Functional Characterization of TtnD and TtnF, Unveiling New Insights into Tautomycetin Biosynthesis

	Functional Characterization of TtnD and TtnF, Unveiling New Insights into Tautomycetin Biosynthesis
	Luo, Yinggang ; Li, Wenli ; Ju, Jianhua ; Yuan, Qiuping ; Peters, Noel R. ; Hoffmann, F. Michael ; Huang, Sheng-Xiong ; Bugni, Tim S. ; Rajski, Scott ; Osada, Hiroyuki ; Shen, Ben
刊名	JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
	2010
卷号	132 期号:19 页码:6663-6671
ISSN号	0002-7863
通讯作者	Shen, B, Univ Wisconsin, Div Pharmaceut Sci, Madison, WI 53705 USA
产权排序	5
中文摘要	The biosynthetic gene cluster for tautomycetin (TTN), a highly potent and selective protein phosphatase (PP) inhibitor isolated from Streptomyces griseochromogenes, has recently been cloned and sequenced. To better understand the transformations responsible for converting the post-polyketide synthase product into the exciting anticancer and immunosuppressive chemotherapeutic candidate UN, we produced and characterized new analogues resulting from inactivation of two genes, ttnD and ttnF, in S. griseochromogenes. Inactivation of ttnD and ttnF, which encode for putative decarboxylase and dehydratase enzymes, respectively, afforded mutant strains SB13013 and SB13014. The Delta ttnD mutant SB13013 accumulated four new TIN analogues, TTN D-1, UN D-2, TTN D-3, and UN D-4, whereas the Delta ttnF mutant accumulated only one new UN analogue, TTN F-1. The accumulation of these new UN analogues defines the function of TtnD and TtnF and the timing of their chemistries in relation to installation of the C5 ketone moiety within UN. Notably, all new analogues possess a structurally distinguishing carboxylic acid moiety, revealing that TtnD apparently cannot catalyze decarboxylation in the absence of TtnF. Additionally, cytotoxicity and PP inhibition assays reveal the importance of the functional groups installed by TtnDF and, consistent with earlier proposals, the C2 ''-C5 fragment of TTN to be a critical structural determinant behind the important and unique PP-1 selectivity displayed by TTN.
学科主题	Chemistry, Multidisciplinary
收录类别	SCI
资助信息	NIH [CA113297]; Chinese Academy of Sciences
语种	英语
WOS记录号	WOS:000277721500023
公开日期	2011-07-08
内容类型	期刊论文
源URL	[http://210.75.237.14/handle/351003/18395]
专题	成都生物研究所_天然产物研究
推荐引用方式 GB/T 7714	Luo, Yinggang,Li, Wenli,Ju, Jianhua,et al. Functional Characterization of TtnD and TtnF, Unveiling New Insights into Tautomycetin Biosynthesis[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,2010,132(19):6663-6671.
APA	Luo, Yinggang.,Li, Wenli.,Ju, Jianhua.,Yuan, Qiuping.,Peters, Noel R..,...&Shen, Ben.(2010).Functional Characterization of TtnD and TtnF, Unveiling New Insights into Tautomycetin Biosynthesis.JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,132(19),6663-6671.
MLA	Luo, Yinggang,et al."Functional Characterization of TtnD and TtnF, Unveiling New Insights into Tautomycetin Biosynthesis".JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 132.19(2010):6663-6671.