植物内生真菌抗肿瘤药物研究进展

癌症已经严重威胁人类的健康。从自然界中筛选更新的、更有效的抗癌药物已成为了该领域的研究重点。作为新型抗癌药物的潜在来源,众多从植物内生真菌分离的代谢产物被证明具有抗肿瘤的生物活性。这些内生真菌通常具有特殊的代谢途径,可以在其培养物中积累抗癌活性物质,如紫杉烷类、生物碱类、细胞松弛素、鬼臼毒素、布雷菲德菌素A等。将系统的介绍已分离自植物内生真菌的抗癌药物的研究进展,同时对内生真菌的抗癌药物筛选的策略和发展前景进行简要的展望。     

Chemistry and biological activity of azoprenylated secondary metabolites

N-Prenyl secondary metabolites (isopentenylazo-, geranylazo-, farnesylazo- and their biosynthetic derivatives) represent a family of extremely rare natural products. Only in recent years have these alkaloids been recognized as interesting and valuable biologically active secondary metabolites. To date about 35 alkaloids have been isolated from plants mainly belonging to the Rutaceae family, and from fungi, bacteria, and/or obtained by chemical synthesis. These metabolites comprise anthranilic acid derivatives, diazepinones, and indole, and xanthine alkaloids. Many of the isolated prenylazo secondary metabolites and their semisynthetic derivatives are shown to exert valuable in vitro and in vivo anti-cancer, anti-inflammatory, anti-bacterial, anti-viral, and anti-fungal effects. The aim of this comprehensive review is to examine the different types of prenylazo natural products from a chemical, phytochemical and biological perspective.     

Secondary metabolites in taxonomy of the <Emphasis Type="Italic">Penicillium</Emphasis> fungi

A correlation was established between species specificity and synthesis of specific secondary metabolites by the Penicillium fungi. Strains of the subgenus Aspergilloides usually synthesize metabolites of polyketide nature. Most strains of the subgenus Furcatum produce clavine ergot alkaloids and metabolites of diketopiperazine nature. The only clavine ergot alkaloids and diketopiperazine alkaloids produced by strains of the subgenus Biverticillium are rugulovasines and rugulosuvines, respectively. Species designations of the strains of the subgenus Penicillium isolated from permafrost soil, the Mir orbital complex, and sites undergoing anthropogenic load were refined based on the marker secondary metabolites. Changes in the taxonomic position of some strains in the genus Penicillium are suggested.     

炭角菌属真菌化学成分与生物活性研究进展

炭角菌属真菌广泛分布于温带、热带和亚热带地区,主要含有萜类、生物碱、甾醇和聚酮等次级代谢产物,具有抗氧化、抑菌和抗肿瘤等药理活性。本文综述了近10年来国内外有关炭角菌属真菌的研究情况,对其次级代谢产物进行了归纳,总结了相关代谢产物的抗氧化、抑菌和抗肿瘤等生物活性。     

草原与荒漠植物内生真菌次生代谢产物研究进展

草原与荒漠植物内生真菌是一类特殊生境真菌类群,由于其独特的生存与生态环境,该类真菌在进化的过程中产生出具有不同生态与生物功能的次生代谢产物。相对于其他植物内生真菌而言,该类真菌化学研究相对薄弱与零散,但是目前仍然从这类特殊生境真菌类群中发现了大量结构新颖、活性独特并具有不同化学生态与生物功能的次生代谢产物。本文主要从化学结构角度综述近年来从草原与荒漠植物内生真菌中分离的次生代谢产物(生物碱、聚酮、酚酸、萜类、环肽等5类结构)、药理活性(抗病毒,免疫调节,促进骨髓增殖,细胞毒及Hsp90抑制剂活性等)与化学生态功能活性(杀虫、拒食与动物神经毒活性等),拟为该类特殊生境真菌类群次生代谢产物进一步开发提供研究基础与理论依据,同时对该领域研究存在的问题进行分析与探讨并提出展望。     

Isolation of Penicillium DIERCKX 1901--a producer of diketopiperazine alkaloids rokefortin and 3,12-dihydrokefortin--from permafrost

Secondary metabolites of the three strains of Penicillium aurantiogriseum, isolated from permafrost sediments, were identified. It was found that these fungi synthesized diketopiperazine alkaloids roquefortine and 3,12-dihydroroquefortine. The strain VKM FW-766 synthesized alkaloids in in the course of certain growth-related processes. When the strain was grown on a mineral medium, time courses of roquefortine and 3,12-dihydroroquefortine concentrations were characterized by biphasic curves.     

Penicillium aurantiogriseum Dierckx 1901: Producer of Diketopiperazine Alkaloids (Roquefortine and 3,12-Dihydroroquefortine), Isolated from Permafrost

Secondary metabolites of three strains of Penicillium aurantiogriseumisolated from permafrost sediments were identified. It was found that these fungi synthesized the diketopiperazine alkaloids roquefortine and 3,12-dihydroroquefortine. The strain VKM FW-766 synthesized alkaloids in the course of certain growth-related processes. When the strain was grown on a mineral medium, the time courses of the roquefortine and 3,12-dihydroroquefortine concentrations were characterized by biphasic curves.     

The fungus Penicillium citrinum Thom 1910 VKM FW-800 isolated from ancient permafrost sediments as a producer of the ergot alkaloids agroclavine-1 and epoxyagroclavine-1

The study of the secondary metabolites of the relict strain Penicillium citrinum VKM FW-800 isolated from ancient Arctic permafrost sediments showed that this fungus produces agroclavine-1 and epoxyagroclavine-1, which are rare ergot alkaloids with the 5R,10S configuration of the tetracyclic ergoline ring system. The production of the alkaloids by the fungus showed a biphasic behavior, being intense in the phase of active growth and slowing down in the adaptive lag phase and in the stationary growth phase. The addition of zinc ions to the incubation medium led to a fivefold increase in the yield of the alkaloids. The alkaloids-producing Penicillium fungi isolated from different regions exhibited the same tendencies of growth and alkaloid production.     

Major bioactive metabolites from marine fungi: A Review

Biologists and chemists of the world have been attracted towards marine natural products for the last five decades. Approximately 16,000 marine natural products have been isolated from marine organisms which have been reported in approximately 6,800 publications, proving marine microorganisms to be a invaluable source for the production of novel antibiotic, anti tumor, and anti inflammatory agents. The marine fungi particularly those associated with marine alga, sponge, invertebrates, and sediments appear to be a rich source for secondary metabolites, possessing Antibiotic, antiviral, antifungal and antiyeast activities. Besides, a few growth stimulant properties which may be useful in studies on wound healing, carcinogenic properties, and in the study of cancers are reported. Recent investigations on marine filamentous fungi looking for biologically active secondary metabolites indicate the tremendous potential of them as a source of new medicines. The present study reviews about some important bioactive metabolites reported from marine fungal strains which are anti bacterial, anti tumour and anti inflammatory in action. It highlights the chemistry and biological activity of the major bioactive alkaloids, polyketides, terpenoids, isoprenoid and non-isoprenoid compounds, quinones, isolated from marine fungi.     

青霉属真菌次级代谢产物的结构类型及其药用活性的研究进展

青霉属(Penicillium)真菌属于腐生类真菌,是自然界中一类重要的分解者。其可以产生多种多样的次级代谢产物。这些结构新颖、功能特殊的次级代谢产物在抗菌、抗氧化、抗肿瘤等药物开发中发挥重要作用,主要由聚酮类、生物碱、萜类、大环内酯等化学结构类型组成。本文综述了青霉属真菌次级代谢产物的结构类型以及丰富的生物药用活性,该内容可为后续青霉属真菌新型天然药物的开发提供研究思路。     

The Fungus Penicillium citrinum Thom 1910 VKM FW-800 Isolated from Ancient Permafrost Sediments As a Producer of the Ergot Alkaloids Agroclavine-1 and Epoxyagroclavine-1

The study of the secondary metabolites of the relict strain Penicillium citrinum VKM FW-800 isolated from ancient Arctic permafrost sediments showed that this fungus produces agroclavine-1 and epoxyagroclavine-1, which are rare ergot alkaloids with the 5R,10S configuration of the tetracyclic ergoline ring system. The production of the alkaloids by the fungus showed a biphasic behavior, being intense in the phase of active growth and slowing down in the adaptive lag phase and in the stationary growth phase. The addition of zinc ions to the incubation medium led to a fivefold increase in the yield of the alkaloids. The alkaloid-producing Penicillium fungi isolated from different regions exhibited the same tendencies of growth and alkaloid production.     

内生真菌X1-2次级代谢产物研究

在从神农架地区特有植物内生真菌中寻找各种活性次级代谢产物的过程中,从濒危植物珙桐叶片中分离得到一株内生真菌X1-2。经过高效液相色谱(HPLC)和薄板色谱(TLC)分析其固体发酵产物多样性,通过正相硅胶柱层析、重结晶、高效液相色谱制备等手段纯化次级代谢产物,从该真菌中分离获得四个次级代谢产物。经核磁共振波谱(NMR),质谱(MS)等波谱学方法鉴定其结构,四个化合物分别为icosalide A1(1),militarinone A(2),(+)-N-deoxymilitarinone A(3),β-hydroxytetradecanoyl-β-hydroxyl tetraecanoyl-Rha-Rha-C_(14)-C_(14)(4),其中icosalide A1(1),militarinone A(2),(+)-N-deoxymilitarinone A(3)为三个复杂的生物碱类化合物,而化合物4是首次从真菌中获得。     

丛枝菌根真菌对植物次生代谢的影响

丛枝菌根(AM)是自然界中分布最为广泛、最为重要的一类菌根,许多研究已经观察到丛枝菌根真菌与植物次生代谢的相关性,丛枝菌根真菌能够直接或间接地影响植物的次生代谢过程。植物的次生代谢产物主要分为萜类物质、酚类物质和含氮化合物(主要是生物碱)三大类群,该文简要介绍了丛枝菌根真菌对这3类植物次生代谢产物的影响。丛枝菌根真菌与萜类物质代谢关系的研究比较细致和深入,有些工作已经从细胞及分子水平探讨其间的作用机制,如Blumenin、类胡萝卜素等。丛枝菌根真菌与酚类物质代谢关系的研究也比较深入,其中具有特殊功能的酚类物质——植保素、细胞壁酚酸、类黄酮/异类黄酮等倍受关注。目前有关丛枝菌根真菌与生物碱关系的研究相对较少,不过现有的研究表明,菌根的形成有助于生物碱积累。     

Derivation of the multiply-branched ergot alkaloid pathway of fungi

Ergot alkaloids are a large family of fungal specialized metabolites that are important as toxins in agriculture and as the foundation of powerful pharmaceuticals. Fungi from several lineages and diverse ecological niches produce ergot alkaloids from at least one of several branches of the ergot alkaloid pathway. The biochemical and genetic bases for the different branches have been established and are summarized briefly herein. Several pathway branches overlap among fungal lineages and ecological niches, indicating activities of ergot alkaloids benefit fungi in different environments and conditions. Understanding the functions of the multiple genes in each branch of the pathway allows researchers to parse the abundant genomic sequence data available in public databases in order to assess the ergot alkaloid biosynthesis capacity of previously unexplored fungi. Moreover, the characterization of the genes involved in the various branches provides opportunities and resources for the biotechnological manipulation of ergot alkaloids for experimentation and pharmaceutical development.     

Secondary metabolites of <Emphasis Type="Italic">Penicillium</Emphasis> fungi isolated from permafrost deposits as chemotaxonomic markers

Species identification of slow-growing fungi of the genus Penicillium isolated from ancient permafrost deposits was performed using micro- and macromorphological characteristics as well as the composition of secondary metabolites. The strains producing clavine ergot alkaloids fumigaclavines A and B and festuclavine were assigned to the species P. palitans Westling 1911, whereas the strains forming ochratoxins A and B were identified as P. verrucosum Dierckx 1901.     

Molecular characterization of a seed transmitted clavicipitaceous fungus occurring on dicotyledoneous plants (Convolvulaceae)

Ergoline alkaloids (syn. ergot alkaloids) are constituents of clavicipitaceous fungi (Ascomycota) and of one particular dicotyledonous plant family, the Convolvulaceae. While the biology of fungal ergoline alkaloids is rather well understood, the evolutionary and biosynthetic origin of ergoline alkaloids within the family Convolvulaceae is unknown. To investigate the possible origin of ergoline alkaloids from a plant-associated fungus, 12 endophytic fungi and one epibiotic fungus were isolated from an ergoline alkaloid-containing Convolvulaceae plant, Ipomoea asarifolia Roem. & Schult. Phylogenetic trees constructed from 18S rDNA genes as well as internal transcribed spacer (ITS) revealed that the epibiotic fungus belongs to the family Clavicipitaceae (Ascomycota) whereas none of the endophytic fungi does. In vitro and in vivo cultivation on intact plants gave no evidence that the endophytic fungi are responsible for the accumulation of ergoline alkaloids in I. asarifolia whereas the epibiotic clavicipitaceous fungus very likely is equipped with the genetic material to synthesize these compounds. This fungus resisted in vitro and in vivo cultivation and is seed transmitted. Several observations strongly indicate that this plant-associated fungus and its hitherto unidentified relatives occurring on different Convolvulaceae plants are responsible for the isolated occurrence of ergoline alkaloids in Convolvulaceae. This is the first report of an ergot alkaloid producing clavicipitaceous fungus associated with a dicotyledonous plant.Data deposition: The sequences reported in this paper have been deposited in the GenBank (accession numbers are given in the text and in Fig. 3) Dedicated to Dr. Dr. h. c. mult. Albert Hofmann, the great pioneer of ergot research, on the occasion of his 100th birthday     

Consoramides A–C,New Zwitterionic Alkaloids from the Fungus Irpex consors

In our ongoing search for new secondary metabolites from fungi, a basidiomycete fungus Irpex consors was selected for mycochemical investigation, and three new zwitterionic alkaloids (1-3) and five known compounds (4-8) were isolated from the culture broth (16 l) of I. consors. The culture filtrate was fractionated by a series of column chromatography including Diaion HP-20, silica gel, and Sephadex LH-20, Sep-Pak C₁₈ cartridge, medium pressure liquid chromatography (MPLC), and high pressure liquid chromatography (HPLC) to yield eight compounds (1-8). The structures of the isolated compounds were elucidated by the interpretation of nuclear magnetic resonance (NMR) spectra and high-resolution mass spectrometry (HR-MS). Their antioxidant and antibacterial activities were examined. The zwitterionic structures of three new sesquiterpene alkaloids (1-3) were determined together with five known compounds identified as stereumamide E (4), stereumamide G (5), stereumamide H (6), stereumamide D (7), and sterostrein H (8). This is the first report of the zwitterionic alkaloids in the culture broth of I. consors. Three new zwitterionic alkaloids were named as consoramides A–C (1-3).     

后基因组时代的丝状真菌基因组学与代谢工程

丝状真菌不仅是传统发酵工业中抗生素、酶制剂和有机酸的主要生产者,而且也是代谢工程育种中异源蛋白表达的重要细胞工厂。丝状真菌的遗传修饰和代谢工程研究是现代工业生物技术领域最具活力的研究方向之一。特别是与细菌和酵母相比,丝状真菌在细胞生长、营养需求、环境适应性、翻译后修饰、蛋白分泌能力和生物安全性等方面具有显著的优势。文章综述了丝状真菌作为异源蛋白表达系统在基因组学技术研究和代谢工程研究方面的最新进展。作者在分析丝状真菌基因组结构、特点的基础上,阐述了比较基因组学、蛋白质组学、转录组学和代谢组学等对丝状真菌的代谢途径重构、新型蛋白挖掘和代谢工程育种中的作用和意义。另一方面,作者分析了丝状真菌在表达外源蛋白时遇到的瓶颈问题,总结了丝状真菌代谢工程育种中的常用策略包括异源基因的融合表达、反义核酸技术、蛋白分泌途径改造、密码子优化和蛋白酶缺陷宿主的选育等技术和手段。最后,对该领域的发展趋势进行了展望。     

Microalgae in the postgenomic era: a blooming reservoir for new natural products

Bacteria, fungi, algae and higher plants are the most prolific producers of natural products (secondary metabolites). Compared to macroalgae, considerably fewer natural products have been isolated from microalgae, which offer the possibility of obtaining sufficient and well-defined biological material from laboratory cultures. Interest in microalgae is reinforced by large-scale data sets from genome sequencing projects and the development of genetic tools such as transformation protocols. This review highlights what is currently known about the biosynthesis and biological role of natural products in microalgae, with examples from isoprenoids, complex polyketides, nonribosomal peptides, polyunsaturated fatty acids and oxylipins, alkaloids, and aromatic secondary metabolites. In addition, we introduce a bioinformatic analysis of available genome sequences from totally 16 microalgae, belonging to the green and red algae, heterokonts and haptophytes. The results suggest that the biosynthetic potential of microalgae is underestimated and many microalgal natural products remain to be discovered.     

Antifungal stress metabolites from Solanum aviculare

The steroidal alkaloids 5β-solasodan-3-one and solasodenone were isolated as antifungal stress metabolites from leaves of Solanum aviculare stressed by vacuum infiltration with water. The constitutive leaf alkaloids, solasodine and solamargine, also showed antifungal activity.