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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Mechanism in Inhibition of Histone Deacetylase by CyclicTetrapeptides with Various Functional GroupsMd. Shahidul Islam 1 , Md. Nurul Islam 1 , Nsiama Tienabe 1 ,Naoto Oishi 1 , Tamaki Kato 1 , Norikazu Nishino 1 , Akihiro Ito 2 ,and Minoru Yoshida 21 Graduate School of Life Science and Systems Engineering, Kyushu Instituteof Technology, Wakamatsu, Kitakyushu, 808-0196, Japan; 2 RIKEN,Saitama, 351-0198, JapanIntroductionClass 1 and 2 histone deacetylases (HDACs) involve zinc atom at the active centre toemploy metalloprotease-like mechanism in cleavage of acetyl group. As natural inhibitorsof these HDAC enzymes, two different types of metabolites have been known. One groupincludes tricostatin A, which bears hydroxamic acid functional moiety at the end of themolecule. Cyclic tetrapeptides in another group have typically epoxyketone moiety as apart of quite unusual amino acid in the cyclic peptides. Having epoxyketone is notnecessary to function as the natural inhibitors. Simple ketone and hydroxymethylketonesare also found as HDAC inhibitors so far. In the last decade, a number of HDAC inhibitorshave been reported in literature and patented as the possible candidate of cancer drug.However, they have randomly different type of so-called zinc ligand which is expected tobind to the enzyme strongly at the active site. The functional groups are, for instance,hydroxamic acid, retro-hydroxamic acid, o-aminoanilide, ketone, trifluoromethylketone,hydroxymethylketone, methoxymethylketone, mercaptan, disulfide, thioether, thioacetate,borate, phosphate and so on. In order to evaluate such functional groups in the samemolecular condition as HDAC inhibitory activity, we introduced new (azide, click product,acryloyl and carboxyl) and known functional groups to the chlamydocin framework,cyclo(-L-AA-Aib-L-Phe-D-Pro-), (where AA bears different possible zinc ligands at theend of side chain) as standard of comparison.Results and DiscussionFinnin, et al. [1] proposed a first explanation of the catalytic activity of these enzymes. Theenzyme contains a zinc ion at the bottom of the active site, and the active center consists ofa tyrosine, two aspartic acids, and three histidines. In this mechanism, the carbonyl oxygenof the substrate binds the zinc ion and is located adjacent to a water molecule. Theelectrophilicity of the carbonyl carbon is increased by coordination to the zinc ion, and sothe carbonyl carbon is attacked by the water molecule activated by His 140 and His 141.This nucleophilic attack results in a tetrahedral transition state, which is stabilized by azinc-oxygen interaction and by hydrogen bonds with Tyr 303 and His 140.In the final step, proton transfer from His 141 to the nitrogen of the intermediatetriggers scission of the carbon-nitrogen bond to afford the acetate and lysine products. Thenaturally occurring cyclic tetrapeptide chlamydocin is a very potent inhibitor of cellproliferation [2]. It has also been reported as a highly potent HDAC inhibitor. In ourFig. 1. Structures of the reported and synthesized compounds.350