| Structural highlights
Function
ANM5_HUMAN Arginine methyltransferase that can both catalyze the formation of omega-N monomethylarginine (MMA) and symmetrical dimethylarginine (sDMA), with a preference for the formation of MMA. Specifically mediates the symmetrical dimethylation of arginine residues in the small nuclear ribonucleoproteins Sm D1 (SNRPD1) and Sm D3 (SNRPD3); such methylation being required for the assembly and biogenesis of snRNP core particles. Methylates SUPT5H. Mono- and dimethylates arginine residues of myelin basic protein (MBP) in vitro. Plays a role in the assembly of snRNP core particles. May play a role in cytokine-activated transduction pathways. Negatively regulates cyclin E1 promoter activity and cellular proliferation. May regulate the SUPT5H transcriptional elongation properties. May be part of a pathway that is connected to a chloride current, possibly through cytoskeletal rearrangement. Methylates histone H2A and H4 'Arg-3' during germ cell development. Methylates histone H3 'Arg-8', which may repress transcription. Methylates the Piwi proteins (PIWIL1, PIWIL2 and PIWIL4), methylation of Piwi proteins being required for the interaction with Tudor domain-containing proteins and subsequent localization to the meiotic nuage. Methylates RPS10. Attenuates EGF signaling through the MAPK1/MAPK3 pathway acting at 2 levels. First, monomethylates EGFR; this enhances EGFR 'Tyr-1197' phosphorylation and PTPN6 recruitment, eventually leading to reduced SOS1 phosphorylation. Second, methylates RAF1 and probably BRAF, hence destabilizing these 2 signaling proteins and reducing their catalytic activity. Required for induction of E-selectin and VCAM-1, on the endothelial cells surface at sites of inflammation. Methylates HOXA9. Methylates and regulates SRGAP2 which is involved in cell migration and differentiation. Acts as a transcriptional corepressor in CRY1-mediated repression of the core circadian component PER1 by regulating the H4R3 dimethylation at the PER1 promoter.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]
Publication Abstract from PubMed
It has been shown that PRMT5 inhibition by small molecules can selectively kill cancer cells with homozygous deletion of the MTAP gene if the inhibitors can leverage the consequence of MTAP deletion, namely, accumulation of the MTAP substrate MTA. Herein, we describe the discovery of TNG908, a potent inhibitor that binds the PRMT5.MTA complex, leading to 15-fold-selective killing of MTAP-deleted (MTAP-null) cells compared to MTAPintact (MTAP WT) cells. TNG908 shows selective antitumor activity when dosed orally in mouse xenograft models, and its physicochemical properties are amenable for crossing the blood-brain barrier (BBB), supporting clinical study for the treatment of both CNS and non-CNS tumors with MTAP loss.
Discovery of TNG908: A Selective, Brain Penetrant, MTA-Cooperative PRMT5 Inhibitor That Is Synthetically Lethal with MTAP-Deleted Cancers.,Cottrell KM, Briggs KJ, Whittington DA, Jahic H, Ali JA, Davis CB, Gong S, Gotur D, Gu L, McCarren P, Tonini MR, Tsai A, Wilker EW, Yuan H, Zhang M, Zhang W, Huang A, Maxwell JP J Med Chem. 2024 Apr 25;67(8):6064-6080. doi: 10.1021/acs.jmedchem.4c00133. Epub , 2024 Apr 10. PMID:38595098[12]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Pollack BP, Kotenko SV, He W, Izotova LS, Barnoski BL, Pestka S. The human homologue of the yeast proteins Skb1 and Hsl7p interacts with Jak kinases and contains protein methyltransferase activity. J Biol Chem. 1999 Oct 29;274(44):31531-42. PMID:10531356
- ↑ Rho J, Choi S, Seong YR, Cho WK, Kim SH, Im DS. Prmt5, which forms distinct homo-oligomers, is a member of the protein-arginine methyltransferase family. J Biol Chem. 2001 Apr 6;276(14):11393-401. Epub 2001 Jan 10. PMID:11152681 doi:http://dx.doi.org/10.1074/jbc.M008660200
- ↑ Meister G, Eggert C, Buhler D, Brahms H, Kambach C, Fischer U. Methylation of Sm proteins by a complex containing PRMT5 and the putative U snRNP assembly factor pICln. Curr Biol. 2001 Dec 11;11(24):1990-4. PMID:11747828
- ↑ Meister G, Fischer U. Assisted RNP assembly: SMN and PRMT5 complexes cooperate in the formation of spliceosomal UsnRNPs. EMBO J. 2002 Nov 1;21(21):5853-63. PMID:12411503
- ↑ Jiang W, Roemer ME, Newsham IF. The tumor suppressor DAL-1/4.1B modulates protein arginine N-methyltransferase 5 activity in a substrate-specific manner. Biochem Biophys Res Commun. 2005 Apr 8;329(2):522-30. PMID:15737618 doi:http://dx.doi.org/10.1016/j.bbrc.2005.01.153
- ↑ Gonsalvez GB, Tian L, Ospina JK, Boisvert FM, Lamond AI, Matera AG. Two distinct arginine methyltransferases are required for biogenesis of Sm-class ribonucleoproteins. J Cell Biol. 2007 Aug 27;178(5):733-40. Epub 2007 Aug 20. PMID:17709427 doi:http://dx.doi.org/jcb.200702147
- ↑ Ren J, Wang Y, Liang Y, Zhang Y, Bao S, Xu Z. Methylation of ribosomal protein S10 by protein-arginine methyltransferase 5 regulates ribosome biogenesis. J Biol Chem. 2010 Apr 23;285(17):12695-705. doi: 10.1074/jbc.M110.103911. Epub, 2010 Feb 16. PMID:20159986 doi:http://dx.doi.org/10.1074/jbc.M110.103911
- ↑ Guo S, Bao S. srGAP2 arginine methylation regulates cell migration and cell spreading through promoting dimerization. J Biol Chem. 2010 Nov 5;285(45):35133-41. doi: 10.1074/jbc.M110.153429. Epub 2010, Sep 1. PMID:20810653 doi:10.1074/jbc.M110.153429
- ↑ Hsu JM, Chen CT, Chou CK, Kuo HP, Li LY, Lin CY, Lee HJ, Wang YN, Liu M, Liao HW, Shi B, Lai CC, Bedford MT, Tsai CH, Hung MC. Crosstalk between Arg 1175 methylation and Tyr 1173 phosphorylation negatively modulates EGFR-mediated ERK activation. Nat Cell Biol. 2011 Feb;13(2):174-81. doi: 10.1038/ncb2158. Epub 2011 Jan 23. PMID:21258366 doi:10.1038/ncb2158
- ↑ Andreu-Perez P, Esteve-Puig R, de Torre-Minguela C, Lopez-Fauqued M, Bech-Serra JJ, Tenbaum S, Garcia-Trevijano ER, Canals F, Merlino G, Avila MA, Recio JA. Protein arginine methyltransferase 5 regulates ERK1/2 signal transduction amplitude and cell fate through CRAF. Sci Signal. 2011 Sep 13;4(190):ra58. doi: 10.1126/scisignal.2001936. PMID:21917714 doi:http://dx.doi.org/10.1126/scisignal.2001936
- ↑ Bandyopadhyay S, Harris DP, Adams GN, Lause GE, McHugh A, Tillmaand EG, Money A, Willard B, Fox PL, Dicorleto PE. HOXA9 methylation by PRMT5 is essential for endothelial cell expression of leukocyte adhesion molecules. Mol Cell Biol. 2012 Apr;32(7):1202-13. doi: 10.1128/MCB.05977-11. Epub 2012 Jan, 23. PMID:22269951 doi:http://dx.doi.org/10.1128/MCB.05977-11
- ↑ Cottrell KM, Briggs KJ, Whittington DA, Jahic H, Ali JA, Davis CB, Gong S, Gotur D, Gu L, McCarren P, Tonini MR, Tsai A, Wilker EW, Yuan H, Zhang M, Zhang W, Huang A, Maxwell JP. Discovery of TNG908: A Selective, Brain Penetrant, MTA-Cooperative PRMT5 Inhibitor That Is Synthetically Lethal with MTAP-Deleted Cancers. J Med Chem. 2024 Apr 25;67(8):6064-6080. PMID:38595098 doi:10.1021/acs.jmedchem.4c00133
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