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Information on EC 2.1.1.299 - protein N-terminal monomethyltransferase and Organism(s) Homo sapiens and UniProt Accession Q5VVY1
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2.1.1.299 protein N-terminal monomethyltransferaseIUBMB Comments
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. In contrast to EC 2.1.1.244, protein N-terminal methyltransferase, the protein only adds one methyl group to the N-terminal.
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The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
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N-terminal-(A,P,S)PK-[protein]
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N-terminal-N-methyl-N-(A,P,S)PK-[protein]
Synonyms
nrmt2, ntmt2, mettl11b, n-terminal monomethylase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
METTL11B
SYSTEMATIC NAME
IUBMB Comments
S-adenosyl-L-methionine:N-terminal-(A,P,S)PK-[protein] monomethyltransferase
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. In contrast to EC 2.1.1.244, protein N-terminal methyltransferase, the protein only adds one methyl group to the N-terminal.
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
2 S-adenosyl-L-methionine + PPKRIA
2 S-adenosyl-L-homocysteine + ?
mono- and dimethylation by NTMT2
-
-
?
3 S-adenosyl-L-methionine + GPKRIA
3 S-adenosyl-L-homocysteine + ?
mono-, di-, and trimethylation by NTMT2
-
-
?
N-terminal L-alanyl-L-prolyl-L-lysyl-[protein] + 3 S-adenosyl-L-methionine
N-terminal N,N,N-trimethyl-L-alanyl-L-prolyl-L-lysyl-[protein] + 3 S-adenosyl-L-homocysteine
-
-
-
?
S-adenosyl-L-methionine + APKRIA
S-adenosyl-L-homocysteine + ?
monomethylation by NTMT2
-
-
?
S-adenosyl-L-methionine + CPKRIA
S-adenosyl-L-homocysteine + ?
monomethylation by NTMT2
-
-
?
S-adenosyl-L-methionine + FPKRIA
S-adenosyl-L-homocysteine + ?
monomethylation by NTMT2
-
-
?
S-adenosyl-L-methionine + HPKRIA
S-adenosyl-L-homocysteine + ?
monomethylation by NTMT2
-
-
?
S-adenosyl-L-methionine + KPKRIA
S-adenosyl-L-homocysteine + ?
monomethylation by NTMT2, very low activity
-
-
?
S-adenosyl-L-methionine + LPKRIA
S-adenosyl-L-homocysteine + ?
monomethylation by NTMT2, very low activity
-
-
?
S-adenosyl-L-methionine + MPKRIA
S-adenosyl-L-homocysteine + ?
monomethylation by NTMT2
-
-
?
S-adenosyl-L-methionine + N-terminal-(A,P,S)PK-[protein]
S-adenosyl-L-homocysteine + N-terminal-N-methyl-N-(A,P,S)PK-[protein]
-
-
-
?
S-adenosyl-L-methionine + N-terminal-Ala-Pro-Lys-[protein]
S-adenosyl-L-homocysteine + N-terminal-N-methyl-N-Ala-Pro-Lys-[protein]
the 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. In contrast to EC 2.1.1.244, protein N-terminal methyltransferase, the protein only adds one methyl group to the N-terminal
-
-
?
S-adenosyl-L-methionine + N-terminal-Pro-Pro-Lys-[protein]
S-adenosyl-L-homocysteine + N-terminal-N-methyl-Pro-Pro-Lys-[protein]
the 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. In contrast to EC 2.1.1.244, protein N-terminal methyltransferase, the protein only adds one methyl group to the N-terminal
-
-
?
S-adenosyl-L-methionine + N-terminal-Ser-Pro-Lys-[protein]
S-adenosyl-L-homocysteine + N-terminal-N-methyl-Ser-Pro-Lys-[protein]
the 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. In contrast to EC 2.1.1.244, protein N-terminal methyltransferase, the protein only adds one methyl group to the N-terminal
-
-
?
S-adenosyl-L-methionine + RPKRIA
S-adenosyl-L-homocysteine + ?
monomethylation by NTMT2
-
-
?
S-adenosyl-L-methionine + SPKRIA
S-adenosyl-L-homocysteine + ?
binding structure of SAM/SAH and of the substrate peptide, overview. SPKRIA peptide is derived from N-terminus of RCC1 protein. NTMT2, unlike NTMT1 (EC 2.1.1.244), fails to di-/tri-methylate SPKRIA
-
-
?
S-adenosyl-L-methionine + SPKRIAKRRSPPADA
?
substrate peptide consisting of the first 15 amino acids of RCC1
-
-
?
S-adenosyl-L-methionine + WPKRIA
S-adenosyl-L-homocysteine + ?
monomethylation by NTMT2
-
-
?
S-adenosyl-L-methionine + YPKRIA
S-adenosyl-L-homocysteine + ?
monomethylation by NTMT2
-
-
?
additional information
?
-
NRMT2 exhibits monomethylase activity in vitro. Isozymes NRMT1 and NRMT2 can interact both in vitro and in vivo, modeling of NRMT1 and NRMT2 interactions. No activity with the MYL9 peptide SSKRAKAKTTKKRP
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-
-
additional information
?
-
NTMT2 is a mono-methyltransferase, substrate specificity, overview. But NTMT2 is also able to di-/tri-methylate the GPKRIA peptide and di-methylate the PPKRIA peptide, otherwise it is predominantly a mono-methyltransferase. The residue N89 of NTMT2 serves as a gatekeeper residue that regulates the binding of unmethylated versus mono-methylated substrate peptide.The substrate peptide is deeply inserted into the binding pocket through hydrophilic and hydrophobic interactions, and the alpha-amine of the first residue (S1) points towards the sulfur atom of SAH. In the NTMT2 complex, S1 fits snugly into the channel, where the main-chain O atom is anchored by N223 in NTMT2 (N168 in NTMT1, EC 2.1.1.244) through hydrogen bonding. No activity with peptides TPKRIA, VPKRIA, IPKRIA, DPKRIA, EPKRIA, NPKRIA, and QPKRIA
-
-
-
additional information
?
-
-
NTMT2 is a mono-methyltransferase, substrate specificity, overview. But NTMT2 is also able to di-/tri-methylate the GPKRIA peptide and di-methylate the PPKRIA peptide, otherwise it is predominantly a mono-methyltransferase. The residue N89 of NTMT2 serves as a gatekeeper residue that regulates the binding of unmethylated versus mono-methylated substrate peptide.The substrate peptide is deeply inserted into the binding pocket through hydrophilic and hydrophobic interactions, and the alpha-amine of the first residue (S1) points towards the sulfur atom of SAH. In the NTMT2 complex, S1 fits snugly into the channel, where the main-chain O atom is anchored by N223 in NTMT2 (N168 in NTMT1, EC 2.1.1.244) through hydrogen bonding. No activity with peptides TPKRIA, VPKRIA, IPKRIA, DPKRIA, EPKRIA, NPKRIA, and QPKRIA
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-
-
additional information
?
-
the substrate recognition motif is X-P-K/R. Although NTMT2 is proposed to be a monomethylase, it can also fully methylate both GPKRIA and PPKRIA peptides, but to a low level. NTMT2 is able to methylate hexamer peptides
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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
N-terminal L-alanyl-L-prolyl-L-lysyl-[protein] + 3 S-adenosyl-L-methionine
N-terminal N,N,N-trimethyl-L-alanyl-L-prolyl-L-lysyl-[protein] + 3 S-adenosyl-L-homocysteine
-
-
-
?
S-adenosyl-L-methionine + N-terminal-(A,P,S)PK-[protein]
S-adenosyl-L-homocysteine + N-terminal-N-methyl-N-(A,P,S)PK-[protein]
-
-
-
?
S-adenosyl-L-methionine + N-terminal-Ala-Pro-Lys-[protein]
S-adenosyl-L-homocysteine + N-terminal-N-methyl-N-Ala-Pro-Lys-[protein]
the 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. In contrast to EC 2.1.1.244, protein N-terminal methyltransferase, the protein only adds one methyl group to the N-terminal
-
-
?
S-adenosyl-L-methionine + N-terminal-Pro-Pro-Lys-[protein]
S-adenosyl-L-homocysteine + N-terminal-N-methyl-Pro-Pro-Lys-[protein]
the 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. In contrast to EC 2.1.1.244, protein N-terminal methyltransferase, the protein only adds one methyl group to the N-terminal
-
-
?
S-adenosyl-L-methionine + N-terminal-Ser-Pro-Lys-[protein]
S-adenosyl-L-homocysteine + N-terminal-N-methyl-Ser-Pro-Lys-[protein]
the 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. In contrast to EC 2.1.1.244, protein N-terminal methyltransferase, the protein only adds one methyl group to the N-terminal
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
S-adenosyl-L-methionine
dependent on, binding structure of SAM/SAH, overview
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0556
SPKRIAKRRSPPADA
recombinant NRMT2, pH and temperature not specified in the publication
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
additional information
additional information
NRMT2 is a monomethylase expressed at low levels in a tissue-specific manner
additional information
NTMT2 is predominantly expressed in heart and skeletal muscle tissues
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
when expressed in HeLa cells the enzyme is enriched in the nuclear compartment
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
malfunction
the N209I endometrial and P211S lung cancer mutants decrease the trimethylation level of RCC1, whereas the Q144H lung cancer mutant increases the trimethylation level of RCC1 with minimal levels of mono- and dimethylated RCC1. For NTMT2, the V224L breast cancer mutant shows marginal methylation activity for methylation states. Those data infer that methylation levels may play different roles in different cancers
metabolism
protein alpha-N-terminal methylation is catalyzed by prokaryotic and eukaryotic protein N-terminal methyltransferases. The prevalent occurrence of this methylation in ribosomes, myosin, and histones implies its function in protein-protein interactions. Functions of methylated glycine, alanine, and serine, overview
physiological function
additional information
evolution
structural comparison of isozymes NTMT1 and NTMT2, structural alignment of NTMT1 (PDB ID 5E1B) and NTMT2, overview. NTMT1 and NTMT2 employ a similar substrate recognition mode. NTMT2 is a SAM-dependent class I methyltransferase
evolution
the enzyme belongs to the methyltransferase like (METTL) family of class I methyltransferases containing seven-beta-strand methyltransferase motifs and Rossman folds for binding SAM. The N-terminal methyltransferase homologs NRMT1 (N-terminal RCC1 methyltransferase 1) and NRMT2 (N-terminal RCC1 methyltransferase 2), which following cleavage of the initiating methionine, methylate the alpha-amine of the first N-terminal residue of their substrates. NRMT1 and NRMT2 are 50% identical and 75% similar and share an N-terminal X-P-K consensus sequence. Although structurally similar, they differ in their catalytic activities
physiological function
isozyme NRMT2 expression activates isozyme NRMT1 activity, not through priming, but by increasing its stability and substrate affinity. NRMT2 overexpression cannot rescue NRMT1 knockout phenotypes
physiological function
protein methylation participates in regulation of a broad spectrum of cellular processes. Besides the extensively studied protein lysine/arginine methylation, the addition of a methyl group at the free alpha-N-termini of proteins represents a unique mode of post-translational modification
additional information
analysis of crystal structures of NRMT1 and NRMT2 (PDB IDs 2EX4 and 5UBB, determined to 1.75 and 2.0 A, respectively), homology modeling. Modeling of NRMT1 and NRMT2 heterotrimer, interaction analysis, overview
additional information
substrate and ligand binding structures of NTMT1 (EC 2.1.1.244) and NTMT2, and proposed catalytic mechanism of NTMT2, overview
additional information
-
substrate and ligand binding structures of NTMT1 (EC 2.1.1.244) and NTMT2, and proposed catalytic mechanism of NTMT2, overview
additional information
substrate recognition and catalytic mechanisms, 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). NTM1B_HUMAN
283
0
32400
Swiss-Prot
Mitochondrion (Reliability: 3)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
monomer
1 * 35700, recombinant isozyme NRMT2, SDS-PAGE and analytical ultracentrifugation
additional information
additional information
based on the folding pattern, NTMT2 is a SAM-dependent class I methyltransferase, which consists of a central seven-stranded beta-sheet (beta1-beta5 and beta8-beta9), flanked by three alpha-helices (alpha3-alpha5) and two alpha-helices (alpha6-alpha7) on each side, respectively. In addition, NTMT2 contains two auxiliary regions: an N-terminal alpha-lid (nu1, alpha1-alpha2), and a beta-lid (beta6-beta7) inserted between beta5 and alpha8. These two lids cover the core domain that contributes to the substrate recognition
additional information
-
based on the folding pattern, NTMT2 is a SAM-dependent class I methyltransferase, which consists of a central seven-stranded beta-sheet (beta1-beta5 and beta8-beta9), flanked by three alpha-helices (alpha3-alpha5) and two alpha-helices (alpha6-alpha7) on each side, respectively. In addition, NTMT2 contains two auxiliary regions: an N-terminal alpha-lid (nu1, alpha1-alpha2), and a beta-lid (beta6-beta7) inserted between beta5 and alpha8. These two lids cover the core domain that contributes to the substrate recognition
additional information
enzyme NRMT1 primarily exists as a monomer. Isozymes NRMT1 and NRMT2, when co-expressed, form a heterotrimer, interaction analysis, overview
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
analysis of crystal structures of NRMT1 and NRMT2 (PDB IDs 2EX4 and 5UBB, determined to 1.75 and 2.0 A, respectively), homology modeling
purified recombinant NTMT2 in binary complex with S-adenosyl-L-methionine and in ternary complex with S-adenosyl-L-homocysteine and unmethylated substrate peptide SPKRIA, X-ray diffraction structure determination and analysis at 1.20-2.0 A resolution. A methylated alpha-amino group in the N-terminus of the peptide is traced in the crystal structure
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
N89G
site-directed mutagenesis, the mutant shows profoundly altered catalytic activities and product specificities
additional information
co-expression of NRMT2 with NRMT1 increases the trimethylation rate of NRMT1. Generation of truncation constructs of NRMT2
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene NTMT2, recombinant expression of His-tagged NRMT2 in Escherichia coli and of wild-type and mutant FLAG-tagged NRMT2s in HEK-293 cells, recombinant expression of GFP-tagged enzyme in HCT-116 cells
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Petkowski, J.J.; Bonsignore, L.A.; Tooley, J.G.; Wilkey, D.W.; Merchant, M.L.; Macara, I.G.; Schaner Tooley, C.E.
NRMT2 is an N-terminal monomethylase that primes for its homologue NRMT1
Biochem. J.
456
453-462
2013
Homo sapiens (Q5VVY1), Homo sapiens, Mus musculus
Huang, R.
Chemical biology of protein N-terminal methyltransferases
ChemBioChem
20
976-984
2019
Homo sapiens (Q5VVY1)
Dong, C.; Dong, G.; Li, L.; Zhu, L.; Tempel, W.; Liu, Y.; Huang, R.; Min, J.
An asparagine/glycine switch governs product specificity of human N-terminal methyltransferase NTMT2
Commun. Biol.
1
183
2018
Homo sapiens (Q5VVY1), Homo sapiens
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