111109-98-9Relevant academic research and scientific papers
Structure-guided design of a methyl donor cofactor that controls a viral histone H3 lysine 27 methyltransferase activity
Li, Jiaojie,Wei, Hua,Zhou, Ming-Ming
, p. 7734 - 7738 (2012/01/13)
vSET (a viral SET domain protein) is an attractive polycomb repressive complex 2 (PRC2) surrogate to study the effect of histone H3 lysine 27 (H3K27) methylation on gene transcription, as both catalyze histone H3K27 trimethylation. To control the enzymatic activity of vSET in vivo with an engineered S-adenosyl-l-methionine (SAM) analogue as methyl donor cofactor, we have carried out structure-guided design, synthesis, and characterization of orthogonal vSET methyltransferase mutant/SAM analogue pairs using a "bump-and-hole" strategy.
Design of allele-specific protein methyltransferase inhibitors
Lin,Jiang,Schultz,Gray
, p. 11608 - 11613 (2007/10/03)
Protein arginine methyltransferases, which catalyze the transfer of methyl groups from S-adenosylmethionine (SAM) to arginine side chains in target proteins, regulate transcription, RNA processing, and receptor-mediated signaling. To specifically address the functional role of the individual members of this family, we took a "bump-and-hole" approach and designed a series of N6-substituted S-adenosylhomocysteine (SAH) analogues that are targeted toward a yeast protein methyltransferase RMT1. A point mutation was identified (E117G) in Rmt1 that renders the enzyme susceptible to selective inhibition by the SAH analogues. A mass spectrometry based enzymatic assay revealed that two compounds, N6-benzyl- and N6-naphthylmethyl-SAH, can inhibit the mutant enzyme over the wild-type with the selectivity greater than 20. When the E117G mutation was introduced into the Saccharomyces cerevisiae chromosome, the methylation of Np13p, a known in vivo Rmt1 substrate, could be moderately reduced by N6-naphthylmethyl-SAH in the resulting allele. In addition, an N6-benzyl-SAM analogue was found to serve as an orthogonal SAM cofactor. This analogue is preferentially utilized by the mutant methyltransferase relative to the wild-type enzyme with a selectivity greater than 67. This specific enzyme/inhibitor and enzyme/substrate design should be applicable to other members of this protein family and facilitate the characterization of protein methyltransferase function in vivo when combined with RNA expression analysis.
N6,5'-disubstituted adenosine derivatives as partial agonists for the human adenosine A3 receptor
Van Tilburg, Erica W.,Von Frijtag Drabbe Künzel, Jacobien,De Groote, Miriam,Vollinga, Roel C.,Lorenzen, Anna,IJzerman, Ad P.
, p. 1393 - 1400 (2007/10/03)
5'-(Alkylthio)-substituted analogues of N6-benzyl- and N6-(3- iodobenzyl)adenosine were synthesized in 37-61% overall yields. The affinities of these compounds for the adenosine A1, A(2A), and A3 receptors were determined using rat brain cortex, rat brain striata, and stably transfected human A3 receptors in HEK 293 cells, respectively. The compounds proved to be selective for the adenosine A3 receptor and displayed affinities in the nanomolar range. Compounds 8, 10, and 11 had the highest affinities for the A3 receptor with K(i) values ranging from 8.8 to 27.7 nM. In the N6-benzyl series, compound 4 (LUF 5403), with a 5'-methylthio group, maintained a reasonable affinity and had the highest selectivity for the A3 receptor. Compound 12 (LUF 5411), with an N6-(3-iodobenzyl) group and a 5'- (n-propylthio) substituent, had the highest A3 selectivity of all of the compounds and also displayed high affinity for this receptor (K(i) = 44.3 nM). The compounds were also evaluated for their ability to stimulate [35S]GTPγ[S] binding in cell membranes expressing the human adenosine A3 receptor. It appeared that the N6,5'-disubstituted adenosine derivatives behaved as partial agonists. Compounds 2, 4, 8, and 10 had the highest intrinsic activities. Additionally, when tested in a cAMP assay, these compounds also behaved as partial agonists.
