2.1.1.- Methyltransferases

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2.1.1.- Methyltransferases

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Enzymes

TYMS (thymidylate synthetase) C Show summary »« Hide summary More detailed page go icon to follow link

DNA methyltransferase 1 Show summary »« Hide summary More detailed page go icon to follow link

DNA (cytosine-5-)-methyltransferase 3α Show summary »« Hide summary More detailed page go icon to follow link

methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit Show summary »« Hide summary

Target Id

3181

Nomenclature

methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit

Previous and unofficial names

methyltransferase-like 3 | methyltransferase 3 | methyltransferase like 3 | mRNA (2'-O-methyladenosine-N⁶-)-methyltransferase | N⁶-adenosine-methyltransferase 70 kDa subunit

Genes

METTL3 (Hs), Mettl3 (Mm), Mettl3 (Rn)

Ensembl ID

ENSG00000165819 (Hs), ENSMUSG00000022160 (Mm), ENSRNOG00000013111 (Rn)

UniProtKB AC

Q86U44 (Hs), Q8C3P7 (Mm)

Ligands

WD6305 (Binding) (PROTAC) [4]

Inhibitors

UZH2 pIC₅₀ 8.3 [3]

STC-15 pIC₅₀ 8.2 [2]

Selective inhibitors

STM2457 pIC₅₀ 7.8 [11]

Comment

Catalytic subunit of the METTL3-METTL14 methyltransferase complex that 'writes' methyl marks onto adenine residues in mRNA [7,10]. METTL3 has been linked to the initiation and maintenance of cancer [9,13], and is a target for selective drug-like inhibitor development [1,11].

nicotinamide N-methyltransferase Show summary »« Hide summary

Target Id

3205

Nomenclature

nicotinamide N-methyltransferase

Genes

NNMT (Hs)

Ensembl ID

ENSG00000166741 (Hs)

UniProtKB AC

P40261 (Hs)

EC number

2.1.1.1

Inhibitors

NNMT inhibitor 14 [PMID: 35904556] pIC₅₀ 9.0 [12], 6.4 [12]

Comment

NNMT is a ubiquitously expressed intracellular enzyme that catalyses the methylation of nicotinamide (N-methylation). The reaction uses S-adenosyl methionine as the methyl donor. The association of NNMT overexpression with human diseases has led to the search for selective, small molecule NNMT inhibitors [6,8,12].

References

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1. Bedi RK, Huang D, Eberle SA, Wiedmer L, Śledź P, Caflisch A. (2020) Small-Molecule Inhibitors of METTL3, the Major Human Epitranscriptomic Writer. ChemMedChem, 15 (9): 744-748. [PMID:32159918]

2. Blackaby WP, Hardick DJ, Thomas EJ, Brookfield FA, Shepherd J, Bubert C, Ridgill MP. (2021) Polyheterocyclic compounds as mettl3 inhibitors. Patent number: WO2021111124A1. Assignee: Storm Therapeutics Limited. Priority date: 01/12/2020. Publication date: 10/06/2021.

3. Dolbois A, Bedi RK, Bochenkova E, Müller A, Moroz-Omori EV, Huang D, Caflisch A. (2021) 1,4,9-Triazaspiro[5.5]undecan-2-one Derivatives as Potent and Selective METTL3 Inhibitors. J Med Chem, 64 (17): 12738-12760. [PMID:34431664]

4. Du W, Huang Y, Chen X, Deng Y, Sun Y, Yang H, Shi Q, Wu F, Liu G, Huang H et al.. (2024) Discovery of a PROTAC degrader for METTL3-METTL14 complex. Cell Chem Biol, 31 (1): 177-183.e17. [PMID:38194973]

5. Gangjee A, Zhao Y, Ihnat MA, Thorpe JE, Bailey-Downs LC, Kisliuk RL. (2012) Novel tricyclic indeno[2,1-d]pyrimidines with dual antiangiogenic and cytotoxic activities as potent antitumor agents. Bioorg Med Chem, 20 (14): 4217-25. [PMID:22739090]

6. Gao Y, van Haren MJ, Buijs N, Innocenti P, Zhang Y, Sartini D, Campagna R, Emanuelli M, Parsons RB, Jespers W et al.. (2021) Potent Inhibition of Nicotinamide N-Methyltransferase by Alkene-Linked Bisubstrate Mimics Bearing Electron Deficient Aromatics. J Med Chem, 64 (17): 12938-12963. [PMID:34424711]

7. Liu J, Yue Y, Han D, Wang X, Fu Y, Zhang L, Jia G, Yu M, Lu Z, Deng X et al.. (2014) A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol, 10 (2): 93-5. [PMID:24316715]

8. Neelakantan H, Wang HY, Vance V, Hommel JD, McHardy SF, Watowich SJ. (2017) Structure-Activity Relationship for Small Molecule Inhibitors of Nicotinamide N-Methyltransferase. J Med Chem, 60 (12): 5015-5028. [PMID:28548833]

9. Tong J, Flavell RA, Li HB. (2018) RNA m⁶A modification and its function in diseases. Front Med, 12 (4): 481-489. [PMID:30097961]

10. Wang X, Feng J, Xue Y, Guan Z, Zhang D, Liu Z, Gong Z, Wang Q, Huang J, Tang C et al.. (2016) Structural basis of N(6)-adenosine methylation by the METTL3-METTL14 complex. Nature, 534 (7608): 575-8. [PMID:27281194]

11. Yankova E, Blackaby W, Albertella M, Rak J, De Braekeleer E, Tsagkogeorga G, Pilka ES, Aspris D, Leggate D, Hendrick AG et al.. (2021) Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia. Nature, 593 (7860): 597-601. [PMID:33902106]

12. Yoshida S, Uehara S, Kondo N, Takahashi Y, Yamamoto S, Kameda A, Kawagoe S, Inoue N, Yamada M, Yoshimura N et al.. (2022) Peptide-to-Small Molecule: A Pharmacophore-Guided Small Molecule Lead Generation Strategy from High-Affinity Macrocyclic Peptides. J Med Chem, 65 (15): 10655-10673. [PMID:35904556]

13. Zeng C, Huang W, Li Y, Weng H. (2020) Roles of METTL3 in cancer: mechanisms and therapeutic targeting. J Hematol Oncol, 13 (1): 117. [PMID:32854717]

How to cite this family page

Database page citation:

2.1.1.- Methyltransferases. Accessed on 16/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=843.

Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Fabbro D, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: Enzymes. Br J Pharmacol. 180 Suppl 2:S289-373.