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1.
《中国科学:生命科学》2017,(5)
天然产物尤其是次级代谢产物在药物化学和化学生物学中扮演重要角色.基于天然产物获得结构多样性的类似物对于新药的筛选和医学研究具有重要意义.天然产物均由生物体代谢产生,在了解其生物合成机制的基础上,对生物合成过程进行合理化改造,可以极大地丰富天然产物的结构多样性,获得许多具有重要生理活性和有机化学不易合成的天然产物类似物.本文以硫肽类抗生素中的硫链丝菌素和聚酮聚肽类化合物为例,对生物合成方法在天然产物结构多样性中的应用进行总结和展望. 相似文献
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真菌芳香聚酮化合物是由真菌非还原聚酮合酶(NR-PKSs)催化形成的具有广泛生物活性的一类天然产物。大部分内源真菌菌株存在难培养、致病性或产率低等问题,从根本上限制了真菌芳香聚酮化合物的开发和应用。随着合成生物学和代谢工程的发展,很多具有生物活性的聚酮产物实现了在工业微生物(如酿酒酵母、构巢曲霉等)中的异源生产,相关研究逐渐成为热点。从合成途径解析与挖掘、底盘细胞的构建与改造等方面综述了近年来真菌芳香聚酮化合物的合成生物学研究进展,为未来真菌芳香聚酮化合物人工代谢途径的高效构建和实现工业化生产奠定基础。 相似文献
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真菌芳香聚酮化合物是由真菌非还原聚酮合酶(NR-PKSs)催化形成的具有广泛生物活性的一类天然产物。大部分内源真菌菌株存在难培养、致病性或产率低等问题,从根本上限制了真菌芳香聚酮化合物的开发和应用。随着合成生物学和代谢工程的发展,很多具有生物活性的聚酮产物实现了在工业微生物(如酿酒酵母、构巢曲霉等)中的异源生产,相关研究逐渐成为热点。从合成途径解析与挖掘、底盘细胞的构建与改造等方面综述了近年来真菌芳香聚酮化合物的合成生物学研究进展,为未来真菌芳香聚酮化合物人工代谢途径的高效构建和实现工业化生产奠定基础。 相似文献
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植物Ⅲ型聚酮合酶的分子机制与应用前景 总被引:1,自引:0,他引:1
植物III型聚酮合酶能催化生成一系列结构各异、具有不同生理活性、包含查耳酮合酶基本骨架的植物次生代谢产物,这类次生代谢产物不仅使植物体本身的抗逆性提高,并且对人类健康医疗有很好的应用前景。以下综述了近年来从植物中克隆、鉴定III型聚酮合酶的研究进展,着重论述了其分子结构、催化反应的类型和机制、表达调控及其在转基因工程方面的研究和应用前景。这些研究将为有效地对其进行基因改造,合成一些难以化学合成的新型天然化合物奠定基础,并且为将来进一步开展III型聚酮合酶的转基因工程提供了参考。 相似文献
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聚酮是一大类具有重要生物活性的天然产物,其生物合成途径复杂多样。利用异源宿主合成聚酮化合物要比使用天然生产菌有很多优点。异源宿主的选择是异源生物合成聚酮的关键。这种宿主必须能够大量表达大分子聚酮合成酶(300 kDa或更大)且能够大规模的转译后修饰这些蛋白;还要能够形成大量的像丙二酰CoA、甲基丙二酰CoA等细胞内起始单元。随着各种技术的不断进步,异源宿主很可能成为大规模生产聚酮化合物的一个强有力平台。本文对聚酮合成酶,异源生产聚酮的优点、条件和应用都有所阐述。 相似文献
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聚酮化合物是通过聚酮合成途径产生的一大类结构和生物活性多样的次级代谢产物,是链霉菌产生的主要次级代谢产物,具有重要的经济价值。为了在链霉菌中提高聚酮化合物产量,以满足工业生产需求,近年来,代谢工程的方法被广泛应用,例如,过表达合成途径中限速酶或途径特异性激活蛋白、强化前体供应、去除产物反馈抑制、合成基因簇异源表达等。本文将从代谢工程改造实例入手,全面综述链霉菌中聚酮化合物高效生物合成的研究方法及进展,并对利用合成生物学策略智能动态适配各个相关途径,进而提高该类化合物产量的研究思路进行展望。 相似文献
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埃博霉素(Epothilones)的PKS/NRPS杂合基因簇 总被引:2,自引:0,他引:2
埃博霉素是由粘细菌纤维堆囊菌产生的一类具有促微管聚合活性的大环内酯类化合物。埃博霉素生物合成的多酶复合体是一个由多个功能模块组成,同时含有多聚酮合酶(PKS)和非核糖体肽合成酶(NRPS)的大操纵子。根据同位素标记试验结果和合成酶全基因簇功能的推测,埃博霉素的生物合成包括聚酮链的引发、链合成的起始和噻唑环的形成、链的延伸和转移、链合成的终止释放和环化、及产物的后修饰5个阶段。埃博霉素的PKS/NRPS杂合基因簇是开展组合生物合成研究的良好材料。 相似文献
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解淀粉芽胞杆菌(Bacillus amyloliquefaciens)属于芽胞杆菌属,是一种重要的益生菌。该菌对植物病原性微生物具有显著抑制作用,并能促进农作物生长。研究发现,该菌在产生抑菌活性物质的同时,还能产生具有重要应用价值的生物多聚物。就解淀粉芽胞杆菌产生的几种重要生物多聚物,包括γ-聚谷氨酸、胞外多糖、果糖均聚物、聚酮化合物的特性、结构、合成及功能进行了描述,概括了各种生物多聚物的应用,为深入了解、研究、开发和利用这些生物多聚物提供参考。 相似文献
11.
ZHU Xiang-Cheng HUFFMAN Justin GERBER Ryan LOU Li-Li XIE Yun-Xuan LIN Ting JORGENSON Joel MARESCH Andrew VOGELER Chad WANG Qiao-Mei SHEN Yue-Mao DU Liang-Cheng 《云南植物研究》2008,30(3):249-278
Polyketides are one of the largest groups of natural products produced by bacteria, fungi, and plants. Many of these metabolites have highly complex chemical structures and very important biological activities, including antibiotic, anticancer, immunosuppressant, and anti-cholesterol activities. In the past two decades, extensive investigations have been carried out to understand the molecular mechanisms for polyketide biosynthesis. These efforts have led to the development of various rational approaches toward engineered biosynthesis of new polyketides. More recently, the research efforts have shifted to the elucidation of the three-dimentional structure of the complex enzyme machineries for polyketide biosynthesis and to the exploitation of new sources for polyketide production, such as filamentous fungi and marine microorganisms. This review summarizes our general understanding of the biosynthetic mechanisms and the progress in engineered biosynthesis of polyketides. 相似文献
12.
Abstract
Type I polyketide synthases are known to produce a wide range of medically and industrially important polyketides. The ketosynthase
(KS) domain is required for the condensation of an extender unit onto the growing polyketide chain during polyketide biosynthesis.
KSs represent a superfamily of complex biosynthetic pathway-associated enzymes found in prokaryotes, fungi, and plants. Although
themselves functionally conserved, KSs are involved in the production of a structurally diverse range of metabolites. Degenerate
oligonucleotide primers, designed for the amplification of KS domains, amplified KS domains from a range of organisms including
cyanobacterial and dinoflagellates. KS domains detected in dinoflagellate cultures appear to have been amplified from the
less than 3-μm filtrate of the nonaxenic culture. Phylogenetic analysis of sequences obtained during this study enabled the
specific identification of KS domains of hybrid or mixed polyketide synthase/peptide synthetase complexes, required for the
condensation of an extender unit onto an amino acid starter unit. The primer sets described in this study were also used for
the detection of novel KS domains directly from environmental samples. The ability to predict function based on primary molecular
structure will be critical for future discovery and rational engineering of polyketides. 相似文献
13.
Polyketides have diverse biological activities, including pharmacological functions such as antibiotic, antitumor and agrochemical
properties. They are biosynthesized from short carboxylic acid precursors by polyketide synthases (PKSs). As natural polyketide
products include many clinically important drugs and the volume of data on polyketides is rapidly increasing, the development
of a database system to manage polyketide data is essential. MapsiDB is an integrated web database formulated to contain data
on type I polyketides and their PKSs, including domain and module composition and related genome information. Data on polyketides
were collected from journals and online resources and processed with analysis programs. Web interfaces were utilized to construct
and to access this database, allowing polyketide researchers to add their data to this database and to use it easily.
MapsiDB is available at . 相似文献
14.
Several polyketide secondary metabolites are shown by feeding experiments to incorporate glycerol-derived 3-carbon starter
units, 2-carbon extender units, or 3-carbon branches into their hydrocarbon chains. In recent years, genetic studies have
begun to elucidate the mechanisms by which this occurs. In this article we review the incorporation of glycerol-derived precursors
into polyketides and propose new mechanisms for the incorporation processes.
Laura J. Walton, Christophe Corre contributed equally to this article 相似文献
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Hyun-Ju Kim Suman Karki So-Yeon Kwon Si-Hyung Park Baek-Hie Nahm Yeon-Ki Kim Hyung-Jin Kwon 《The Journal of biological chemistry》2014,289(50):34557-34568
Galbonolide (GAL) A and B are antifungal macrolactone polyketides produced by Streptomyces galbus. During their polyketide chain assembly, GAL-A and -B incorporate methoxymalonate and methylmalonate, respectively, in the fourth chain extension step. The methoxymalonyl-acyl carrier protein biosynthesis locus (galG to K) is specifically involved in GAL-A biosynthesis, and this locus is neighbored by a gene cluster composed of galA-E. GalA-C constitute a single module, highly reducing type I polyketide synthase (PKS). GalD and GalE are cytochrome P450 and Rieske domain protein, respectively. Gene knock-out experiments verified that galB, -C, and -D are essential for GAL biosynthesis. A galD mutant accumulated a GAL-C that lacked two hydroxyl groups and a double bond when compared with GAL-B. A [U-13C]propionate feeding experiment indicated that no rare precursor other than methoxymalonate was incorporated during GAL biogenesis. A search of the S. galbus genome for a modular type I PKS system, the type that was expected to direct GAL biosynthesis, resulted in the identification of only one modular type I PKS gene cluster. Homology analysis indicated that this PKS gene cluster is the locus for vicenistatin biosynthesis. This cluster was previously reported in Streptomyces halstedii. A gene deletion of the vinP2 ortholog clearly demonstrated that this modular type I PKS system is not involved in GAL biosynthesis. Therefore, we propose that GalA-C direct macrolactone polyketide formation for GAL. Our studies provide a glimpse into a novel biochemical strategy used for polyketide synthesis; that is, the iterative assembly of propionates with highly programmed β-keto group modifications. 相似文献
17.
A collection of actinomycin-producing Streptomycesstrains, their variants with different levels of antibiotic biosynthesis, and recombinant strains were screened in order to select new strains that produce polyketide antibiotics. Screening with the use of the cloned actgene encoding a component of actinorhodin polyketide synthase (PKS) multienzyme complex from Streptomyces coelicolorrevealed that many strains tested can synthesize polyketide antibiotics along with actinomycins. A relationship between the biosynthetic pathways of actinomycins and polyketides is discussed. 相似文献
18.
Mohammad Sayari Emma T. Steenkamp Magriet A. van der Nest Brenda D. Wingfield 《Fungal biology》2018,122(9):856-866
Polyketides are secondary metabolites with diverse biological activities. Polyketide synthases (PKS) are often encoded from genes clustered in the same genomic region. Functional analyses and genomic studies show that most fungi are capable of producing a repertoire of polyketides. We considered the potential of Ceratocystidaceae for producing polyketides using a comparative genomics approach. Our aims were to identify the putative polyketide biosynthesis gene clusters, to characterize them and predict the types of polyketide compounds they might produce. We used sequences from nineteen species in the genera, Ceratocystis, Endoconidiophora, Davidsoniella, Huntiella, Thielaviopsis and Bretziella, to identify and characterize PKS gene clusters, by employing a range of bioinformatics and phylogenetic tools. We showed that the genomes contained putative clusters containing a non-reducing type I PKS and a type III PKS. Phylogenetic analyses suggested that these genes were already present in the ancestor of the Ceratocystidaceae. By contrast, the various reducing type I PKS-containing clusters identified in these genomes appeared to have distinct evolutionary origins. Although one of the identified clusters potentially allows for the production of melanin, their functional characterization will undoubtedly reveal many novel and important compounds implicated in the biology of the Ceratocystidaceae. 相似文献
19.
Polyketide Synthase Genes from Marine Dinoflagellates 总被引:2,自引:0,他引:2
Snyder RV Gibbs PD Palacios A Abiy L Dickey R Lopez JV Rein KS 《Marine biotechnology (New York, N.Y.)》2003,5(1):1-12
20.
Polyketides are a diverse class of molecules sought after for their valuable properties, including as potential pharmaceuticals. Previously, we demonstrated that the oleaginous yeast Yarrowia lipolytica is an optimal host for production of the simple polyketide, triacetic acid lactone (TAL). We here expand the capacities of this host by overcoming previous media challenges and enabling production of more complex polyketides. Specifically, we employ a β-oxidation related strategy to improve polyketide production directly from defined media. Beyond TAL production, we establish biosynthesis of the 4-coumaroyl-CoA derived polyketides: naringenin, resveratrol, and bisdemethoxycurcumin, as well as the diketide intermediate, (E)-5-(4-hydroxyphenyl)-3-oxopent-4-enoic acid. In this background, we enable high-level de novo production of naringenin through import of both a heterologous pathway and a mutant Y. lipolytica allele. In doing so, we generated an averaged maximum titer of 898 mg/L naringenin, the highest titer reported to date in any host. These results demonstrate that Y. lipolytica is an ideal polyketide production host for more complex 4-coumaroyl-CoA derived products. 相似文献