1197020-22-6Relevant articles and documents
Strategy for "Detoxification" of a cancer-derived histone mutant based on mapping its interaction with the methyltransferase PRC2
Brown, Zachary Z.,Müller, Manuel M.,Jain, Siddhant U.,Allis, C. David,Lewis, Peter W.,Muir, Tom W.
, p. 13498 - 13501 (2014)
The histone methyltransferase PRC2 plays a central role in genomic stability and cellular development. Consequently, its misregulation has been implicated in several cancers. Recent work has shown that a histone H3 mutant, where the PRC2 substrate residue Lys27 is replaced by methionine, is also associated with cancer phenotypes and functions as an inhibitor of PRC2. Here we investigate the mechanism of this PRC2 inhibition through kinetic studies and photo-cross-linking. Efficient inhibition is dependent on (1) hydrophobic lysine isosteres blocking the active site, (2) proximal residues, and (3) the H3 tail forming extensive contacts with the EZH2 subunit of PRC2. We further show that naturally occurring post-translational modifications of the same H3 tail, both proximal and distal to K27M, can greatly diminish the inhibition of PRC2. These results suggest that this potent gain of function mutation may be "detoxified by modulating alternate chromatin modification pathways.
AMINO ACID ANALOGUES AND METHODS FOR THEIR SYNTHESIS
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Page/Page column 48; 50, (2014/01/18)
A method for the synthesis of an amino acid analogue or a salt, solvate, derivative, isomer or tautomer thereof comprising the steps of: (i) subjecting an amino acid containing a metathesisable group to metathesis with a compound containing a complementary metathesisable group of formula (I) or (II): (Formulae (I), (II)) wherein R1 and R2 are independently selected from H and substituted or unsubstituted C1 to C4 alkyl; each R3 is either absent or independently selected from a heteroatom, a substituted or unsubstituted C1 to C20 alkyl, and a substituted or unsubstituted C1 to C20 alkyl group interrupted by one or more heteroatoms; and each X is independently selected from H and an effector molecule; in the presence of a reagent to catalyse the metathesis to form a dicarba bridge between the amino acid containing a metathesisable group and the compound containing a complementary metathesisable group; and (ii) reducing the dicarba bridge to form a saturated dicarba bridge, wherein the reagent used to catalyse step (i) also catalyses step (ii).
Total synthesis of cyclocitropside A and its conversion to cyclocitropsides B and C via asparagine deamidation
Thompson, Robert E.,Payne, Richard J.,Jolliffe, Katrina A.
supporting information, p. 5110 - 5113 (2013/01/15)
The total syntheses of three closely related cyclic peptide natural products, cyclocitropsides A-C, are described. Cyclocitropside A could be readily converted into cyclocitropsides B and C through an asparagine deamidation pathway, indicating that this is a plausible biosynthetic route to these compounds.
