Information on EC 2.1.1.244 - protein N-terminal methyltransferase

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The enzyme appears in viruses and cellular organisms

EC NUMBER
COMMENTARY hide
2.1.1.244
-
RECOMMENDED NAME
GeneOntology No.
protein N-terminal methyltransferase
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REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
2 S-adenosyl-L-methionine + N-terminal-PPK-[protein] = 2 S-adenosyl-L-homocysteine + N-terminal-N,N-dimethyl-N-PPK-[protein]
show the reaction diagram
(2)
-
-
-
3 S-adenosyl-L-methionine + N-terminal-(A,S)PK-[protein] = 3 S-adenosyl-L-homocysteine + N-terminal-N,N,N-trimethyl-N-(A,S)PK-[protein]
show the reaction diagram
(1)
-
-
-
S-adenosyl-L-methionine + N-terminal-(A,S)PK-[protein] = S-adenosyl-L-homocysteine + N-terminal-N-methyl-N-(A,S)PK-[protein]
show the reaction diagram
(1a)
-
-
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S-adenosyl-L-methionine + N-terminal-N,N-dimethyl-N-(A,S)PK-serine-[protein] = S-adenosyl-L-homocysteine + N-terminal-N,N,N-trimethyl-N-(A,S)PK-[protein]
show the reaction diagram
(1c)
-
-
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S-adenosyl-L-methionine + N-terminal-N-methyl-N-(A,S)PK-[protein] = S-adenosyl-L-homocysteine + N-terminal-N,N-dimethyl-N-(A,S)PK-[protein]
show the reaction diagram
(1b)
-
-
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S-adenosyl-L-methionine + N-terminal-N-methyl-N-PPK-[protein] = S-adenosyl-L-homocysteine + N-terminal-N,N-dimethyl-N-PPK-[protein]
show the reaction diagram
(2b)
-
-
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S-adenosyl-L-methionine + N-terminal-PPK-[protein] = S-adenosyl-L-homocysteine + N-terminal-N-methyl-N-PPK-[protein]
show the reaction diagram
(2a)
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-
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SYSTEMATIC NAME
IUBMB Comments
S-adenosyl-L-methionine:N-terminal-(A,P,S)PK-[protein] methyltransferase
This enzyme methylates the N-terminus of target proteins containing the N-terminal motif [Ala/Pro/Ser]-Pro-Lys after the initiator L-methionine is cleaved. When the terminal amino acid is L-proline, the enzyme catalyses two successive methylations of its alpha-amino group. When the first amino acid is either L-alanine or L-serine, the enzyme catalyses three successive methylations. The Pro-Lys in positions 2-3 cannot be exchanged for other amino acids [1,2].
CAS REGISTRY NUMBER
COMMENTARY hide
9068-28-4
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ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
genes METTL11A and METTL11B
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-
Manually annotated by BRENDA team
gene rbcMTS
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-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
malfunction
physiological function
additional information
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
3 S-adenosyl-L-methionine + N-terminal-dimethyl-SPKRIAKRRS-[RCC1]
3 S-adenosyl-L-homocysteine + N-terminal-trimethyl-SPKRIAKRRS-[RCC1]
show the reaction diagram
-
-
-
-
?
3 S-adenosyl-L-methionine + N-terminal-LPKRIA-[RCC1]
3 S-adenosyl-L-homocysteine + N-terminal-trimethyl-LPKRIA-[RCC1]
show the reaction diagram
-
-
-
-
?
3 S-adenosyl-L-methionine + N-terminal-methyl-SPKRIAKRRS-[RCC1]
3 S-adenosyl-L-homocysteine + N-terminal-trimethyl-SPKRIAKRRS-[RCC1]
show the reaction diagram
-
-
-
-
?
3 S-adenosyl-L-methionine + N-terminal-peptide-[BAP1 protein]
3 S-adenosyl-L-homocysteine + N-terminal-trimethyl-peptide-[BAP1 protein]
show the reaction diagram
-
i.e. BRCA1 associated protein 1, a DNA repair protein
-
-
?
3 S-adenosyl-L-methionine + N-terminal-peptide-[DDB2 protein]
3 S-adenosyl-L-homocysteine + N-terminal-trimethyl-peptide-[DDB2 protein]
show the reaction diagram
-
DDB2 is a DNA repair protein
-
-
?
3 S-adenosyl-L-methionine + N-terminal-peptide-[PARP3 protein]
3 S-adenosyl-L-homocysteine + N-terminal-trimethyl-peptide-[PARP3 protein]
show the reaction diagram
-
i.e. poly-ADP-ribosylase 3, a DNA repair protein
-
-
?
3 S-adenosyl-L-methionine + N-terminal-PPKRIA-[RCC1]
3 S-adenosyl-L-homocysteine + N-terminal-trimethyl-PPKRIA-[RCC1]
show the reaction diagram
-
best substrate
-
-
?
3 S-adenosyl-L-methionine + N-terminal-RPKRIA-[RCC1]
3 S-adenosyl-L-homocysteine + N-terminal-trimethyl-RPKRIA-[RCC1]
show the reaction diagram
-
-
-
-
?
3 S-adenosyl-L-methionine + N-terminal-SPKRIA-[RCC1]
3 S-adenosyl-L-homocysteine + N-terminal-trimethyl-SPKRIA-[RCC1]
show the reaction diagram
3 S-adenosyl-L-methionine + N-terminal-SPKRIAKRR-[RCC1]
3 S-adenosyl-L-homocysteine + N-terminal-trimethyl-SPKRIAKRR-[RCC1]
show the reaction diagram
-
-
-
-
?
3 S-adenosyl-L-methionine + N-terminal-SPKRIAKRRS-[RCC1]
3 S-adenosyl-L-homocysteine + N-terminal-trimethyl-SPKRIAKRRS-[RCC1]
show the reaction diagram
-
-
-
-
?
3 S-adenosyl-L-methionine + N-terminal-SPKRIAKRRSPP-[RCC1]
3 S-adenosyl-L-homocysteine + N-terminal-trimethyl-SPKRIAKRRSPP-[RCC1]
show the reaction diagram
-
-
-
-
?
3 S-adenosyl-L-methionine + N-terminal-WPKRIA-[RCC1]
3 S-adenosyl-L-homocysteine + N-terminal-trimethyl-WPKRIA-[RCC1]
show the reaction diagram
-
-
-
-
?
3 S-adenosyl-L-methionine + N-terminal-YPKRIA-[RCC1]
3 S-adenosyl-L-homocysteine + N-terminal-trimethyl-YPKRIA-[RCC1]
show the reaction diagram
-
-
-
-
?
S-adenosyl-L-methionine + APKQQLSKY
?
show the reaction diagram
S-adenosyl-L-methionine + human histone H3
S-adenosyl-L-homocysteine + ?
show the reaction diagram
-
lower activity with histone H3 compared to histone H4
-
-
?
S-adenosyl-L-methionine + human histone H4
S-adenosyl-L-homocysteine + ?
show the reaction diagram
-
-
-
-
?
S-adenosyl-L-methionine + PPKQQLSKY
?
show the reaction diagram
S-adenosyl-L-methionine + Ran guanine nucleotide-exchange factor RCC1
S-adenosyl-L-homocysteine + ?
show the reaction diagram
S-adenosyl-L-methionine + retinoblastoma protein
S-adenosyl-L-homocysteine + ?
show the reaction diagram
-
-
-
-
?
S-adenosyl-L-methionine + Rpl12ab
?
show the reaction diagram
-
methylation of Rpl12ab at the N-terminal proline residue
-
-
?
S-adenosyl-L-methionine + Rpl12ab
S-adenosyl-L-homocysteine + ?
show the reaction diagram
S-adenosyl-L-methionine + Rps25a
?
show the reaction diagram
S-adenosyl-L-methionine + Rps25b
?
show the reaction diagram
S-adenosyl-L-methionine + SET/TAF-I/PHAPII
S-adenosyl-L-homocysteine + ?
show the reaction diagram
-
only the SETalpha splicing variant is a substrate for NRMT, since it begins with the NRMT consensus in contrast to the beta splicing variant
-
-
?
S-adenosyl-L-methionine + SPKQQLSKY
?
show the reaction diagram
additional information
?
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
S-adenosyl-L-methionine + Ran guanine nucleotide-exchange factor RCC1
S-adenosyl-L-homocysteine + ?
show the reaction diagram
-
NRMT is the predominant alpha-N-methyltransferase for RCC1
-
-
?
S-adenosyl-L-methionine + retinoblastoma protein
S-adenosyl-L-homocysteine + ?
show the reaction diagram
-
-
-
-
?
S-adenosyl-L-methionine + Rpl12ab
?
show the reaction diagram
-
methylation of Rpl12ab at the N-terminal proline residue
-
-
?
S-adenosyl-L-methionine + Rpl12ab
S-adenosyl-L-homocysteine + ?
show the reaction diagram
S-adenosyl-L-methionine + Rps25a
?
show the reaction diagram
-
-
-
-
?
S-adenosyl-L-methionine + Rps25b
?
show the reaction diagram
-
-
-
-
?
additional information
?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
S-adenosyl-L-methionine
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
me3-RCC1-6
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product inhibition
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N-terminal-acetyl-SPKRIAKRRS-[RCC1]
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noncompetitive versus S-adenosyl-L-methionine and protein substrate
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N-terminal-trimethyl-SPKRIA-[RCC1]
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product inhibition, competitive inhibitor versus protein substrate, noncompetitive versus S-adenosyl-L-methionine
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NAM-TZ-SPKRIA
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the inhibitor is enzyme-specific with a competitive inhibition pattern for both substrates, selective versus protein lysine methyltransferase G9a and arginine methyltransferase 1. The inhibitor substantially suppresses the methylation progression. The sulfur is replaced with a less reactive nitrogen to yield N-adenosyl-L-methionine as a stable analogue of S-adenosyl-L-methionine. Hexapeptide SPKRIA is derived from the N-terminus of regulator of chromosome condensation 1, RCC1. Binding structure modeling using the crystal structure of NTMT1 with S-adenosyl-L-homocysteine, PDB ID 2EX4. The two parts are connected via the triazole linker. NAM-TZ-SPKRIA acts as a competitive inhibitor when the concentration of S-adenosyl-L-methionine is varied from 0.003-0.010 mM and RCC1-10 substrate peptide is at a fixed concentration at 0.003 mM
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S-adenosyl-L-homocysteine
sinefungin
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noncompetitive versus S-adenosyl-L-methionine and protein substrate
additional information
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0043
N-terminal-dimethyl-SPKRIAKRRS-[RCC1]
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recombinant detagged enzyme, pH 7.5, 37C
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0.0054
N-terminal-LPKRIA-[RCC1]
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wild-type enzyme, pH 7.5, 37C
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0.0014
N-terminal-methyl-SPKRIAKRRS-[RCC1]
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recombinant detagged enzyme, pH 7.5, 37C
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0.0003
N-terminal-PPKRIA-[RCC1]
-
wild-type enzyme, pH 7.5, 37C
-
0.004
N-terminal-RPKRIA-[RCC1]
-
wild-type enzyme, pH 7.5, 37C
-
0.0032 - 0.263
N-terminal-SPKRIA-[RCC1]
-
0.0014
N-terminal-SPKRIAKRR-[RCC1]
-
recombinant detagged enzyme, pH 7.5, 37C
-
0.00089
N-terminal-SPKRIAKRRS-[RCC1]
-
recombinant detagged enzyme, pH 7.5, 37C
-
0.0031 - 0.0049
N-terminal-SPKRIAKRRSPP-[RCC1]
-
0.126
N-terminal-WPKRIA-[RCC1]
-
wild-type enzyme, pH 7.5, 37C
-
0.0016
N-terminal-YPKRIA-[RCC1]
-
wild-type enzyme, pH 7.5, 37C
-
additional information
additional information
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0098
N-terminal-dimethyl-SPKRIAKRRS-[RCC1]
Homo sapiens
-
recombinant detagged enzyme, pH 7.5, 37C
-
0.0018
N-terminal-LPKRIA-[RCC1]
Homo sapiens
-
wild-type enzyme, pH 7.5, 37C
-
0.0097
N-terminal-methyl-SPKRIAKRRS-[RCC1]
Homo sapiens
-
recombinant detagged enzyme, pH 7.5, 37C
-
0.0018
N-terminal-PPKRIA-[RCC1]
Homo sapiens
-
wild-type enzyme, pH 7.5, 37C
-
0.0015
N-terminal-RPKRIA-[RCC1]
Homo sapiens
-
wild-type enzyme, pH 7.5, 37C
-
0.0007 - 0.0093
N-terminal-SPKRIA-[RCC1]
-
0.0088
N-terminal-SPKRIAKRR-[RCC1]
Homo sapiens
-
recombinant detagged enzyme, pH 7.5, 37C
-
0.0073
N-terminal-SPKRIAKRRS-[RCC1]
Homo sapiens
-
recombinant detagged enzyme, pH 7.5, 37C
-
0.0095 - 0.013
N-terminal-SPKRIAKRRSPP-[RCC1]
-
0.00167
N-terminal-WPKRIA-[RCC1]
Homo sapiens
-
wild-type enzyme, pH 7.5, 37C
-
0.00067
N-terminal-YPKRIA-[RCC1]
Homo sapiens
-
wild-type enzyme, pH 7.5, 37C
-
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2.28
N-terminal-dimethyl-SPKRIAKRRS-[RCC1]
Homo sapiens
-
recombinant detagged enzyme, pH 7.5, 37C
210540
0.33
N-terminal-LPKRIA-[RCC1]
Homo sapiens
-
wild-type enzyme, pH 7.5, 37C
210536
6.93
N-terminal-methyl-SPKRIAKRRS-[RCC1]
Homo sapiens
-
recombinant detagged enzyme, pH 7.5, 37C
210539
6
N-terminal-PPKRIA-[RCC1]
Homo sapiens
-
wild-type enzyme, pH 7.5, 37C
210532
0.375
N-terminal-RPKRIA-[RCC1]
Homo sapiens
-
wild-type enzyme, pH 7.5, 37C
210534
0.00033 - 2.91
N-terminal-SPKRIA-[RCC1]
210531
6.29
N-terminal-SPKRIAKRR-[RCC1]
Homo sapiens
-
recombinant detagged enzyme, pH 7.5, 37C
210537
8.2
N-terminal-SPKRIAKRRS-[RCC1]
Homo sapiens
-
recombinant detagged enzyme, pH 7.5, 37C
210538
2.65 - 3.07
N-terminal-SPKRIAKRRSPP-[RCC1]
210541
0.013
N-terminal-WPKRIA-[RCC1]
Homo sapiens
-
wild-type enzyme, pH 7.5, 37C
210535
0.419
N-terminal-YPKRIA-[RCC1]
Homo sapiens
-
wild-type enzyme, pH 7.5, 37C
210533
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0002
NAM-TZ-SPKRIA
-
pH and temperature not specified in the publication
-
additional information
additional information
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.025
me3-RCC1-6
Homo sapiens
-
above, wild-type enzyme, pH 7.5, 37C
-
0.0013
NAM-TZ-SPKRIA
Homo sapiens
-
pH and temperature not specified in the publication
-
0.0033
S-adenosyl-L-homocysteine
Homo sapiens
-
wild-type enzyme, pH 7.5, 37C
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.5
-
assay at
8
-
assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
30
-
assay at
37
-
assay at
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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NTMT1 is upregulated in a variety of cancers
Manually annotated by BRENDA team
-
high enzyme expression levels
Manually annotated by BRENDA team
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low enzyme expression level
Manually annotated by BRENDA team
-
low enzyme expression level
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
-
the coding sequence of spinach SSMT includes a putative targeting presequence with sequence identity at a plastid processing site
Manually annotated by BRENDA team
-
-
-
Manually annotated by BRENDA team
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
recombinant purified full-length wild-type NTMT1 in complex with S-adenosyl-L-homocysteine and a peptide derived from either human (SPKRIA) or mouse (PPKRIA) RCC1, or crystals of NTMT1 in complex with S-adenosyl-L-homocysteine and either the RPK or YPK substrate peptide, sitting drop vapor diffusion method, mixing of 0.001 ml of 37 mg/ml protein and ligand in 20 mM Tris-HCl, pH 7.5, 150 mM NaCl, and 0.5 mM TECP, with 0.001 ml of reservoir solution containing 23-28% PET 3350 and 14-18% Tacsimate, pH 6.0, X-ray diffraction structure determination and analysis, molecular replacement
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
native enzyme partially from heart cell cytosol
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recombinant His-tagged METTL11A from Escherichia coli strain BL21(DE3) by nickel affinity chromatography
recombinant N-terminally His6-tagged wild-type and mutant enzymes NTMT1 from Escherichia coli strain BL21(DE3) codon plus RIL by nickel affinity and anion exchange chromatography followed by gel filtration
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recombinant N-terminally His6-tagged wild-type and mutant enzymes NTMT1 from Escherichia coli strain BL21(DE3) codon plus RIL by nickel affinity chromatography, tag cleavage through thrombin, another 3 steps of nickel affinity chromatography and dialysis
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
gene METTL11A
-
gene METTL11A, cloning of the His-tagged human enzyme using vector pET-100/DTOPO that carries a His6 tag in the linker region MRGSHHHHHHGMASMTGGQQMGRDLYDDDDKDHPFT, which is incorporated before the initiator methionine residue of the cloned protein, and expression in Escherichia coli strain BL21(DE3)
generbcMTS, DNA and amino acid sequence determination and analysis, expression of a N-terminal truncated form of spinach SSMT in Escherichia coli
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N-terminally tagged FLAG-NRMT overexpression in HEK 293LT cell nuceli, that show 3fold increased RCC1 alpha-N-methyltransferase activity
-
recombinant expression of N-terminally His6-tagged wild-type and mutant enzymes NTMT1 with a thrombin cleavage site at the N-terminus in Escherichia coli strain BL21(DE3) codon plus RIL
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
NTMT1 is upregulated in a variety of cancers
-
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
D168X
-
site-directed mutagenesis, the mutation has no effect on methylation
D178A/D181A
-
site-directed mutagenesis, mutating the residues Asp178 and Asp181 at the lip of the active site to Ala decreases enzyme activity, which is further decreased by reverse-charge mutagenesis to Lys
D180K
-
site-directed mutagenesis, inactive mutant
D180Y
-
site-directed mutagenesis, inactive mutant
H140K
-
site-directed mutagenesis, inactive mutant
N168K
-
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type enzyme
Q169K
-
site-directed mutagenesis, inactive mutant
S183K
-
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type enzyme
W136F
-
site-directed mutagenesis, almost inactive mutant
W136I
-
site-directed mutagenesis, inactive mutant
additional information
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
drug development
pharmacology
-
NTMT1 inhibitors can be potential anticancer therapeutics