Histone proteins arginine methyltransferases

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). 

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). 

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. 

The identities of several protein arginine methyltransferases are now known, but only a few have been shown to have specificity for histone proteins. The mammalian PRMT1, JBP1, and CARMI, as well as the Saccharomyces Rmtl, have histone methyltransferase activity (McBride and Silver, 2001). However, the catalytic mechanism for the methyl group transfer as well as the makeup of the active sites of PRMTs differ somewhat from SET domain proteins. 

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... 

Histone deacetylases (HDACs), histone acetyltransferases (HMTs), histone demethylases (HDMTs), protein arginine methyltransterases (PRMTs), histone arginine demethylases (HADs), and DNA methyltransferases (DNMTs). 

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. 

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