Thioesterase Domains of Fungal Nonreducing Polyketide Synthases Act as Decision Gates during Combinatorial Biosynthesis
文献类型：期刊论文
| 作者 | Xu, Yuquan1,4; Zhou, Tong2,4; Zhang, Shuwei2,3; Xuan, Li-Jiang3 ; Zhan, Jixun2; Molnar, Istvan1,4
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| 刊名 | JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
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| 出版日期 | 2013-07-24 |
| 卷号 | 135期号:29页码:10783-10791 |
| ISSN号 | 0002-7863 |
| DOI | 10.1021/ja4041362 |
| 文献子类 | Article |
| 英文摘要 | A crucial step during the programmed biosynthesis of fungal polyketide natural products is the release of the final polyketide intermediate from the iterative polyketide synthases (iPKSs), most frequently by a thioesterase (TE) domain. Realization of combinatorial biosynthesis with iPKSs requires TE domains that can accept altered polyketide intermediates generated by hybrid synthase enzymes and successfully release "unnatural products" with the desired structure. Achieving precise control over product release is of paramount importance with O-C bond-forming TE domains capable of macrocyclization, hydrolysis, transesterification, and pyrone formation that channel reactive, pluripotent polyketide intermediates to defined structural classes of bioactive secondary metabolites. By exploiting chimeric iPKS enzymes to offer substrates with controlled structural variety to two orthologous O-C bond-forming TE domains in situ, we show that these enzymes act as nonequivalent decision gates, determining context-dependent release mechanisms and overall product flux. Inappropriate choice of a TE could eradicate product formation in an otherwise highly productive chassis. Conversely, a judicious choice of a TE may allow the production of a desired hybrid metabolite. Finally, a serendipitous choice of a TE may reveal the unexpected productivity of some chassis. The ultimate decision gating role of TE domains influences the observable outcome of combinatorial domain swaps, emphasizing that the deduced programming rules are context dependent. These factors may complicate engineering the biosynthesis of a desired "unnatural product" but may also open additional avenues to create biosynthetic novelty based on fungal nonreduced polyketides. |
| WOS关键词 | RESORCYLIC ACID LACTONES ; HEAT-SHOCK RESPONSE ; GIBBERELLA-ZEAE ; AROMATIC POLYKETIDES ; CHEMOENZYMATIC SYNTHESIS ; ASPERGILLUS-NIDULANS ; CHAETOMIUM-CHIVERSII ; HSP90 INHIBITOR ; CLAISEN CYCLASE ; GENES |
| 资助项目 | National Science Foundation[MCB-0948751] ; National Institutes of Health[AI065357] ; Utah State University[00000000] |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000322432400032 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277535]  |
| 专题 | 上海中药现代化研究中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Zhan, Jixun |
| 作者单位 | 1.Univ Arizona, Nat Prod Ctr, Sch Nat Resources & Environm, Tucson, AZ 85706 USA; 2.Utah State Univ, Dept Biol Engn, Logan, UT 84322 USA; 3.Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 4.Univ Arizona, Bio5 Inst, Tucson, AZ 85721 USA |
| 推荐引用方式 GB/T 7714 | Xu, Yuquan,Zhou, Tong,Zhang, Shuwei,et al. Thioesterase Domains of Fungal Nonreducing Polyketide Synthases Act as Decision Gates during Combinatorial Biosynthesis[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,2013,135(29):10783-10791. |
| APA | Xu, Yuquan,Zhou, Tong,Zhang, Shuwei,Xuan, Li-Jiang,Zhan, Jixun,&Molnar, Istvan.(2013).Thioesterase Domains of Fungal Nonreducing Polyketide Synthases Act as Decision Gates during Combinatorial Biosynthesis.JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,135(29),10783-10791. |
| MLA | Xu, Yuquan,et al."Thioesterase Domains of Fungal Nonreducing Polyketide Synthases Act as Decision Gates during Combinatorial Biosynthesis".JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 135.29(2013):10783-10791. |
入库方式： OAI收割
来源：上海药物研究所
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