Complete elucidation of the late steps of bafilomycin biosynthesis in Streptomyces lohii

doi:10.1074/jbc.M116.751255

CORC > 青岛生物能源与过程研究所 > 中国科学院青岛生物能源与过程研究所 > 酶工程团队

	Complete elucidation of the late steps of bafilomycin biosynthesis in Streptomyces lohii
	Li, Zhong 1,2,3; Du, Lei 1,2,3; Zhang, Wei 1,2; Zhang, Xingwang 1,2; Jiang, Yuanyuan 1,2,3; Liu, Kun 1,2; Men, Ping 1,2; Xu, Huifang 1,2; Fortman, Jeffrey L.4,5,6; Sherman, David H.4,5,6
刊名	JOURNAL OF BIOLOGICAL CHEMISTRY
	2017-04-28
卷号	292 期号:17 页码:7095-7104
DOI	10.1074/jbc.M116.751255
文献子类	Article
英文摘要	Bafilomycins are an important subgroup of polyketides with diverse biological activities and possible applications as specific inhibitors of vacuolar H+-ATPase. However, the general toxicity and structural complexity of bafilomycins present formidable challenges to drug design via chemical modification, prompting interests in improving bafilomycin activities via biosynthetic approaches. Two bafilomycin biosynthetic gene clusters have been identified, but their post-polyketide synthase (PKS) tailoring steps for structural diversification and bioactivity improvement remain largely unknown. In this study, the post-PKS tailoring pathway from bafilomycin A(1) (1)-> C-1 (2)-> B-1 (3) in the marine microorganism Streptomyces lohii was elucidated for the first time by in vivo gene inactivation and in vitro biochemical characterization. We found that fumarate is first adenylated by a novel fumarate adenylyltransferase Orf3. Then, the fumaryl transferase Orf2 is responsible for transferring the fumarate moiety from fumaryl-AMP to the 21-hydroxyl group of 1 to generate 2. Last, the ATP-dependent amide synthetase BafY catalyzes the condensation of 2 and 2-amino-3-hydroxycyclopent-2-enone (C5N) produced by the 5-aminolevulinic acid synthase BafZ and the acyl-CoA ligase BafX, giving rise to the final product 3. The elucidation of fumarate incorporation mechanism represents the first paradigm for biosynthesis of natural products containing the fumarate moiety. Moreover, the bafilomycin post-PKS tailoring pathway features an interesting cross-talk between primary and secondary metabolisms for natural product biosynthesis. Taken together, this work provides significant insights into bafilomycin biosynthesis to inform future pharmacological development of these compounds.
WOS关键词	GLUTAMINE-SYNTHETASE ; GENE-CLUSTER ; MACROLIDE ANTIBIOTICS ; SP CS ; ACID ; A(1) ; INHIBITORS ; MICROORGANISMS ; FERMENTATION ; PURIFICATION
WOS研究方向	Biochemistry & Molecular Biology
语种	英语
WOS记录号	WOS:000400478300020
资助机构	National Natural Science Foundation of China(NSFC 21472204) ; Shandong Provincial Natural Science Foundation(JQ201407) ; Primary Research & Development Plan of Shandong Province(2016GSF121001) ; Applied Basic Research Program of Qingdao(15-9-1-93-jch) ; China Postdoctoral Science Foundation(2016M590669) ; Youth Innovation Promotion Association of CAS(2015166) ; National Institutes of Health(R35GM118101)
内容类型	期刊论文
源URL	[http://ir.qibebt.ac.cn/handle/337004/9616]
专题	青岛生物能源与过程研究所_酶工程团队
作者单位	1.Chinese Acad Sci, Shandong Prov Key Lab Synthet Biol, Qingdao 266101, Shandong, Peoples R China 2.Chinese Acad Sci, CAS Key Lab Biofuels, Qingdao Inst Bioenergy & Bioproc Technol, Qingdao 266101, Shandong, Peoples R China 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 4.Univ Michigan, Life Sci Inst, Dept Med Chem, Ann Arbor, MI 48109 USA 5.Univ Michigan, Life Sci Inst, Dept Chem, Ann Arbor, MI 48109 USA 6.Univ Michigan, Life Sci Inst, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA 7.Sun Yat Sen Univ, Canc Ctr, State Key Lab Oncol South China, Collaborat Innovat Ctr Canc Med, Guangzhou 510060, Guangdong, Peoples R China
推荐引用方式 GB/T 7714	Li, Zhong,Du, Lei,Zhang, Wei,et al. Complete elucidation of the late steps of bafilomycin biosynthesis in Streptomyces lohii[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2017,292(17):7095-7104.
APA	Li, Zhong.,Du, Lei.,Zhang, Wei.,Zhang, Xingwang.,Jiang, Yuanyuan.,...&Li, Shengying.(2017).Complete elucidation of the late steps of bafilomycin biosynthesis in Streptomyces lohii.JOURNAL OF BIOLOGICAL CHEMISTRY,292(17),7095-7104.
MLA	Li, Zhong,et al."Complete elucidation of the late steps of bafilomycin biosynthesis in Streptomyces lohii".JOURNAL OF BIOLOGICAL CHEMISTRY 292.17(2017):7095-7104.