucleolus (SCARNA2 excepted), or function in the nucleolus (SCARNA2), where NSUN2 resides
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additional information
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the iCLIP method identifies tRNA AspGTC, ValAAC, GlyGCC, and LeuCAA as methylation substrates with methylation within the variable arm at cytosines 48, 49, and 50, no additional NSun2 target sites outside the variable arm. vtRNAs are methylation substrates for NSun2, vtRNAs are ncRNAs found as part of the vault ribonucleoprotein complex
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additional information
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development and evaluation of 5-azacytidine-mediated RNA immunoprecipitation, a mechanism-based technique in nine steps that exploits the covalent bond formed between an RNA methyltransferase and the cytidine analogue 5-azacytidine to recover RNA targets by immunoprecipitation, overview. The method enables over 200fold enrichment of tRNAs that are known targets of the enzyme revealing many tRNA and non-coding RNA targets not previously associated with NSUN2. High frequency of C>G transversions at the cytosine residues targeted by the enzyme, allowing identification of the specific methylated cytosine(s) in target RNAs. tRNAGly(GCC), bears four NSUN2 target sites (C40, 48, 49 and 50)
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additional information
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development and evaluation of a customized version of the individual-nucleotide-resolution crosslinking and immunoprecipitation (iCLIP) method for detection of cytosine methylation in RNA species, site-specific methylation in tRNAs and additional messenger and noncoding RNAs (ncRNAs), overview. Identified NSun2 targets are tRNAs, mRNAs, and ncRNAs
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-
?
additional information
?
-
susbtrate specificity of NSUN2, overview. NSUN2 has a much broader target spectrum and is able to modify several positions (C34, C40, C48, C49, and C50) in a number of different tRNAs, as well as other RNA substrates. The enzyme is also active with various mRNAs. M5C modifications in cytoplasmic and mitochondrial tRNAs. Three-dimensional L-shape structure of a tRNA with the positions of m5C modifications and the cognate methyltransferases responsible for installing them marked. The m5C modifications in cytoplasmic and mitochondrial tRNAs. Schematic secondary structure and three-dimensional L-shape structure of a tRNA with the positions of m5C modifications. The broad-spectrum methyltransferase NSUN2 has been suggested to recognize different features in its diverse substrate RNAs. The reported NSUN2-mediated m5C modifications in mRNAs typically lie within highly GC-rich regions, suggesting that the enzyme may preferentially bind such sequences. But all the known NSUN2-mediated m5C modifications in vtRNAs lie within a UCG motif, and mutagenic analysis of the NSUN2 target pre-tRNALeu reveals a consensus sequence of C/A/U32-U/A33-m5C34-A35-A36-G37
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-
-
additional information
?
-
susbtrate specificity of NSUN2, overview. NSUN2 has a much broader target spectrum and is able to modify several positions (C34, C40, C48, C49, and C50) in a number of different tRNAs, as well as other RNA substrates. The enzyme is also active with various mRNAs. M5C modifications in cytoplasmic and mitochondrial tRNAs. Three-dimensional L-shape structure of a tRNA with the positions of m5C modifications and the cognate methyltransferases responsible for installing them marked. The m5C modifications in cytoplasmic and mitochondrial tRNAs. Schematic secondary structure and three-dimensional L-shape structure of a tRNA with the positions of m5C modifications. The broad-spectrum methyltransferase NSUN2 has been suggested to recognize different features in its diverse substrate RNAs. The reported NSUN2-mediated m5C modifications in mRNAs typically lie within highly GC-rich regions, suggesting that the enzyme may preferentially bind such sequences. But all the known NSUN2-mediated m5C modifications in vtRNAs lie within a UCG motif, and mutagenic analysis of the NSUN2 target pre-tRNALeu reveals a consensus sequence of C/A/U32-U/A33-m5C34-A35-A36-G37
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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
S-adenosyl-L-methionine + cytosine72 in tRNACys
S-adenosyl-L-homocysteine + 5-methylcytosine72 in tRNACys
-
-
-
?
S-adenosyl-L-methionine + cytosine72 in tRNACys(GCA)
S-adenosyl-L-homocysteine + 5-methylcytosine72 in tRNACys(GCA)
-
-
-
?
S-adenosyl-L-methionine + cytosine72 in tRNAThr
S-adenosyl-L-homocysteine + 5-methylcytosine72 in tRNAThr
-
-
-
?
S-adenosyl-L-methionine + cytosine15 in vtRNA1.3
S-adenosyl-L-homocysteine + 5-methylcytosine15 in vtRNA1.3
-
-
-
?
S-adenosyl-L-methionine + cytosine27 in vtRNA1.2
S-adenosyl-L-homocysteine + 5-methylcytosine27 in vtRNA1.2
-
-
-
?
S-adenosyl-L-methionine + cytosine27 in vtRNA1.3
S-adenosyl-L-homocysteine + 5-methylcytosine27 in vtRNA1.3
-
-
-
?
S-adenosyl-L-methionine + cytosine34 in tRNA
S-adenosyl-L-homocysteine + 5-methylcytosine34 in tRNA
-
-
-
?
S-adenosyl-L-methionine + cytosine34 in tRNALeu precursor
S-adenosyl-L-homocysteine + 5-methylcytosine34 in tRNALeu precursor
-
-
-
-
?
S-adenosyl-L-methionine + cytosine4( in tRNAPro(AGG)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAPro(AGG)
-
-
-
?
S-adenosyl-L-methionine + cytosine40 in tRNA
S-adenosyl-L-homocysteine + 5-methylcytosine40 in tRNA
-
-
-
?
S-adenosyl-L-methionine + cytosine40 in tRNAGly precursor
S-adenosyl-L-homocysteine + 5-methylcytosine40 in tRNAGly precursor
-
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNAAla(AGC)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAAla(AGC)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNAAla(CGC)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAAla(CGC)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNAAla(UGC)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAAla(UGC)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNAAsp precursor
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAAsp precursor
-
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNAAsp(GUC)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAAsp(GUC)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNAAspGTC
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAAspGTC
-
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNAGln(CUG)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAGln(CUG)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNAGln(UUG)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAGln(UUG)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNAGlu(CUC)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAGlu(CUC)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNAGlu(UUC)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAGlu(UUC)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNAGly precursor
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAGly precursor
-
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNAGly(CCC)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAGly(CCC)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNAGly(GCC)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAGly(GCC)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNAGly(UCC)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAGly(UCC)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNAGlyGCC
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAGlyGCC
-
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNAHis(GUG)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAHis(GUG)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNAIle(AAU)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAIle(AAU)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNALeu(AAG)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNALeu(AAG)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNALeu(CAA) precursor
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNALeu(CAA) precursor
NSUN2-mediated methylation of C34 of tRNALeu(CAA) has been shown to occur exclusively on intron-containing tRNA precursors
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNALeu(CAG)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNALeu(CAG)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNALeu(UAA)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNALeu(UAA)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNALeu(UAG)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNALeu(UAG)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNALeuCAA
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNALeuCAA
-
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNALys(CUU)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNALys(CUU)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNALys(UUU)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNALys(UUU)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNAMet(CAU)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAMet(CAU)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNAPhe(GAA)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAPhe(GAA)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNAPro(CGG)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAPro(CGG)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNAPro(UGG)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAPro(UGG)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNASer(AGA)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNASer(AGA)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNASer(CGA)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNASer(CGA)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNASer(GCU)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNASer(GCU)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNASer(UGA)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNASer(UGA)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNAThr(AGU)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAThr(AGU)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNAThr(CGT)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAThr(CGT)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNAThr(UGU)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAThr(UGU)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNATyr(GUA)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNATyr(GUA)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNAVal(AAC)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAVal(AAC)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNAVal(CAC)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAVal(CAC)
-
-
-
?
S-adenosyl-L-methionine + cytosine48 in tRNAVal(UAC)
S-adenosyl-L-homocysteine + 5-methylcytosine48 in tRNAVal(UAC)
-
-
-
?
S-adenosyl-L-methionine + cytosine49 in tRNAasp precursor
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAAsp precursor
-
-
-
-
?
S-adenosyl-L-methionine + cytosine49 in tRNAAsp(GUC)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAAsp(GUC)
-
-
-
?
S-adenosyl-L-methionine + cytosine49 in tRNAAspGTC
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAAspGTC
-
-
-
-
?
S-adenosyl-L-methionine + cytosine49 in tRNAGln(CUG)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAGln(CUG)
-
-
-
?
S-adenosyl-L-methionine + cytosine49 in tRNAGln(UUG)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAGln(UUG)
-
-
-
?
S-adenosyl-L-methionine + cytosine49 in tRNAGlu(CUC)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAGlu(CUC)
-
-
-
?
S-adenosyl-L-methionine + cytosine49 in tRNAGlu(UUC)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAGlu(UUC)
-
-
-
?
S-adenosyl-L-methionine + cytosine49 in tRNAGly precursor
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAGly precursor
-
-
-
-
?
S-adenosyl-L-methionine + cytosine49 in tRNAGly(CCC)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAGly(CCC)
-
-
-
?
S-adenosyl-L-methionine + cytosine49 in tRNAGly(GCC)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAGly(GCC)
-
-
-
?
S-adenosyl-L-methionine + cytosine49 in tRNAGly(UCC)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAGly(UCC)
-
-
-
?
S-adenosyl-L-methionine + cytosine49 in tRNAGlyGCC
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAGlyGCC
-
-
-
-
?
S-adenosyl-L-methionine + cytosine49 in tRNALeuCAA
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNALeuCAA
-
-
-
-
?
S-adenosyl-L-methionine + cytosine49 in tRNALys(UUU)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNALys(UUU)
-
-
-
?
S-adenosyl-L-methionine + cytosine49 in tRNAPhe(GAA)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAPhe(GAA)
-
-
-
?
S-adenosyl-L-methionine + cytosine49 in tRNAPro(AGG)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAPro(AGG)
-
-
-
?
S-adenosyl-L-methionine + cytosine49 in tRNAPro(CGG)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAPro(CGG)
-
-
-
?
S-adenosyl-L-methionine + cytosine49 in tRNAPro(UGG)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAPro(UGG)
-
-
-
?
S-adenosyl-L-methionine + cytosine49 in tRNAThr(AGU)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAThr(AGU)
-
-
-
?
S-adenosyl-L-methionine + cytosine49 in tRNAVal(AAC)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAVal(AAC)
-
-
-
?
S-adenosyl-L-methionine + cytosine49 in tRNAVal(CAC)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAVal(CAC)
-
-
-
?
S-adenosyl-L-methionine + cytosine49 in tRNAVal(UAC)
S-adenosyl-L-homocysteine + 5-methylcytosine49 in tRNAVal(UAC)
-
-
-
?
S-adenosyl-L-methionine + cytosine50 in tRNAAspGTC
S-adenosyl-L-homocysteine + 5-methylcytosine50 in tRNAAspGTC
-
-
-
-
?
S-adenosyl-L-methionine + cytosine50 in tRNAGlu(CUC)
S-adenosyl-L-homocysteine + 5-methylcytosine50 in tRNAGlu(CUC)
-
-
-
?
S-adenosyl-L-methionine + cytosine50 in tRNAGlu(UUC)
S-adenosyl-L-homocysteine + 5-methylcytosine50 in tRNAGlu(UUC)
-
-
-
?
S-adenosyl-L-methionine + cytosine50 in tRNAGly precursor
S-adenosyl-L-homocysteine + 5-methylcytosine50 in tRNAGly precursor
-
-
-
-
?
S-adenosyl-L-methionine + cytosine50 in tRNAGly(CCC)
S-adenosyl-L-homocysteine + 5-methylcytosine50 in tRNAGly(CCC)
-
-
-
?
S-adenosyl-L-methionine + cytosine50 in tRNAGly(GCC)
S-adenosyl-L-homocysteine + 5-methylcytosine50 in tRNAGly(GCC)
-
-
-
?
S-adenosyl-L-methionine + cytosine50 in tRNAGly(UCC)
S-adenosyl-L-homocysteine + 5-methylcytosine50 in tRNAGly(UCC)
-
-
-
?
S-adenosyl-L-methionine + cytosine50 in tRNAGlyGCC
S-adenosyl-L-homocysteine + 5-methylcytosine50 in tRNAGlyGCC
-
-
-
-
?
S-adenosyl-L-methionine + cytosine50 in tRNALeuCAA
S-adenosyl-L-homocysteine + 5-methylcytosine50 in tRNALeuCAA
-
-
-
-
?
S-adenosyl-L-methionine + cytosine50 in tRNAPro(AGG)
S-adenosyl-L-homocysteine + 5-methylcytosine50 in tRNAPro(AGG)
-
-
-
?
S-adenosyl-L-methionine + cytosine50 in tRNAPro(CGG)
S-adenosyl-L-homocysteine + 5-methylcytosine50 in tRNAPro(CGG)
-
-
-
?
S-adenosyl-L-methionine + cytosine50 in tRNAPro(UGG)
S-adenosyl-L-homocysteine + 5-methylcytosine50 in tRNAPro(UGG)
-
-
-
?
S-adenosyl-L-methionine + cytosine59 in vtRNA1.2
S-adenosyl-L-homocysteine + 5-methylcytosine59 in vtRNA1.2
-
-
-
?
S-adenosyl-L-methionine + cytosine59 in vtRNA1.3
S-adenosyl-L-homocysteine + 5-methylcytosine59 in vtRNA1.3
-
-
-
?
S-adenosyl-L-methionine + cytosine69 in vtRNA1.1
S-adenosyl-L-homocysteine + 5-methylcytosine69 in vtRNA1.1
-
-
-
?
additional information
?
-
-
NSUN2 candidate ncRNA targets identified include RNAs with central functions in the processing, folding and modification of other ncRNAs (RPPH1, Y RNA, SCARNA2), RNAs important for protein synthesis and trafficking (5S rRNA and 7SL RNA) and RNAs involved in multidrug resistance and other processes (Vault RNAs). Notably, all of the NSUN2 targets revealed by 5-azacytidine-mediated RNA immunoprecipitation are either transcribed by RNA Pol III in the nucleolus (SCARNA2 excepted), or function in the nucleolus (SCARNA2), where NSUN2 resides
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-
?
additional information
?
-
-
the iCLIP method identifies tRNA AspGTC, ValAAC, GlyGCC, and LeuCAA as methylation substrates with methylation within the variable arm at cytosines 48, 49, and 50, no additional NSun2 target sites outside the variable arm. vtRNAs are methylation substrates for NSun2, vtRNAs are ncRNAs found as part of the vault ribonucleoprotein complex
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?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
S-adenosyl-L-methionine
cofactor interacting residues in hNSun6 are mainly composed of conserved residues Leu241, Cys242, Pro325 and Leu354. In addition, the side chain of residue Asp293 recognizes the N6 of the adenine ring. Asp293 is conserved as Asp or Glu in the RNA:m5C MTase family
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
5-aza-2'-deoxycytidine
-
the catalytic mechanism is disrupted by the suicide inhibitor
additional information
structure-based drug design toward RNA:m5C methyltransferase-related diseases
-
additional information
-
structure-based drug design toward RNA:m5C methyltransferase-related diseases
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
steady-state kinetic analyses of the methylation of m5Cprobe, tRNA and ssRNA by NSUN2
-
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
additional information
NSUN2 is expressed in stem and progenitor cells during human brain development
additional information
NSUN2 is expressed in early neuroepithelial progenitors of the developing human brain, and its expression is gradually reduced during differentiation of human neuroepithelial stem (NES) cells in vitro. Nucleolar expression of NSUN2 overlaps with SOX1, a marker for early neuroepithelial progenitors in the neural tube. NSUN2 is expressed in early neuroectodermal cells that are capable of differentiating into various region-specific neuronal and glial cell types. NSUN2 co-localized with Nestin and SOX1 in cultured NES cells, both lines Sai1 and AF22 express high levels of the NES cell markers Nestin and SOX2 but very low levels of the neural differentiation marker betaIII-tubulin (TUBB3)
additional information
NSUN2 is overexpressed in a number of human cancers
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
additional information
enzyme NSUN6 localizes to the cytoplasm and appears enriched in proximity to the golgi aparatus and pericentriolar matrix, indicating that methylation of C72 residues is a late maturation event that takes place after nuclear export
-
additional information
enzyme NSUN6 localizes to the cytoplasm and appears enriched in proximity to the golgi aparatus and pericentriolar matrix, indicating that methylation of C72 residues is a late maturation event that takes place after nuclear export
-
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
metabolism
on a global level, depletion, overexpression, or expression of catalytically inactive forms of NSUN2, but not NSUN1, NSUN5, or NSUN6, is reported to alter the total amount of m5C detected in the mRNA pool. Roles of m5C RNA methyltransferases in development and disease, overview
physiological function
cytoplasmic transfer RNAs are methylated by NSUN2, NSUN6, and DNMT2. NSUN6 specifically methylates C72 of particular tRNAs. U73, which has been termed the discriminator base, is critical for substrate recognition by NSUN6, and a flexible base pair (A:U or U:A) at positions 2:71 as well as a rigid base pair (C:G or G:C) formed between positions 3:70 are preferred. The binding pocket of human NSUN6 specifically accommodates U73. Roles of m5C RNA methyltransferases in development and disease, overview
evolution
-
the enzyme belongs to the RsmF/YebU/NSUN2 family of cytosine 5-methylation-RNA methyltransferases utilizing two cysteines in their catalytic pocket
malfunction
metabolism
physiological function
additional information
malfunction
-
autosomal-recessive loss of the NSUN2 gene is a causative link to intellectual disability disorders in humans. Loss of cytosine-5 methylation in vault RNAs causes aberrant processing into Argonaute-associated small RNA fragments that can function as microRNAs. Impaired processing of vault ncRNA may contribute to the etiology of NSun2-deficiency human disorders
malfunction
-
NSUN2 is associated with Myc-induced proliferation of cancer cells, mitotic spindle stability, infertility in male mice, and the balance of selfrenewal and differentiation in skin stem cells. In humans NSUN2 mutations cause an autosomal recessive syndrome characterized by intellectual disability and mental retardation
malfunction
exposure to oxidative stress efficiently repressed NSUN2, causing a reduction of methylation at specific tRNA sites. Loss of NSUN2 alters the biogenesis of tRNA-derived noncoding fragments (tRFs) in response to stress, leading to impaired regulation of protein synthesis. The intracellular accumulation of a specific subset of tRFs correlates with the dynamic repression of global protein synthesis
malfunction
loss-of-function mutations in the NSUN2 gene in both mouse and human cause growth retardation and neurodevelopmental deficits including microcephaly, as well as defects in cognition and motor function. Loss of NSUN2-mediated methylation of tRNA increases their endonucleolytic cleavage by angiogenin, and 5' tRNA fragments accumulate in Nsun2-/- brains. Neural differentiation of NES cells is impaired by both NSUN2 depletion and the presence of angiogenin. Since repression of NSUN2 also inhibits neural cell migration toward the chemoattractant fibroblast growth factor 2, the impaired differentiation capacity in the absence of NSUN2 may be driven by the inability to efficiently respond to growth factors. Upper-layer neurons are decreased in Nsun2 knockout brains, phenotype, detailed overview
malfunction
tRNAs lacking m5C48/49/50 modifications are bound more tightly by angiogenin, leading to accumulation of 5' tRNA-derived small RNA fragments, which trigger cellular stress and are implicated in disease. Expression of catalytically inactive forms of NSUN2, but not NSUN1, NSUN5, or NSUN6, is reported to alter the total amount of m5C detected in the mRNA pool. svRNA4 acts analogously to a microRNA and a concomitant increase in the levels of the svRNA4 target mRNAs CACNG7 and CACNG8 is observed in NSUN2-/- cells. Loss of function mutations in NSUN2 underlie several neurodevelopmental disorders. A homozygous mutation in the NSUN2 gene that leads to the substitution of Gly679 for Arg (p.Gly679Arg) in the protein has been detected in individuals with autosomal-recessive intellectual disability. This amino acid substitution is suggested to impede NSUN2 function by preventing localization of the protein to its site of action in the nucleolus. NSUN2 has also been linked to Dubowitz syndrome, which is characterized by microcephaly, growth and mental retardation, eczema, and characteristic facial features. A homozygous mutation in the canonical splice acceptor of exon 6 leads to use of a cryptic splice donor, instability of the NSUN2 mRNA, a significant decrease in protein levels, and reduced methylation of NSUN2 target RNAs (m5C47/48 of tRNAAsp(GUC)
metabolism
enzyme NSUN2 plays a central role in regulation of the stress respone pathway, detailed overview. tRNAs play multiple regulatory roles in the adaptation of protein synthesis to the cellular stress response
metabolism
m5C methylation of RNA is catalysed by the NOL1/NOP2/Sun domain (NSUN) RNA methyltransferase family, which includes NSUN1-7, as well as the DNA MTase homologue TRDMT1 (formerly DNMT2)
metabolism
on a global level, depletion, overexpression, or expression of catalytically inactive forms of NSUN2, but not NSUN1, NSUN5, or NSUN6, is reported to alter the total amount of m5C detected in the mRNA pool. Roles of m5C RNA methyltransferases in development and disease, overview
physiological function
-
no evidence for a major role of NSun2 or NSun2-mediated cytosine-5 methylation in mRNA stability
physiological function
cytosine-5 methylation in RNA is mediated by a large protein family of conserved RNA:m5C-methyltransferases. NSUN2 is one member of this family and methylates the vast majority of tRNAs as well as a small number of other non-coding (ncRNAs) and coding RNAs (cRNAs). The correct deposition of m5C into RNAs is essential for normal development. Cytosine-5 RNA methylation regulates neural stem cell differentiation and motility. The correct deposition of m5C into RNAs is essential for normal development
physiological function
the cytosine-5 RNA methyltransferase NSUN2 is a sensor for external stress stimuli. NSUN2-driven RNA methylation is functionally required to adapt cell cycle progression to the early stress response. The nucleolus, where NSUN2 resides, can act as a stress sensor. Dynamic changes of site-specific Methylcytosine (m5C) levels require NSUN2. m5C is required to balance anabolic and catabolic pathways during the stress response
physiological function
the m5C-48/49/50 modifications installed by NSUN2 cluster within the variable loop at the junction with the T-stem. A Levitt pair interaction between C48 and G15 in the D-loop is critical for formation of the characteristic L-shaped tertiary fold of most tRNAs. NSUN2-mediated methylations within the variable loop have also been shown to protect tRNAs against stress-induced, angiogenin-mediated endonucleolytic cleavage. During the maturation of the cytoplasmic tRNALeu(CAA), an m5C34 modification is installed by NSUN2 (cf. EC 2.1.1.203). Cytoplasmic transfer RNAs are methylated by NSUN2, NSUN6, and DNMT2
additional information
analysis of the catalytic mechanism of the RNA:m5C methyltransferase family, structure-function analysis of RNA:m5C methyltransferases, overview. Lys248, Asp323, Cys326 and Cys373 are the residues at the active site of hNSun6, they are strictly conserved in NSun6s and in the entire RNA:m5CMTase family, suggesting their conserved roles in catalysis. Multiple roles of Lys248 and Asp323. Motif IVCys (C326) plays a role in product release. In the hNSun6/tRNA complex, instead of nucleotide flipping, the acceptor region of tRNA undergoes a complicated conformational reconstitution for access to hNSun6
additional information
-
analysis of the catalytic mechanism of the RNA:m5C methyltransferase family, structure-function analysis of RNA:m5C methyltransferases, overview. Lys248, Asp323, Cys326 and Cys373 are the residues at the active site of hNSun6, they are strictly conserved in NSun6s and in the entire RNA:m5CMTase family, suggesting their conserved roles in catalysis. Multiple roles of Lys248 and Asp323. Motif IVCys (C326) plays a role in product release. In the hNSun6/tRNA complex, instead of nucleotide flipping, the acceptor region of tRNA undergoes a complicated conformational reconstitution for access to hNSun6
additional information
catalytic mechanism of the enzyme, comparison of NSUN family enzymes, overview. The NSUN family enzymes use the cysteine located in amino acid motif VI for the nucleophilic attack on carbon 6 of the target cytosine in RNA. In all seven human NSUN variants, the catalytic cysteine is preceded by threonine. Hydrogen bonding with the backbone carbonyl of proline and the aspartate side chain in motif IV orients the base in the active site and assists bond formation by transient protonation of the endocyclic N3 of cytidine. The activated nucleobase then accepts a methyl group from the properly positioned SAM cofactor, resulting in the formation of a carbon-carbon bond and generation of S-adenosylhomocysteine (SAH). To complete the reaction, the covalently bound methylated RNA has to be released from the protein. This elimination is assisted by the cysteine located in motif IV of NSUN proteins. This cysteine is located next to the conserved proline and acts as a base to deprotonate the tetrahedral carbon and initiate the elimination reaction that restores the unsaturated m5C heterocycle
additional information
catalytic mechanism of the enzyme, comparison of NSUN family enzymes, overview. The NSUN family enzymes use the cysteine located in amino acid motif VI for the nucleophilic attack on carbon 6 of the target cytosine in RNA. In all seven human NSUN variants, the catalytic cysteine is preceded by threonine. Hydrogen bonding with the backbone carbonyl of proline and the aspartate side chain in motif IV orients the base in the active site and assists bond formation by transient protonation of the endocyclic N3 of cytidine. The activated nucleobase then accepts a methyl group from the properly positioned SAM cofactor, resulting in the formation of a carbon-carbon bond and generation of S-adenosylhomocysteine (SAH). To complete the reaction, the covalently bound methylated RNA has to be released from the protein. This elimination is assisted by the cysteine located in motif IV of NSUN proteins. This cysteine is located next to the conserved proline and acts as a base to deprotonate the tetrahedral carbon and initiate the elimination reaction that restores the unsaturated m5C heterocycle
additional information
catalytic mechanism of the enzyme, comparison of NSUN family enzymes, overview. The NSUN family enzymes use the cysteine located in amino acid motif VI for the nucleophilic attack on carbon 6 of the target cytosine in RNA. In all seven human NSUN variants, the catalytic cysteine is preceded by threonine. Hydrogen bonding with the backbone carbonyl of proline and the aspartate side chain in motif IV orients the base in the active site and assists bond formation by transient protonation of the endocyclic N3 of cytidine. The activated nucleobase then accepts a methyl group from the properly positioned SAM cofactor, resulting in the formation of a carbon-carbon bond and generation of S-adenosylhomocysteine (SAH). To complete the reaction, the covalently bound methylated RNA has to be released from the protein. This elimination is assisted by the cysteine located in motif IV of NSUN proteins. This cysteine is located next to the conserved proline and acts as a base to deprotonate the tetrahedral carbon and initiate the elimination reaction that restores the unsaturated m5C heterocycle
additional information
catalytic mechanism of the enzyme, comparison of NSUN family enzymes, overview. The NSUN family enzymes use the cysteine located in amino acid motif VI for the nucleophilic attack on carbon 6 of the target cytosine in RNA. In all seven human NSUN variants, the catalytic cysteine is preceded by threonine. Hydrogen bonding with the backbone carbonyl of proline and the aspartate side chain in motif IV orients the base in the active site and assists bond formation by transient protonation of the endocyclic N3 of cytidine. The activated nucleobase then accepts a methyl group from the properly positioned SAM cofactor, resulting in the formation of a carbon-carbon bond and generation of S-adenosylhomocysteine (SAH). To complete the reaction, the covalently bound methylated RNA has to be released from the protein. This elimination is assisted by the cysteine located in motif IV of NSUN proteins. This cysteine is located next to the conserved proline and acts as a base to deprotonate the tetrahedral carbon and initiate the elimination reaction that restores the unsaturated m5C heterocycle
additional information
development of m5C-responsive probes, as a strategy for discriminating RNA and DNA m5C methyltransferase activity in cells (cf. EC 2.1.1.37), i.e. the m5C-switchable probe strategy, method development and evaluation, overview. The m5C-probe contains a 5'-terminal fluorescent nucleotide PC (2'-O-methyl 6-phenylpyrrolocytidine), which lights up spontaneously in response to m5C-induced terminal sugar pucker switch. When the probe is unmethylated, pC is able to base-pair with guanine in the complementary strand and stack strongly with its adjacent base. This results in efficient quenching of pC fluorescence through photoinduced electron transfer. m5C methylation of the probe by RNA:m5C MTase (e.g. NSUN2), however, is expected to trigger a C2'-endo to C3'-endo sugar pucker switch in PC and, since the sugar ring pucker defines the glycosidic bond angle, such a change in sugar puckering will also convert the orientation of PC base from axial to equatorial. This, in turn, disrupts its base-pairing and base-stacking interactions, leading to fluorescence activation. Schematic representation of 2'-OMe RNA probes and their methylated counterparts. The composition of the probes is confirmed through MALDI-TOF mass spectrometric analysis
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). CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
crystal structure of NSUN6 with target RNA showing the arrangement and key contacts between the amino acids in the active site and the target cytosine (C72) in RNA (PDB ID 5WWS)
purified recombinant His6-tagged enzyme, hanging drop vapor diffusion method, mixing of 0.001 ml of 4.8 mg/ml protein in 20 mM Tris-HCl, pH 7.0, 300 mM NaCl, 5 mM MgCl2, and 5 mM DTT, with 0.001 ml of reservoir solution consisting of 2% dioxane, 0.1 M bicine, pH 8.6, 18% w/v PEG 8000, and 10 mM yttrium(III) chloride hexahydrate, 16°C. For the hNSun6/tRNA complex, solutions are prepared with 0.075 mM MhNSun6 and 0.075 mM MtRNA, for the hNSun6/tRNA/SAM and hNSun6/tRNA/SFG complexes, hNSun6 is mixed with tRNA at a 1:1 molar ratio, adding either 1 mM SAM or SFG, crystals are obtained by mixing 0.001 ml of this solution with 0.001 ml of reservoir solution containing 0.1 M SPG, pH 8.0-10.0, 24-28% w/v PEG 1500, and 50 mM NaF, X-ray diffraction structure determination and analysis. Of different human tRNACys and tRNAThr isoacceptors and their variants, only tRNACys(GCA)-G2A:C71U can be cocrystallized with hNSun6, molecular replacement using the MTase domain structure of Pyrococcus horikoshii PH0851 (PDB ID: 2YXL) and the PUA domain structure of Pyrococcus horikoshii archaeosine tRNA-guanine transglycosylase (PDB ID: 1J2B) as starting models
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C326A
site-directed mutagenesis, tRNA binding structure compared to wild-type enzyme, the C326A mutation hampers the breakdown of the covalent intermediates
D266A
site-directed mutagenesis, the mutant shows highly increased binding affinity for SAM and highly reduced methylation activity
D293A
site-directed mutagenesis, the mutation leads to a loss of SAM binding capability and a loss of methylation activity to tRNACys
D323A
site-directed mutagenesis, the mutant shows highly increased binding affinity for SAM and highly reduced methylation activity
F141A
site-directed mutagenesis, the mutant shows activity similar to wild-type enzyme
K159A
site-directed mutagenesis, the mutant shows moderately decreased activity compared to wild-type enzyme
K159A/R181A
site-directed mutagenesis, the mutant shows highly decreased activity compared to wild-type enzyme
K160A
site-directed mutagenesis, the mutant shows moderately decreased activity compared to wild-type enzyme
K160A/R181A
site-directed mutagenesis, the mutant shows highly decreased activity compared to wild-type enzyme
K248A
site-directed mutagenesis, the mutant shows 5fold increased binding affinity for SAM
K271A
site-directed mutagenesis, the mutant shows highly increased binding affinity for SAM and highly reduced methylation activity
R181A
site-directed mutagenesis, the mutant shows highly decreased activity compared to wild-type enzyme
C271A
-
site-directed mutagenesis, the mutant enzyme forms an irreversible covalent crosslink between itself and the methylated cytosine in its target RNA
additional information
additional information
-
the only mRNA identified by miCLIP that is differentially expressed when NSun2 is inhibited by RNAi in HEK293 cells is NSun2 itself
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant His6-tagged enzyme HNSun6, hNSun6 and hNSun6-C326A-RNA complexes by nickel affinity chromatography
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant expression of His6-tagged wild-type enzyme HNSun6 and mutant enzymes
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
exposure to oxidative stress efficiently repressed NSUN2, causing a reduction of methylation at specific tRNA sites. Nucleophosmin (NPMI) is a marker for nucleolar stress, and a rapid, strong down-regulation of both NPMI and NSUN2 is observed upon arsenite treatment. Additional NSUN family members residing in the mitochondria (NSUN3, NSUN4) and cytoplasm (NSUN6) are similarly repressed in response to arsenite stress
sequenced cDNA libraries prepared from small RNA isolated from NSUN2+/- and NSUN2-/- human fibroblasts reveal that eight of the 43 ncRNAs are differentially regulated
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
changes in tRNA methylation profiles are sufficient to specify cellular metabolic states and efficiently adapt protein synthesis rates to cell stress
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Hussain, S.; Sajini, A.A.; Blanco, S.; Dietmann, S.; Lombard, P.; Sugimoto, Y.; Paramor, M.; Gleeson, J.G.; Odom, D.T.; Ule, J.; Frye, M.
NSun2-mediated cytosine-5 methylation of vault noncoding RNA determines its processing into regulatory small RNAs
Cell Rep.
4
255-261
2013
Homo sapiens
Khoddami, V.; Cairns, B.R.
Identification of direct targets and modified bases of RNA cytosine methyltransferases
Nat. Biotechnol.
31
458-464
2013
Homo sapiens
Bohnsack, K.; Hoebartner, C.; Bohnsack, M.
Eukaryotic 5-methylcytosine (M5C) RNA methyltransferases mechanisms, cellular functions, and links to disease
Genes (Basel)
10
102
2019
Homo sapiens (Q08J23), Homo sapiens (Q8TEA1), Pyrococcus horikoshii (O57712), Pyrococcus horikoshii ATCC 700860 (O57712), Pyrococcus horikoshii DSM 12428 (O57712), Pyrococcus horikoshii JCM 9974 (O57712), Pyrococcus horikoshii NBRC 100139 (O57712), Pyrococcus horikoshii OT-3 (O57712)
Liu, R.; Long, T.; Li, J.; Li, H.; Wang, E.
Structural basis for substrate binding and catalytic mechanism of a human RNA m5C methyltransferase NSun6
Nucleic Acids Res.
45
6684-6697
2017
Homo sapiens (Q8TEA1), Homo sapiens, Schizosaccharomyces pombe (O13935), Schizosaccharomyces pombe (Q9HGQ2), Schizosaccharomyces pombe 972 (O13935), Schizosaccharomyces pombe 972 (Q9HGQ2), Schizosaccharomyces pombe ATCC 24843 (O13935), Schizosaccharomyces pombe ATCC 24843 (Q9HGQ2)
Yang, T.; Low, J.J.A.; Woon, E.C.Y.
A general strategy exploiting m5C duplex-remodelling effect for selective detection of RNA and DNA m5C methyltransferase activity in cells
Nucleic Acids Res.
48
e5
2020
Homo sapiens (O14717)
Gkatza, N.A.; Castro, C.; Harvey, R.F.; Heiss, M.; Popis, M.C.; Blanco, S.; Borneloev, S.; Sajini, A.A.; Gleeson, J.G.; Griffin, J.L.; West, J.A.; Kellner, S.; Willis, A.E.; Dietmann, S.; Frye, M.
Cytosine-5 RNA methylation links protein synthesis to cell metabolism
PLoS Biol.
17
e3000297
2019
Homo sapiens (O14717), Mus musculus (O55055)
Flores, J.V.; Cordero-Espinoza, L.; Oeztuerk-Winder, F.; Andersson-Rolf, A.; Selmi, T.; Blanco, S.; Tailor, J.; Dietmann, S.; Frye, M.
Cytosine-5 RNA methylation regulates neural stem cell differentiation and motility
Stem Cell Reports
8
112-124
2017
Homo sapiens (O14717), Mus musculus (O55055)
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