Histone arginine methyltransferase

Spannhoff A., Heinke, R., Bauer, 1., Trojer, P., Meteger, E., Gust, R. etal. (2007) Target-based approach to inhibitors of histone arginine methyltransferases. Journal of Medicinal Chemistry, 50, 2319-2325. 

Virtual Screening and Biological Characterisation of Novel Histone Arginine Methyltransferase PRMTl Inhibitors. 3 (in press). 

Jung et al. applied this approach to develop inhibitors for a histone modifying enzyme - the histone arginine methyltransferase PRMTl.An identical PRMTl inhibitor with cellular activity was obtained which blocks both the cofactor S-adenosylmethionine (SAM) and the substrate... 

Structure-Based VS for Histone Arginine Methyltransferase PRMT1 Inhibitors... 

Heinke, R., Spannhoff, A., Meier, R., Trojer, P., Bauer, I., Jung, M., and Sippl, W. (2009) Virtual screening and biological characterization of novel histone arginine methyltransferase PRMTl inhibitors. ChemMedChem, 4, 69—77. 

Schurter BT, Koh SS, Chen D, Bunick GJ, Harp JM, Hanson BL, Henschen-Edman A, Mackay DR, Stallcup MR, Aswad DW (2001) Methylation of histone H3 by coactivator-associated arginine methyltransferase 1. Biochemistry 40 5747—5756... 

Histone-lysine methyltransferases are chromatin-bound enzymes that catalyses the addition of methyl groups onto lysine or arginine residues of chromatin-bound H3 and H4 [151]. The methyl group is transferred enzymatically to the histone with S-adenosyl methionine as the methyl donor. Histone methylases have been isolated from HeLa S-3 cells [182], chick embryo nuclei [183], and rat brain chromatin [184]. The histone methyltransferases methylated H3 and H4 in nucleosomes [184]. Histone-lysine methyltransferase is a chromatin-bound enzyme [129,151]. Initial characterization of the Tetrahymena macronuclear H3 methyltransferase suggests that the enzyme has a molecular mass of 400 kDa. The enzyme preferred free histones rather than nucleosomes as substrate [138]. More recent studies have now... 

During the past several years, a variety of crystal structures of histone lysine and arginine methyltransferase in complex with the cofactor analog SAH and/or in complex with peptide substrates have been reported [92]. However, no 3D structure of a complex between a histone methyltransferase (HMT) and an inhibitor has been reported so far. Due to the lack of experimental structures, a variety of molecular modeling and docking studies has been carried out for H MTs in order to understand the structural requirements for inhibitor binding. 

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). 

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. 

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