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

3205

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 27/04/2024. 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.