Structural Insights into the Mechanism of a Polyketide Synthase Thiocysteine Lyase Domain
文献类型：期刊论文
| 作者 | Steele, Andrew D.1,9; Meng, Song1,3,8; Li, Gengnan1,2; Kalkreuter, Edward1,4; Chang, Changsoo5; Shen, Ben6,7,9 |
| 刊名 | JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
 |
| 出版日期 | 2024-11-15 |
| 卷号 | 146期号:47页码:32605-32617 |
| ISSN号 | 0002-7863 |
| DOI | 10.1021/jacs.4c11656 |
| 英文摘要 | Polyketide synthases (PKSs) are renowned for the structural diversity of the polyketide natural products they produce, but sulfur-containing functionalities are rarely installed by PKSs. We previously characterized thiocysteine lyase (SH) domains involved in the biosynthesis of the leinamycin (LNM) family of natural products, exemplified by LnmJ-SH and guangnanmycin (GnmT-SH). Here we report a detailed investigation into the PLP-dependent reaction catalyzed by the SH domains, guided by a 1.8 & Aring; resolution crystal structure of GnmT-SH. A series of elaborate substrate mimics were synthesized to answer specific questions garnered from the crystal structure and from the biosynthetic logic of the LNM family of natural products. Through a combination of bioinformatics, molecular modeling, in vitro assays, and mutagenesis, we have developed a detailed model of acyl carrier protein (ACP)-tethered substrate-SH, and interdomain interactions, that contribute to the observed substrate specificity. Comparison of the GnmT-SH structure with archetypical PLP-dependent enzyme structures revealed how Nature, via evolution, has modified a common protein structural motif to accommodate an ACP-tethered substrate, which is significantly larger than any of those previously characterized. Overall, this study demonstrates how PLP-dependent chemistry can be incorporated into the context of PKS assembly lines and sets the stage for engineering PKSs to produce sulfur-containing polyketides. |
| WOS关键词 | BIOSYNTHESIS ; LEINAMYCIN ; STREPTOMYCES ; ERYTHROMYCIN ; DIVERSITY ; EVOLUTION |
| 资助项目 | NIH[GM134954] ; NIH[GM133114] ; NIH[GM134688] |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:001356538300001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/314545]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Shen, Ben |
| 作者单位 | 1.Herbert Wertheim UF Scripps Inst Biomed Innovat &, Dept Chem, Jupiter, FL 33458 USA 2.CentivaxInc, One Tower Pl,Eight Floor, South San Francisco, CA 94080 USA 3.Chinese Acad Sci, Shanghai Inst Mat Med, Nat Prod Res Ctr, Shanghai 201203, Peoples R China 4.Florida State Univ, Dept Chem & Biochem, Labs Mol Recognit, 95 Chieftan Way, Tallahassee, FL 32306 USA 5.Argonne Natl Lab, Struct Biol Ctr, X ray Sci Div, Lemont, IL 60439 USA 6.Herbert Wertheim UF Scripps Inst Biomed Innovat &, Dept Mol Med, Dept Chem, Jupiter, FL 33458 USA 7.Scripps Res, Skaggs Grad Sch Chem & Biol Sci, Jupiter, FL 33458 USA 8.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 9.Herbert Wertheim UF Scripps Inst Biomed Innovat &, Nat Prod Discovery Ctr, Jupiter, FL 33458 USA |
| 推荐引用方式 GB/T 7714 | Steele, Andrew D.,Meng, Song,Li, Gengnan,et al. Structural Insights into the Mechanism of a Polyketide Synthase Thiocysteine Lyase Domain[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,2024,146(47):32605-32617. |
| APA | Steele, Andrew D.,Meng, Song,Li, Gengnan,Kalkreuter, Edward,Chang, Changsoo,&Shen, Ben.(2024).Structural Insights into the Mechanism of a Polyketide Synthase Thiocysteine Lyase Domain.JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,146(47),32605-32617. |
| MLA | Steele, Andrew D.,et al."Structural Insights into the Mechanism of a Polyketide Synthase Thiocysteine Lyase Domain".JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 146.47(2024):32605-32617. |
入库方式： OAI收割
来源：上海药物研究所
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