Methionine turnover

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Methionine turnover

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

3341

Targets of relevance to immunopharmacology are highlighted in blue

5-methyltetrahydrofolate-homocysteine methyltransferase Show summary »« Hide summary More detailed page go icon to follow link

Target Id

3099

Nomenclature

5-methyltetrahydrofolate-homocysteine methyltransferase

Previous and unofficial names

cblG | cobalamin-dependent methionine synthase | vitamin-B12 dependent methionine synthase

Genes

MTR (Hs), Mtr (Mm), Mtr (Rn)

Ensembl ID

ENSG00000116984 (Hs), ENSMUSG00000021311 (Mm), ENSRNOG00000017593 (Rn)

UniProtKB AC

Q99707 (Hs), A6H5Y3 (Mm), Q9Z2Q4 (Rn)

EC number

2.1.1.13

5-methyltetrahydrofolate + L-homocysteine <=> tetrahydrofolate + L-methionine

methionine adenosyltransferase 2A Show summary »« Hide summary

Target Id

3341

Nomenclature

methionine adenosyltransferase 2A

Previous and unofficial names

methionine adenosyltransferase II, alpha (MAT-II) | S-adenosylmethionine synthase isoform type-2 (SAMS2) | AdoMet synthetase

Genes

MAT2A (Hs), Mat2a (Mm), Mat2a (Rn)

Ensembl ID

ENSG00000168906 (Hs), ENSMUSG00000053907 (Mm), ENSRNOG00000013520 (Rn)

UniProtKB AC

P31153 (Hs), Q3THS6 (Mm), P18298 (Rn)

EC number

2.5.1.6

L-methionine + ATP + H₂O = S-adenosyl-L-methionine + phosphate + diphosphate

Inhibitors

ZS34 pIC₅₀ 7.9 [9]

IDE397 pIC₅₀ >6.7 [1]

Allosteric modulators

SCR‐7952 (Inhibition) pK_i 7.8 [11]

SCR‐7952 (Inhibition) pIC₅₀ 7.7 [11]

compound 28 [PMID: 33900758] (Inhibition) pIC₅₀ 7.7 [2]

AG-270 (Inhibition) pIC₅₀ 7.8 [4], 7.2 [11]

Comment

Catalyzes the synthesis of S-adenosylmethionine (SAMe/AdoMet) that is an essential methyl donor for DNA, proteins, and phospholipids.
In cancer cells deficient in methylthioadenosine phosphorylase (MTAP), MAT2A activity becomes crucial for SAM production and cell survival processes. This has led to the proposal of MAT2A as a synthetic lethal target for the development of drugs against MTAP-deficient cancers [3-9]. A few inhibitors are listed here. Clinical development of AG-270 (as the first-in-class, oral MAT2A inhibitor) was stopped in 2022. In early 2026 Gilead announced a deal with Suzhou Genhouse Bio to develop their MAT2A candidate GH31 (likely one of the compounds claimed in patent US20240391923 [10]).

References

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1. Alam F, Cleary L, Fleury M, Pei Z, Steel R, Sutton J, Knox JE, Newby ZER. (2021) 2-oxoquinazoline derivatives as methionine adenosyltransferase 2A inhibitors. Patent number: US11046691B1. Assignee: Ideaya Biosciences Inc. Priority date: 12/02/2021. Publication date: 29/06/2021.

2. De Fusco C, Schimpl M, Börjesson U, Cheung T, Collie I, Evans L, Narasimhan P, Stubbs C, Vazquez-Chantada M, Wagner DJ et al.. (2021) Fragment-Based Design of a Potent MAT2a Inhibitor and in Vivo Evaluation in an MTAP Null Xenograft Model. J Med Chem, 64 (10): 6814-6826. [PMID:33900758]

3. Guo J, Yang Y, Buettner R, Rosen ST. (2022) Targeting the methionine-methionine adenosyl transferase 2A- S -adenosyl methionine axis for cancer therapy. Curr Opin Oncol, 34 (5): 546-551. [PMID:35788128]

4. Konteatis Z, Travins J, Gross S, Marjon K, Barnett A, Mandley E, Nicolay B, Nagaraja R, Chen Y, Sun Y et al.. (2021) Discovery of AG-270, a First-in-Class Oral MAT2A Inhibitor for the Treatment of Tumors with Homozygous MTAP Deletion. J Med Chem, 64 (8): 4430-4449. [PMID:33829783]

5. Li C, Gui G, Zhang L, Qin A, Zhou C, Zha X. (2022) Overview of Methionine Adenosyltransferase 2A (MAT2A) as an Anticancer Target: Structure, Function, and Inhibitors. J Med Chem, 65 (14): 9531-9547. [PMID:35796517]

6. Marjon K, Cameron MJ, Quang P, Clasquin MF, Mandley E, Kunii K, McVay M, Choe S, Kernytsky A, Gross S et al.. (2016) MTAP Deletions in Cancer Create Vulnerability to Targeting of the MAT2A/PRMT5/RIOK1 Axis. Cell Rep, 15 (3): 574-587. [PMID:27068473]

7. Mavrakis KJ, McDonald 3rd ER, Schlabach MR, Billy E, Hoffman GR, deWeck A, Ruddy DA, Venkatesan K, Yu J, McAllister G et al.. (2016) Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5. Science, 351 (6278): 1208-13. [PMID:26912361]

8. Rodon J, Johnson ML, George B, Shah PA, Arbour KC. (2026) MTAP Deletion in Oncogenesis: A Synthetic Lethality Scenario. Cancer Res, [Epub ahead of print]. [PMID:41512197]

9. Shi Z, Lin K, Lin L, Chen Z, Xie Z, Sun Y, Cui R, Zhang S, Zheng M, Xu S. (2025) Furo[2,3-f]quinazolin-7(6H)-one Derivatives as Potent, Selective, and Orally Bioavailable MAT2A Inhibitors for MTAP-Deficient Cancer Therapy. J Med Chem, 68 (22): 24213-24231. [PMID:41247922]

10. Wang K, Zhang G, Li J, Faridoon, Zheng J, Tong C, Zhang W, Zhang T, Shen Y. (2024) Methionine adenosyltransferase 2a inhibitor for treating mtap deletion-type cancer. Patent number: US20240391923A1. Assignee: Suzhou Genhouse Bio Co Ltd. Priority date: 25/07/2024. Publication date: 28/11/2024.

11. Yu Z, Kuang Y, Xue L, Ma X, Li T, Yuan L, Li M, Xue G, Li Z, Tang F et al.. (2024) SCR-7952, a highly selective MAT2A inhibitor, demonstrates synergistic antitumor activities in combination with the S-adenosylmethionine-competitive or the methylthioadenosine-cooperative protein arginine methyltransferase 5 inhibitors in methylthioadenosine phosphorylase-deleted tumors. MedComm (2020), 5 (10): e705. [PMID:39309689]

How to cite this family page

Database page citation:

Methionine turnover. Accessed on 12/03/2026. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1027.

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.