美國俄勒岡衛(wèi)生與科學大學(Oregon Health & Science University，OHSU)的研究人員在Endobugula sertula細菌身上發(fā)現(xiàn)一大群基因,，能保護海洋生物苔蘚蟲(Bugula neritina)的幼蟲,，不受到掠食者的侵害，這個現(xiàn)象非常令科學家好奇,，研究人員后來也發(fā)現(xiàn)這些物質(zhì)具有成為抗癌藥的潛力,。此研究發(fā)表于近期的Journal of Natural Products期刊。
Endobugula sertula這種細菌會與它的宿主,，也就是海洋苔蘚蟲形成共生(symbiont)的狀態(tài),，它也會分泌一種化學分子bryostatin保護著苔蘚蟲不被魚類掠食。許多研究也已證實bryostatin具備干擾許多癌細胞株生長的能力,。Haygood教授表示：苔蘚蟲幼蟲的皮膚表面覆蓋著bryostatin,，甚至于在成蟲的部份結(jié)構(gòu)也布滿這種化合物，也許bryostatin能幫助他們鞏固好領土范圍以保護幼蟲不受到魚類的掠食,。
而研究人員也發(fā)現(xiàn)特別是稱為bryostatin 1的這一型化合物,，具有抗癌的能力，包括對抗胰臟癌,、腎臟癌,、血癌、非霍奇金氏癥淋巴瘤以及黑色素瘤等,。目前bryostatin 1也已進入臨床試驗的第一期,，并佐以其它藥物進入臨床試驗的第二期。然而,，問題來了,，bryostatins在醫(yī)藥的使用量那么大，但是,，卻很難在苔蘚蟲以外的環(huán)境培養(yǎng)Endobugula sertula,，而在溶液中培養(yǎng)苔蘚蟲以萃取bryostatin化合物的價格非常昂貴，因此bryostatin的取得是相當困難的。
因此,，Haygood與她在Scripps海洋學院以及密西根大學的研究團隊一起討論如何讓bryostatins這類的化合物能成為商業(yè)化生產(chǎn),。研究人員分析了兩種不同種類的苔蘚蟲(一個是生長在深海中，另一種則生長在較淺層的海中)身上的細菌株,，然后從中篩選分離出相關的基因組,，透過基因工程的方式誘導其生合成bryostatins的前驅(qū)物，目前取得的bryostatins前驅(qū)物已超過20種以上,，并將這些前驅(qū)物稱為bryostatin 0,。
Haygood表示，下一個步驟就是將來自細菌的基因轉(zhuǎn)移到宿主之中,，這樣就可以在實驗室中讓宿主生產(chǎn)bryostatins,，過程當中除了會產(chǎn)生bryostatins外，也會產(chǎn)生bryostatins的部分片段,，或是生產(chǎn)全新的bryostatins相關化合物,。最后希望能夠透過工業(yè)生產(chǎn)的方式大量制備，以供應未來廣大的醫(yī)藥需求,。
(資料來源 : Bio.com)
部分英文原文：
Identification of the Putative Bryostatin Polyketide Synthase Gene Cluster from “Candidatus Endobugula sertula”, the Uncultivated Microbial Symbiont of the Marine Bryozoan Bugula neritina
Sebastian Sudek,† Nicole B. Lopanik,‡,§ Laura E. Waggoner,†,§ Mark Hildebrand,† Christine Anderson,† Haibin Liu,‡ Amrish Patel,† David H. Sherman,‡ and Margo G. Haygood*,†
Scripps Institution of Oceanography, Marine Biology Research DiVision, and Center for Marine Biotechnology and Biomedicine, UniVersity of California San Diego, La Jolla, California 92093-0202, and Department of Medicinal Chemistry, Life Sciences Institute, UniVersity of Michigan, Ann Arbor, Michigan 48109-2216 ReceiVed July 21, 2006
The bryostatins are protein kinase C modulators with unique structural features and potential anticancer and neurological activities. These complex polyketides were isolated from the marine bryozoan Bugula neritina, but recent studies indicate that they are produced by the uncultured symbiotic bacterium “Candidatus Endobugula sertula” (“E. sertula”). Here we present the putative biosynthetic genes: five modular polyketide synthase (PKS) genes, a discrete acyltransferase, a â-ketosynthase, a hydroxy-methyl-glutaryl CoA synthase (HMG-CS), and a methyltransferase. The cluster was sequenced in two closely related “E. sertula” strains from different host species. In one strain the gene cluster is contiguous, while in the other strain it is split into two loci, with one locus containing the PKS genes and the other containing the accessory genes. Here, we propose a hypothesis for the biosynthesis of the bryostatins. Thirteen PKS modules form the core macrolactone ring, and the pendent methyl ester groups are added by the HMG-CS gene cassette. The resulting hypothetical compound bryostatin 0 is the common basis for the 20 known bryostatins. As “E. sertula” is to date uncultured, heterologous expression of this biosynthetic gene cluster has the potential of producing the bioactive bryostatins in large enough quantities for development into a pharmaceutical.
英文全文鏈接：http://pubs.acs.org/cgi-bin/sample.cgi/jnprdf/2007/70/i01/html/np060361d.html
