Arginine methyltransferases

Protein phosphatase 2C Protein arginine methyltransferase Protein arginine methyltransferase Arylalkylamine N-acetyltransferase SARS Cov 3C-like protease AHAS... 

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... 

Lysine methyltransferases have a well-established role in cancer whereas the arginine methyltransferases role is relatively less explored. Inspite of that there... 

Amur SG, Shanker G, Cochran JM, Ved HS, Pieringer RA (1986) Correlation between inhibition of myelin basic protein (arginine) methyltransferase by sinefungin and lack of compact myelin formation in cultures of cerebral cells from embryonic mice. J Neurosci Res 16 367-376 An W, Kim J, Roeder RG (2004) Ordered cooperative functions of PRMTl, p300, and CARMl in transcriptional activation by p53. Celll 17 735-748... 

Cheng D, Yadav N, King RW, Swanson MS, Weinstein EJ, Bedford MT (2004) Small molecule regulators of protein arginine methyltransferases. J Biol Chem 279 23892—23899... 

Co vie M, Hassa PO, Saccani S, Buerki C, Meier Nl, Lombardi C, Imhof R, Bedford MT, Natoli G, Hottiger MO (2005) Arginine methyltransferase CARMl is a promoter-specific regulator of NF-kappaB-dependent gene expression. EMBO J 24 85-96... 

Lee, J.H., Cook, J.R. and Pesfka, S. (2007) Protein arginine methyltransferases Evolution and assessment of then-pharmacological and therapeutic potential. Pharmacology ej Therapeutics, 113 (1), 50-87. 

Zhang, X. and Cheng, X. (2003) Structure of the Predominant Protein Arginine Methyltransferase PRMTl and Analysis of Its Binding to Substrate Peptides. Structure (Camb), 11 (5), 509-520. 

Zhang, X., Zhou, L. and Cheng, X. (2000) Crystal structure of the conserved core of protein arginine methyltransferase PRMT3. The EM BO Journal, 19 (14), 3509-3519. 

Troffer-Charlier, N., Cura, V., Hassenboehler, P., Moras, D. and Cavarelli, J. (2007) Functional insights from structures of coactivator-assodated arginine methyltransferase 1 domains. The EMBO Journal, 26 (20), 4391 401. 

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. 

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. 

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). 

A coupled enyzmatic assay makes use of S-adenosylhomocysteine hydrolase (SAHH) which hydrolyzes the methyltransfer product SAH to homocysteine and adenosine. The homocysteine concentration can be determined by conjugation of its free sulfhydryl moiety to a thiol-sensitive fluorophore [61]. This could of course also be used for arginine methyltransferases. 

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... 

Table 12.1 Selected arginine methyltransferases and links to disease.

So far nine arginine methyltransferases [46] and more than 20 lysine methyltransferases [11] have been identified in humans. Many of them show links to cancer. We discuss several of these subtypes below and an overview can be found in Tables 12.1 and 12.2. For lysine methyltransferases traditionally individual names have been used for the various subtypes. Lately, a common nomenclature for chromatin modifying enzymes has been proposed. For the human lysine methyltransferases the name KMTs should be used in analogy to (P)RMTs and eight groups (KMTl-8) with different subtypes suggested for some members [47]. But this nomenclature is not used consistently even throughout the recent literature so we provide both names if available in Table 12.2. 

---