PRMTs 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). 

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... 

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

PRMT Protein Arg(R) methyltransferase, catalyzes the transfer of methyl group from S-adenosylmethionine to the... 

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. 

Like the SET domain containing methyltransferases, PRMTs require AdoMet as a cofactor and methyl group donor. The PRMTs identified so far exist as members of multisubunit complexes, the formation of which is critical for in vivo methyltransferase activity (Teyssier et al., 2002). Many of the arginine methyltransferases also form homo-dimers or homooligomers, a step that is required for their catalytic activity (Weiss et al., 2000). This need to oligomerize has not been demonstrated for any known lysine methyltransferases. 

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. 

Fig. 7. Sequence alignment of known protein arginine methyltransferases (PRMTs). Sequences essential for AdoMet and substrate binding are indicated by blue and red bars. (See Color Insert.)...

Also contained in the, 3-barrel structure of many PRMTs is a helix-turn-helix antenna motif that is involved in the formation of PRMT homodimers or homo-oligomers (Weiss et al., 2000). This dimerization usually occurs via hydrophobic contacts between the helix-turn-helix motif of one monomer and the N-terminal SAM binding domain of another (Weiss et al., 2000 Zhang et al, 2000). Several PRMTs have been shown to form either dimers or oligomers through this interaction, a process that is essential to their methyltransferase activity (Teyssier et al, 2002). 

Kleinschmidt MA, de Graaf P, van Teeffelen HA, Timmers HT. Cell cycle regulation by the PRMT 6 arginine methyltransferase through repression of cyclin-dependent kinase inhibitors. PLoS One. 2012 55 7978-87. 

Arginine methylation is catalysed by protein arginine methyltransferases (PRMTs, EC number 2.1.1.125), and thus far eight human PRMTs have been identified, with several more putative enzymes predicted. Two subclasses of PRMTs exist Class I PRMTs catalyse asymmetric dimethylation, while Class II PRMTs catalyse symmetric dimethylation of arginine. All three methyl-transferase subfamilies (SET-domain KMTs, DOTIL and PRMTs) utilise S-adenosylmethionine as an electrophilic methyl source. 

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