Relationship between Secondary Metabolism and Fungal Development

Filamentous fungi are unique organisms—rivaled only by actinomycetes and plants—in producing a wide range of natural products called secondary metabolites. These compounds are very diverse in structure and perform functions that are not always known. However, most secondary metabolites are produced after the fungus has completed its initial growth phase and is beginning a stage of development represented by the formation of spores. In this review, we describe secondary metabolites produced by fungi that act as sporogenic factors to influence fungal development, are required for spore viability, or are produced at a time in the life cycle that coincides with development. We describe environmental and genetic factors that can influence the production of secondary metabolites. In the case of the filamentous fungus Aspergillus nidulans, we review the only described work that genetically links the sporulation of this fungus to the production of the mycotoxin sterigmatocystin through a shared G-protein signaling pathway.     

CDP-Diacylglycerol Synthetase Coordinates Cell Growth and Fat Storage through Phosphatidylinositol Metabolism and the Insulin Pathway

During development, animals usually undergo a rapid growth phase followed by a homeostatic stage when growth has ceased. The increase in cell size and number during the growth phase requires a large amount of lipids; while in the static state, excess lipids are usually stored in adipose tissues in preparation for nutrient-limited conditions. How cells coordinate growth and fat storage is not fully understood. Through a genetic screen we identified Drosophila melanogaster CDP-diacylglycerol synthetase (CDS/CdsA), which diverts phosphatidic acid from triacylglycerol synthesis to phosphatidylinositol (PI) synthesis and coordinates cell growth and fat storage. Loss of CdsA function causes significant accumulation of neutral lipids in many tissues along with reduced cell/organ size. These phenotypes can be traced back to reduced PI levels and, subsequently, low insulin pathway activity. Overexpressing CdsA rescues the fat storage and cell growth phenotypes of insulin pathway mutants, suggesting that CdsA coordinates cell/tissue growth and lipid storage through the insulin pathway. We also revealed that a DAG-to-PE route mediated by the choline/ethanolamine phosphotransferase Bbc may contribute to the growth of fat cells in CdsA RNAi.     

Pleiotropic Control of Secondary Metabolism and Morphological Development by KsbC,a Butyrolactone Autoregulator Receptor Homologue in Kitasatospora setae

The γ-butyrolactone autoregulator signaling cascades have been shown to control secondary metabolism and/or morphological development among many Streptomyces species. However, the conservation and variation of the regulatory systems among actinomycetes remain to be clarified. The genome sequence of Kitasatospora setae, which also belongs to the family Streptomycetaceae containing the genus Streptomyces, has revealed the presence of three homologues of the autoregulator receptor: KsbA, which has previously been confirmed to be involved only in secondary metabolism; KsbB; and KsbC. We describe here the characterization of ksbC, whose regulatory cluster closely resembles the Streptomyces virginiae barA locus responsible for the autoregulator signaling cascade. Deletion of the gene ksbC resulted in lowered production of bafilomycin and a defect of aerial mycelium formation, together with the early and enhanced production of a novel β-carboline alkaloid named kitasetaline. A putative kitasetaline biosynthetic gene cluster was identified, and its expression in a heterologous host led to the production of kitasetaline together with JBIR-133, the production of which is also detected in the ksbC disruptant, and JBIR-134 as novel β-carboline alkaloids, indicating that these genes were biosynthetic genes for β-carboline alkaloid and thus are the first such genes to be discovered in bacteria.     

Neuronal Control of Metabolism through Nutrient-Dependent Modulation of Tracheal Branching

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Geminin Coordinates Cell Cycle and Developmental Control

Growth and differentiation are two major themes in embryonic development. Numerous cell divisions have to be regulated on the path from a unicellular embryo, the zygote, to the multicellular structures of a mature being. Numerous functions, specializations and cellular identities have to be generated, in order to form a complex and mature animal. Numerous mechanisms have to control the correct assignment and acquisition of cellular fates, as well as the right timing and allocation of cells. Therefore, a strict coordination has to occur between embryonic patterning and the cell cycle. From this point of view, dual roles or mutual interactions of typical proliferation and developmental control genes are likely. Recently, new light was shed on these issues by identifying the nuclear protein Geminin as a molecular coordinator between the cell cycle and axial patterning. We summarize the role of Geminin in cell cycle, in the embryonic patterning controlled by Hox genes, providing insights into cell cycle regulators in embryonic development, and, conversely, typical developmental control genes in cell cycle regulation.     

链霉菌基因组及次生代谢研究进展

链霉菌属革兰氏阳性放线菌,具有复杂的生活周期和次生代谢途径,并产生大量具有重要价值的天然代谢物。本文概述了链霉菌基因组染色体的独特结构与次生代谢途径的研究进展,重点论述了利用基因组信息改造和调控链霉菌次生代谢途径的研究成果。后基因组时代的功能基因组研究使人类能深入了解链霉菌家族,对链霉菌进行更加合理高效的遗传操作,为提高具有重要价值的天然代谢物的产量和获得新代谢物创造更有利的条件。     

真菌次级代谢转录调控研究进展

真菌次级代谢产物具有多样复杂的结构和良好的生物活性,广泛应用于工业、农业、医疗等领域。次级代谢产物的产生受多个层级的调控,尤其是转录水平的调控至关重要。文中首先介绍了在真菌转录调控过程中参与次级代谢的代表性转录因子和蛋白质复合体,进而举例说明了转录调控在挖掘真菌新颖次级代谢产物领域的重要作用;期望相关研究者全面认识真菌次级代谢产物的生物合成及转录调控,为发现新的具有良好生物活性的天然产物提供思路。     

Autoregulatory Factors of Secondary Metabolism and Morphogenesis in Actinomycetes

Abstract

The Gram-positive bacterial genus Streptomyces possesses interesting biological aspects, such as the ability to produce a wide variety of secondary metabolites and a mycelial form of growth that culminates in sporulation. A close relationship of secondary metabolism and cell differentiation has been well recognized; secondary metabolism might be a physiological expression of cell differentiation. A variety of diffusible low-molecular-weight chemical substances have been found to function in general as regulatory factors, like “hormones” in eukaryotes, for secondary metabolism and cell differentiation. Among these factors, A-factor has been most extensively studied. This review summarizes recent research on the chemical structures, functions, biosyntheses, and mode of action of these regulatory factors.     

植物萜类次生代谢及其调控

植物次生代谢在植物生长发育、环境适应、抵御病虫害等方面发挥着重要作用,这些天然产物组成地球上最丰富的有机化合物的宝库．萜类是植物代谢产物中种类最多的一类,具有重要的生理和生态功能,一些成分还有应用价值．近十几年来,人们在萜类化合物的分离、鉴定、应用、生物合成、相关基因与基因族、酶蛋白结构和功能、代谢调控以及代谢工程等各方面取得了重大进展．本文概述了植物萜类化合物代谢及其调控领域的研究进展与发展趋势．     

Novel 1,4-dihydropyridine induces apoptosis in human cancer cells through overexpression of Sirtuin1

1,4-Dihydropyridines (1,4-DHPs) are important as a class of heterocyclic compounds that exhibit wide range of biological actions. Many of its derivatives are already characterized as medicinally important drugs and used worldwide. In this study, we have screened some novel Hantzsch 1,4-DHP compounds using both in silico (QSAR and Pharmacophore) and in vitro (cytotoxic screening). 1,4-DHP showed selective cytotoxicity against five human cancerous cell lines; A375, A549, HeLa, HepG2 and SH-SY5Y but limited effect towards normal skin keratinocyte (HaCaT), lung fibroblast (WL-38) and healthy peripheral blood mononuclear cells. In A375 and HepG2 cells, one of the 1,4-DHP derivative (DHP-8) was found to inhibit cell proliferation, and simultaneously increased the apoptotic population as well as mitochondrial membrane depolarization. Furthermore, the mitochondrial signal was triggered with the activation of cleaved Caspase9, Caspase3 and PARP. The treatment with DHP-8 also increased the expression level of SIRT1, subsequently decreasing the level of pAKT^ser473 and survivin. Reduced pAKT^ser473 expression led to decrease the phosphorylated inactive form of GSK3β^ser9 and as a result, proteasomal degradation of Mcl-1 occurred in both the cell lines. Here, we suggest that the apoptotic effect of DHP-8 in A375 and HepG2 cells was mediated by AKT and survivin pathways through SIRT1 activation. The involvement of DHP-8 in SIRT1 activation was further verified by co-treatment of nicotinamide with DHP-8 in both A375 and HepG2 cells. Overall, this study emphasizes the possible potential and therapeutic role of DHP-8 in skin and liver cancer.     

植物次生代谢途径的遗传修饰研究进展

通过过量表达或反义抑制等遗传修饰手段,人们尝试对研究较为清楚的植物次生代谢途径进行了基因工程改造。对萜类、生物碱、苯丙烷类3类植物次生代谢工程的研究进展进行了综述。     

Sequential Primary and Secondary Shunt Metabolism in Penicillium chrysogenum

Penicillium chrysogenum was grown on a rich medium and on a more sparse medium which favored penicillin production. Mycelia grown on both media were examined for changes in lipid, mannitol, erythritol, glycerol, pentitol, trehalose, and residual mycelium, and the filtrates were examined for penicillin. Penicillin production took place after the bulk of trehalose, polyol, and lipid had accumulated, and hence the sequential pattern of primary and secondary shunt metabolism, as observed in the case of ergot alkaloid production by Claviceps purpurea, was demonstrated in this example of penicillin production.     

一株Streptosporangium sp.的次生代谢产物的研究

通过对Streptosporangium sp.菌株发酵液的初步分离纯化,得到二个化合物,由波谱数据解析鉴定其结构分别为YXJE1(1),7,4′-二羟基黄酮(2)。其中化合物1是新化合物。活性实验证明化合物1,2具有一定的抑制乙酰胆碱酯酶活性。