Protein lysine methyltransferases

Yeates TO (2002) Structures of set domain proteins protein lysine methyltransferases make their mark. Cell 111 5-7... 

Figure 1 Covalent modifications of DNA and histones play a fundamental role in the regulation of differentiation and development. The writers, readers, and erasers of this dynamic code are potentially amenable to modulation with small molecules. Lysine methylation is a critical posttranslational modification influencing chromatin function (PMT = protein lysine methyltransferase, royal family proteins bind KMe, KDM = lysine demethylase).

Figure 2 Selected human protein lysine methyltransferases and their target sites on histones [11].

Qian, C. and Zhou, M.M. (2006) SET domain protein lysine methyltransferases Structure, specificity and catalysis. Cellular and Molecular Life Sciences, 63 (23), 2755-2763. 

Dillon, S.C., Zhang, X., Trievel, R.C. and Cheng, X. (2005) The SFT-domain protein superfamily protein lysine methyltransferases. Genome Biol(, 6 (8), 111. 

Rathert, P., Dhayalan, A., Murakami, M., Zhang, X., Tamas, R., Jurkowska, R., Komatsu, Y., Shinkai, Y, Cheng, X. and Jeltsch, A. (2008) Protein lysine methyltransferase G9a acts on non-histone targets. Nature Chemical Biology,... 

Protein lysine methyltransferases (PKMTs) are a family of enzymes that transfer the activated methyl group from S-adenosyl-L-methionine (SAM) to specific lysine residues on various substrates. The PKMTs have been causally linked to various human diseases including cancer [140], Huntington s disease [141], and growth defects [142, 143]. The substrates of the PKMTs are typically histones [144-146], but there are several methyltransferases methylate non-histone substrates, such as the tumor suppressor p53 [147, 148], the estrogen receptor ERa [149], and the ATPase Reptin [150]. Given the importance of these enzymes in normal and... 

Islam K, Zheng W, Yu H et al (2011) Expanding cofactor repertoire of protein lysine methyltransferase for substrate labeling. ACS Chem Biol 6(7) 679-684... 

Rathert P, Dhayalan A, Murakami M et al (2008) Protein lysine methyltransferase G9a acts on non-histone targets. Nat Chem Biol 4 344-346... 

Protein (lysine) Methyltransferase. The enzyme which methylates lysine residues of proteins was named protein methylase III by Paik and Kim (210). Its recommended trivial name is protein (lysine) methyltransferase (S-adenosyl-L-methionine protein-lysine methyltransferase EC 2.1.1.25). Protein (lysine) methyltransferase was found in all rat organs examined and was localized exclusively in the nuclei. Paik and Kim (210) solubilized the enzyme from an acetone powder of calf thymus and purified it 1.3-fold. The enzyme was difficult to work with in the solubilized state, since its activity was lost on overnight storage at either — 10° or 3°C. The enzyme was most effective in methylating histones, especially arginine-rich histone. Denaturation of histone by heating at 100°C for 30 min had no effect on the rate at which protein-lysine) methyltransferase methylated it. Poly lysine and protamine were methylated at slower rates, but horse heart cytochrome c did not serve as substrate. Km for S-adenosyl-L-methionine was 3.0 X 10"6M. 

Just as with protein (arginine) methyltransferase, it is likely that there are several protein (lysine) methyltransferases. Neurospora and wheat germ cytochrome cs contain only c-N-trimethyllysine (196), while pea embryo histone III and bovine retina opsin contain either c-N-mono-or c-N-dimethyllysine, but not c-N-trimethyllysine (211). Flagella protein from Salmonella serpens contains only c-N-monomethyllysine (212). 

There is a school of thought, which believes that HMTases are tumor suppressors especially the lysine methyltransferases because of the loss of SET domain proteins in tumor conditions, exceptions do exist like Ezh2. The well-known example of the above is RIZl, which interacts with Rb protein (again the same tumor suppressor). RIZ-1 is in chromosome lp36 region, which is commonly deleted, in more than a dozen different types of human cancers. Riz-1 expression is commonly silenced in many tumors including breast cancer, liver cancer, colon cancer, neuroblastoma, melanoma, lung cancer and osteosarcoma (Kim et al, 2003). 

Histone methylation by methyltransferases is another vddely described modification that also plays an important role in regulation of transcriptional activity. Methylation can occur either on arginine or on lysine residues in the N-termini of histones and therefore this group of enzymes can be separated into protein arginine methyltransferases (PRMTs) and lysine methyltransferases (KMTs). 

Lysine methyltransferases catalyze the transfer of methyl groups from the cosubstrate SAM to certain lysine residues in histone proteins. To characterize modulators of these transferases, the above-mentioned antibody-based assay protocols are also applicable. 

Histone methylation participates in the regulation of gene expression patterns. Unlike histone acetylation, histone methylation does not alter the charge of the amino acid and hence the histone tail. There are changes in the basicity and the hydrophobicity which are relatively small when viewed at the scale of the histone but still influence the affinity of the histone tails to certain proteins, for example transcription factors, which in turn result in certain signaling events. The histone methyltransferases are usually subdivided into three classes SET domain lysine methyltransfeases, nonSET domain lysine methyltransferases and arginine methyltransferases (PRMTs). All of them utilize S-adenosylmethionine (SAM) as cosubstrate for the methylation reaction... 

A number of proteins such as histones, cytochrome c and certain flagellar proteins are found to contain methylated amino acids (19). Three different methylases have been characterized and all require S-adenosylmethionine (SAM) as the methyl donor (20-23). Protein methylase I (SAM-protein arginine methyl transferase) methylates the guanidine side chain of arginine residue protein methylase II (SAM-protein carboxyl methyltransferase) transfers methyl groups only to 8- and y-carboxyl groups in the peptide chain. Carboxyl groups in the a position cannot serve as acceptors. Protein methylase III (SAM-protein lysine... 

The protein methylases which add methyl groups to lysine, arginine, and histidine residues of proteins may be too specific to have potential application in food protein modification. Protein O-methyltransferase appears to methylate the carboxyl groups of numerous proteins and could have broad enough specificity to be important for increasing the hydro-phobic properties of proteins through esterification of carboxyl groups. 

Similarly, histone arginine/lysine methylation can be the target for the development of therapeutics. The status of histone arginine methylation is intimately involved in gene transcription. Recently, several compounds were found to inhibit protein arginine methyltransferases (PRMTs) [54]. It can also be interesting to explore how this small molecule could be exploited for developing therapeutics. 

In humans, carnitine is either obtained from the diet or synthesised de novo (Fig. 1). Carnitine biosynthesis in higher eukaryotes starts when protein-bound L-lysine is trimethylated by a protein-dependent methyltransferase to form e-N-trimethyllysine. Upon degradation of these proteins, free e-N-trimethyllysine becomes available and is... 

---