The Human Protein Methyltransferases
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The human protein methyltransferases Methyltransferases are enzymes that facilitate the transfer of a methyl (–CH3) group to of methyl ‘marks’ as regulators of gene expression. Human protein methyltransferases specific nucleophilic sites on proteins, nucleic acids or other biomolecules. They share (PMTs) fall into two major families—protein lysine methyltransferases (PKMTs) and a reaction mechanism in which the nucleophilic acceptor site attacks the electrophilic protein arginine methyltransferases (PRMTs)—that are distinguishable by the amino carbon of S-adenosyl-L-methionine (SAM) in an SN2 displacement reaction that pro- acid that accepts the methyl group and by the conserved sequences of their respective duces a methylated biomolecule and S-adenosyl-L-homocysteine (SAH) as a byprod- catalytic domains. Given their involvement in many cellular processes, PMTs have at- Supplement to Nature Publishing Group Journals uct. Methylation reactions are essential transformations in small-molecule metabolism, tracted attention as potential drug targets, spurring the search for small-molecule PMT and methylation is a common modification of DNA and RNA. The recent discovery of inhibitors. Several classes of inhibitors have been identified, but new specific chemi- dynamic and reversible methylation of amino acid side chains of chromatin proteins, cal probes that are active in cells will be required to elucidate the biological roles of particularly within the N-terminal tail of histone proteins, has revealed the importance PMTs and serve as potent leads for PMT-focused drug development. Protein arginine methyltransferases (PRMTs) Protein lysine methyltransferases (PKMTs) H CH3 CH3 H3C H C CH3 H The phylogenetic tree shows 51 genes predicted to encode PKMTs, which are positioned H H H H H 3 The human PRMT phylogenetic tree comprises 45 predicted enzymes including the PKMT H N H N H N H H3C N H H3C N H 1 N H N CH3 N CH3 CH3 1 N in the tree on the basis of the similarities of their amino acid sequences . This tree ex- DOT1L . There are two major types of PRMT; both catalyze the formation of monomethylarginine N N N HN H PKMT PKMT PKMT PRMT HN H PRMT HN H HN cludes one validated PKMT, DOT1L, which lacks a SET domain—the catalytic domain (Rme1) but distinct reaction mechanisms yield symmetric (Rme2s) or asymmetric (Rme2a) OR CH3 conserved in this family—and clusters more closely with the PRMTs. The tree has four SAM SAH SAM SAH SAM SAH dimethylarginine. A small number of predicted PRMTs have validated activity (highlighted in SAM SAH SAM SAH major branches, and each branch contains enzymes with validated methyltransferase ac- H blue). In addition to PRMTs, this tree includes validated RNA methyltransferases (highlighted in H N N tivity (highlighted in red). Some PKMTs add a single methyl group, resulting in a mono- H green) and biosynthetic enzymes (highlighted in violet). It remains uncertain whether these latter H O O methylated product (Kme), whereas others produce di- (Kme2) or trimethylated (Kme3) Lysine (K) Kme1 Kme2 Kme3 enzymes have PRMT activity, despite their shared structural features. Substrates for the enzymes Arginine (R) Rme1 Rme2a Rme2s lysine modifications. Many of the validated PKMTs methylate lysines on histones, though shown include RNA, metabolites, histones and RNA-binding and spliceosomal proteins. nonhistone substrates have also been identified. O Cl O O H HN N N N Cl H METTL11A SUV420H1 N HO MLL4 SUV420H2 MLL NH METTL11B SMYD1 OMe N AZ505 ref. 5 SETD1B SMYD5 N N OMe METTL13 SMYD3 N SETD3 SETD1A ECE2 COQ3 SETD4 SMYD2 O O ALKBH8 EZH2 H EZH1 BIX-01294 ref. 7 S N N S H SMYD4 O O SETD6 METTL12 WBSCR22 PRMT7 METTL7B SETD7 MLL2 O H METTL7A HO H N ref. 10 N O PRMT10 WBSCR27 MLL3 S METTL20 N S S N AS3MT SETD8 S N NH2 O N COQ5 H2N H OH METTL10 N DOT1L O N H O PRMT6 N NH HO2C N PRMT2 PRMT5 C20orf7 HO OH NH Chaetocin ref. 15 PRMT3 ref. 6 PRMT1 CARM1 MeO PRDM5 SUV39H1 PRMT8 N HN N HO2C O N PRDM3 S O N O NH N SUV39H2 O H2N H NH NH2 H2N N HN HO OH PRDM16 HN I N N EHMT1 N CF O PRDM2 3 N N IBAO ref. 13 EHMT2 F C N 3 S ref. 11 HO OH PRDM1 SETMAR N O SETDB1 N EPZ004777 ref. 4 N N PRDM11 Q6ZW69 H SETDB2 N N NH2 ASMT PRDM14 NH O PRDM7 OMe PRDM12 N ref. 12 PRDM6 N N O N PRDM9 PRDM4 N ASH1L METTL2A METTL6 PRDM8 PRDM15 SETD2 UNC-0224 ref. 8 MLL5 METTL8 METTL2B PRDM13 PRDM10 PRMT9 NOP2 SETD5 NSUN7 PRMT11 NSUN5B N NSUN5C NH O NNMT OMe NSD1 N PNMT N O N HO N OH INMT Br Br WHSC1L1 UNC-0638 ref. 9 NSUN4 NSUN5 ref. 14 NSUN3 NSUN2 NSUN6 WHSC1 • A selection of small-molecule PMT inhibitors • DOT1L is a validated therapeutic target for mixed-lineage leukemia4. The major- • Priority therapeutic targets also • Additional PMTs • Elucidation of the biological function of PMTs would be facilitated by the development • Understanding the mechanisms Targeting with some target selectivity is shown (minimally ity of these leukemias result from chromosomal rearrangements that cause aber- include MLL for leukemias; SETD1B have been implicated of selective chemical probes; this is a compelling area for future chemical biology studies, that govern substrate specificity, validated in quantitative in vitro assays) around the rant recruitment of DOT1L to MLL-fusion target genes. Inhibition of DOT1L with and CARM1 for neurodegeneration; in human diseases and given the paucity of available tool compounds, many of which remain to be validated in especially for nonhistone targets, trees along with the name of the molecule, citation EPZ004777 demonstrated that these leukemia cells are addicted to DOT1L activity as well as EZH2, SMYD3 and EHMTs may yet emerge as cells. In particular, the emergence of these enzyme families as therapeutic targets suggests merits additional study. PMTs 2,3 information and the chemical structure . and established proof of concept for DOT1L inhibition as a therapeutic option. for multiple cancers. therapeutic targets. that such chemical probes could yield lead compounds for drug development. Epizyme is leading the discovery and development of small-molecule protein methyltransferase (PMT) Sponsor contacts Substrates and products References Poster content Robert A. Copeland and Victoria Richon are at Epizyme, 325 Vassar Street, inhibitors, a new class of personally targeted therapeutics for the treatment of genetically defined can- 1. Richon, V.M. et al. Chem. Biol. Drug. Disc. 78, 199–210 (2011). 8. Liu, F. et al. J. Med. Chem. 52, 7950–7953 (2009). Written and edited by Terry L. Sheppard and Amy Donner; Suite 2B, Cambridge, MA 02139, USA. Phone: (617) 229-5872 SAM, S-adenosyl-L-methionine SAH, S-adenosyl-L-homocysteine cer patients, on the basis of breakthroughs in the field of epigenetics. Epigenetic enzymes are strongly 2. Copeland, R.A., Solomon M.E. & Richon, V.M. Nat. Rev. Drug Discov. 8, 724–732 (2009). 9. Vedadi, M. et al. Nat. Chem. Biol. 7, 566–574 (2011). copyedited by Yasmin Tayag; art by Katie Vicari; Dr. Robert A. Copeland 3. Copeland, R.A. Drug Discov. Today: Therapeutic Strategies, published online 16 September 2011, 10. Spannhoff, A. et al. Biorg. Med. Chem. Lett. 17, 4150–4153 (2007). N N designed by Lewis Long. associated with the underlying causes of multiple human diseases. Our patient-driven approach to the NH2 NH2 doi: 10.1016/j.ddstr.2011.08.001. 11. Allan, M. et al. Bioorg. Med. Chem. Lett. 19, 1218–1223 (2009). Executive Vice President & Chief Scientific Officer H2N H H2N H N N 4. Daigle, S.R. et al. Cancer Cell 20, 53–65 (2011). 12. Huynh, T. et al. Biorg. Med. Chem. Lett. 19, 2924–2927 (2009). © 2011 Nature Publishing Group creation of personalized therapeutics represents the future of cancer therapy, creating better therapeu- [email protected] O N O N HO2C S HO2C S 5. Ferguson, A.D. et al. Structure 19, 1262–1273 (2011). 13. Yao, Y. et al. J. Am. Chem. Soc. 133, 16746–16749 (2011). Dr. Victoria Richon N N tics matched to the right patients more quickly and at lower cost than traditional approaches. Me 6. Mori, S. et al. Bioorg. Med. Chem. 18, 8158–8166 (2010). 14. Cheng, D. et al. J. Med. Chem. 54, 4928–4932 (2011). Available online at: www.epizyme.com Vice President, Biological Sciences HO OH HO OH 7. Kubicek, S. et al. Mol. Cell 25, 473–481 (2007). 15. Greiner, D. et al. Nat. Chem. Biol. 1, 143–145 (2005). http://www.nature.com/nchembio/poster/hpm.pdf [email protected].