{"id":2242,"date":"2010-05-07T17:51:43","date_gmt":"2010-05-07T15:51:43","guid":{"rendered":"http:\/\/localhost\/azgad\/wordpress\/?p=2242"},"modified":"2010-05-07T17:51:43","modified_gmt":"2010-05-07T15:51:43","slug":"moving-beyond-the-genome-to-fight-cancer","status":"publish","type":"post","link":"https:\/\/azgad.com\/?p=2242","title":{"rendered":"Moving beyond the genome to fight cancer"},"content":{"rendered":"

.
\nThe first total synthesis of the complex natural product chaetocin
\nexpands the tools to reverse lethal gene expressions<\/strong>
\n.
\nUnlocking our genetic blueprint is well underway with the sequencing of the
\n human genome, but a secondary layer of structure on the genome that
\n affects gene expression, the \u2018epigenome,\u2019 remains largely unmapped.
\nThe packing structure of the epigenome can be altered by chemically modifying
\n histones, spool-like proteins around which DNA strands are wrapped within our
\n cells. Histones physically control access to genes, and adding small functional
\ngroups such as acetyl or methyl units to them can selectively switch certain genes
\n.
\non and off.<\/strong>
\n.
\nRecent developments in methods that can controllably influence these DNA
\narchitectures have focused on the methylation of histone proteins. Now, a research
\nteam led by Mikiko Sodeoka from the RIKEN Advanced Science Institute in Wako,
\nJapan, has produced the first total synthesis of chaetocin1, a natural product that
\n inhibits the activity of histone methyltransferases\u2014enzymes that play critical roles
\n in gene expression (Fig. 1). The results of this work could enable new therapeutics
\nfor destructive diseases such as cancer.
\n.
\nA \u2018tail\u2019 of influence<\/strong>
\n.
\nHistones contain floppy \u2018tail\u2019 regions, terminated by an amino acid with a free amine
\ngroup, that extend from the body of the protein. These tails can influence the epigenome
\n structure and serve as extremely active sites for chemical modification. Histone
\n methyltransferase enzymes catalyze the addition of methyl units to lysine and arginine
\n amino acid side chains in this tail, forming strong bonds in the process. This reaction
\ndoes not change the genetic code of the protein, but radically influences transcription
\n processes\u2014giving histone methylation an influential role in inherited gene expression
\npatterns.
\n.
\n.Normally, the levels of histone methylation are delicately balanced within our cells.
\nHowever, dysfunction of histone methyltransferases can alter the epigenome and
\nlead to abnormalities\u2014notably, the loss of expression of tumor-suppressing genes.
\nTherapies that can selectively control the activity of these enzymes hold great potential
\nfor new cancer therapeutics without the dangerous side effects of chemotherapy.
\nNatural guides
\n.
\nThe number of chemicals that can modulate histone methyltransferase enzymes is
\nlimited. According to team-member Yoshitaka Hamashima, also from RIKEN, only
\na few compounds that can selectively inhibit these enzymes have been reported to date.
\nHe says, \u201cit is only chaetocin that comes from natural sources.\u201d
\n.
\nChaetocin is a natural alkaloid produced by Chaetomium minutum, a form of wood
\nmold. The complex and elegantly symmetric structure of this molecule features eight rings
\nand several functional groups, most notably a pair of disulfide bridges attached to two
\nterminal rings. Chaetocin has been extensively investigated for its antibacterial behavior
\n and ability to suppress cell growth, and has the potential to play an important role in
\nmodifying the epigenome.
\n.
\nSeveral research groups have produced related analogues of chaetocin, but the total
\nsynthesis of this molecule has eluded organic chemists since its discovery forty years
\n ago\u2014setting up a significant test to the synthetic skills of Sodeoka and her team. \u201cThe fact
\n that no one had succeeded in the total synthesis after its isolation in 1970 drove us to
\nembark on this formidable challenge,\u201d says Hamashima.
\n.
\nRisk and reward<\/strong>
\n.
\nThe final part of the reaction\u2014construction of the disulfide bridges\u2014involved some
\nrisky chemistry, Hamashima notes. \u201cIn our initial plan, we expected that the
\n double-decker structure of chaetocin might control the approach of hydrogen sulfide
\nfrom the outer side. But nobody was convinced that it would work well.\u201d The team was
\nextremely gratified when the final step in the reaction, which involved ten bond-forming
\nand -cleaving events, generated chaetocin with the correct geometrical structure.
\n .
\nOverall, the team\u2019s method demonstrates a highly efficient way to produce chaetocin,
\nbecause the total synthesis required only nine chemical transformations.
\n.
\nBridging differences<\/strong>
\n.
\nWith the chemical synthesis of chaetocin complete, Sodeoka and colleagues prepared
\nvarious analogues of the molecule\u2014two optical isomers of chaetocin, and a version
\nmissing the disulfide bridges. The latter allowed them to examine the structure\u2013activity
\n relationship between this natural product and a particular histone methyltransferase
\nenzyme called G9a, in collaboration with Minoru Yoshida\u2019s group also from RIKEN
\nAdvanced Science Institute. Although both chaetocin isomers showed strong inhibitory
\n activity, the molecule without the sulfur bridges was inactive\u2014demonstrating the critical
\n .
\nrole of this functionality.<\/strong>
\n.
\nHamashima says that the target enzyme has a domain, close to chaetocin\u2019s binding site,
\n which is full of amino acids called cysteines. Cysteines have a thiol (-SH) side chain
\n that may be able to form transitory bonds with the critical disulfide bridges of chaetocin.
\n\u201cWhile the exact mechanism is still unclear,\u201d he says, \u201cwe speculate that such chemical
\n bond formations are responsible for the inhibition of G9a.\u201d
\n.
\nThe researchers believe that further studies into the molecular mechanisms of chaetocin
\nshould deliver a new generation of enzyme-specific pharmaceuticals that can control gene
\n expression patterns\u2014an important step in the treatment of cancerous diseases.
\n\u201cContributing to human health by creating new drugs is our goal,\u201d says Hamashima.
\n \u201cIn the future, the day will come when we can wake up silent genes in cells at will by
\nsimply adding chemical modulators.\u201d<\/p>\n","protected":false},"excerpt":{"rendered":"

. The first total synthesis of the complex natural product chaetocin expands the tools to reverse lethal gene expressions . Unlocking our genetic blueprint is well underway with the sequencing of the human genome, but a secondary layer of structure on the genome that affects gene expression, the \u2018epigenome,\u2019 remains largely unmapped. The packing structure … <\/p>\n

\u05d4\u05de\u05e9\u05d9\u05db\u05d5 \u05d1\u05e7\u05e8\u05d9\u05d0\u05d4<\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_monsterinsights_skip_tracking":false,"_monsterinsights_sitenote_active":false,"_monsterinsights_sitenote_note":"","_monsterinsights_sitenote_category":0,"footnotes":""},"categories":[10],"tags":[261,513,186,262],"class_list":["post-2242","post","type-post","status-publish","format-standard","hentry","category-10","tag-261","tag-513","tag-186","tag-262","nodate","item-wrap"],"_links":{"self":[{"href":"https:\/\/azgad.com\/index.php?rest_route=\/wp\/v2\/posts\/2242","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/azgad.com\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/azgad.com\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/azgad.com\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/azgad.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=2242"}],"version-history":[{"count":1,"href":"https:\/\/azgad.com\/index.php?rest_route=\/wp\/v2\/posts\/2242\/revisions"}],"predecessor-version":[{"id":2243,"href":"https:\/\/azgad.com\/index.php?rest_route=\/wp\/v2\/posts\/2242\/revisions\/2243"}],"wp:attachment":[{"href":"https:\/\/azgad.com\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=2242"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/azgad.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=2242"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/azgad.com\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=2242"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}