Biosynthesis-based artificial evolution of microbial natural products

Lin, Zhi; Chen, Dandan; Liu, Wen

doi:10.1007/s11426-016-0062-x

Cited by 7 publications

(4 citation statements)

References 100 publications

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“…For the formation of a Sch40832-like, stable series c thiopeptide, further aldehyde reduction by a NADPH-dependent reductase and thiol S -methylation by a SAM-dependent methyltransferase are necessary. Considering incomplete conversions observed in vitro with SchZ and SchY activities, the possibility that imidazopiperidine formation starts at an earlier stage cannot be excluded currently, e.g., where related enzymatic processing might occur on a side-ring opening, immature series b/a thiostrepton/thiopeptin-type intermediate. ,, The observations reported here further the understanding in the biosynthesis of thiopeptide antibiotics, which provides a unique paradigm exemplifying the process of how nature develops structural complexity and diversity from a Cys and Ser/Thr-rich peptide sequence, and thus will facilitate bioinspired engineering to expand their molecular diversity and utility. − …”

Section: Discussionmentioning

confidence: 86%

Dissection of the Enzymatic Process for Forming a Central Imidazopiperidine Heterocycle in the Biosynthesis of a Series c Thiopeptide Antibiotic

et al. 2021

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Thiopeptide antibiotics are a family of ribosomally synthesized and posttranslationally modified peptide natural products of significant interest in anti-infective agent development. These antibiotics are classified into five subfamilies according to differences in the central 6-membered heterocycle of the thiopeptide framework. The mechanism through which imidazopiperidine, the most heavily functionalized central domain characteristic of a series c thiopeptide, is formed remains unclear. Based on mining and characterization of the genes specifically involved in the biosynthesis of Sch40832, we here report an enzymatic process for transforming a series b thiopeptide into a series c product through a series a intermediate. This process starts with F 420 -dependent hydrogenation of the central dehydropiperidine unit to a saturated piperidine unit. With the activity of a cytochrome P450 monooxygenase, the piperidine-thiazole motif of the intermediate undergoes an unusual oxygenation-mediated rearrangement to provide an imidazopiperidine heterocycle subjected to further S-methylation and aldehyde reduction. This study represents the first biochemical reconstitution of the pathway forming a stable series c thiopeptide.

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Section: Discussionmentioning

confidence: 86%

Dissection of the Enzymatic Process for Forming a Central Imidazopiperidine Heterocycle in the Biosynthesis of a Series c Thiopeptide Antibiotic

et al. 2021

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“…在获得放线菌天然产物 BGC 的基础上, 需要考虑如何实现后续的多种研究需求. 例如, 针对已知结构的天然产物, 一般着眼于深入开展生物合成机制研究以及与目标天然产物高产、优产相关的产业化研究; 针对未知结构的天然产物, 则往往专注于沉默基因簇的激活以及未知天然产物的挖掘 [4,5] . 无论是哪种需求, 都可能涉及基因敲除(gene knockout)、启动子置换(promotor replacement)、定点突变(site-directed mutation)、过量表达 (over-expression)等基因编辑工作.…”

Section: 基因簇的编辑与重构unclassified

“…在以放线菌为代表的多数微生物体内, 编码天然产物生物合成的基因往往成簇排列, 由此形成的生物合成基因簇(biosynthetic gene cluster, BGC)除了含有编码天然产物骨架形成和后修饰的结构基因(structural genes) 以外, 还可能含有控制合成起讫和强弱的调控基因 (regulator genes)以及解除宿主自身毒性的抗性基因 (resistance genes)、转运基因(transporter genes)等 [3] . 这些 BGC 通过表达功能性蛋白严密控制着天然产物在体内的生物合成过程, 是菌种遗传改造的主要靶标 [4,5] . 在遵循生物合成一般规律的基础上, 合理运用生物学技术开展菌种代谢网络的工程化改造, 是创制以结构和活性为导向的新型天然产物的有效途径 [6] , 也是生产效价提图 1 著名的活性放线菌天然产物 Figure 1 Famous bioactive natural products in actinomycetes 高、组分优化的活性天然产物的有力手段 [7] .…”

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Application of CRISPR/Cas9 Gene Editing System in Obtaining Natural Products in Actinomycetes

Qiao¹,

Chen²,

Liu³

et al. 2021

Chinese Journal of Organic Chemistry

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As important source of clinical drugs, the natural products in actinomycetes and their derivatives have been developed on a large scale and used in clinical practice. In order to achieve efficient synthesis of active natural products, structural derivation of new natural products, and targeted mining of unknown natural products, researches mainly focus on the biosynthetic gene clusters from actinomycetes, which should be rationally engineered by advanced biotechnology. CRISPR/ Cas, which represents the clustered regularly interspaced short palindromic repeats and the associated protein, is an adaptive immune system developed by some bacteria and archaea in the long-term natural evolution process to resist the invasion of foreign genetic materials. As a representative of gene editing system, the clustered regularly interspaced short palindromic repeats and the associated protein 9 (CRISPR/Cas9) has been widely used in the targeted editing of deoxyribonucleic acid (DNA) fragments, which provides unlimited possibilities for the development of biotechnology. This paper reviews the application of the CRISPR/Cas9 system in the genetic manipulation of actinomycetes, including the recent research progress in capture, editing and reconstruction of gene clusters, in situ homologous recombination and metabolic regulation, which involves the novel CRISPR/Cas9-mediated gene editing methods and the representative successful cases. This paper will provide valuable information for the efficient use of CRISPR/Cas9 to obtain natural products in actinomycetes.

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“…[2] In addition to sequence permutation of the precursor peptide for changes in amino acid constitution, [3] individualized PTMs are necessary for specializing the common thiopeptide framework to different thiopeptide antibiotics that are composed of over 100 naturally occurring chemical entities, thereby exemplifying a process of how nature develops structural complexity and diversity from a Ser/Thr and Cys-rich sequence. [4] Scheme 1. Structures, biosynthetic pathway and enzymatic reactions associated with TsrE activity.…”

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confidence: 99%

Oxidative Indole Dearomatization for Asymmetric Furoindoline Synthesis by a Flavin‐Dependent Monooxygenase Involved in the Biosynthesis of Bicyclic Thiopeptide Thiostrepton

et al. 2021

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Biosynthesis-based artificial evolution of microbial natural products

Cited by 7 publications

References 100 publications

Dissection of the Enzymatic Process for Forming a Central Imidazopiperidine Heterocycle in the Biosynthesis of a Series c Thiopeptide Antibiotic

Dissection of the Enzymatic Process for Forming a Central Imidazopiperidine Heterocycle in the Biosynthesis of a Series c Thiopeptide Antibiotic

Application of CRISPR/Cas9 Gene Editing System in Obtaining Natural Products in Actinomycetes

Oxidative Indole Dearomatization for Asymmetric Furoindoline Synthesis by a Flavin‐Dependent Monooxygenase Involved in the Biosynthesis of Bicyclic Thiopeptide Thiostrepton

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