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At least 19 recordsLinked to original sources
PubMed2005

[Research progress in genetic engineering of plant secondary metabolism].

Secondary metabolism plays an important role in plant life as well as the interaction between plants and environmental factors. Many secondary metabolites derived from plants have been used for the production of medicines, dyes, insecticides, food flavors, fragrances and so on. With increasingly comprehensive understanding of the plant metabolic networks, great progress has been made in the genetic improvement of plant secondary metabolic pathways through gene engineering. Strategies for the genetic engineering of plant secondary metabolism include: (1) enabling the host plant to accumulate a novel desirable compound by transformation of single/multiple enzyme gene (s) or a whole metabolic pathway; (2) decreasing target gene expression or inhibiting competitive metabolic pathway to achieve metabolic flux towards higher production of particular molecules through antisense RNA and RNA interference technologies; (3) effectively manipulating the transcription factors responsible for the metabolic regulation at multiple steps in a given pathway so as to have a great synthesis of the target bio-chemicals. Basing on author's research work on flavonoid synthesis mechanism in soybean seed and its gene engineering, recent progress in the engineering of plant secondary metabolism involved in the synthesis of anthocyanins, flavonoids, alkaloids, terpenoids, benzoic acid derivatives etc are reviewed.

Gene Expression Regulation, Plant↗
PubMed1990

Roles of trace metals in transcriptional control of microbial secondary metabolism.

Secondary metabolism in bacteria and fungi requires a much narrower range of environmental concentrations of key trace metals than that permitted for primary metabolism. The cells acquire appropriate quantities of the key metals at the initiation of the shift from primary to secondary metabolism. Evidence suggests that these essential micronutrients participate in regulating the expression of genes responsible for synthesis of secondary metabolites and/or morphological alterations associated with cellular differentiation.

Bacteria↗
PubMed1992

Origins of secondary metabolism.

Secondary metabolites generally benefit their producers as poisons that protect them against competitors, predators or parasites. They are produced from universally present precursors (most often acetyl-CoA, amino acids or shikimate) by specific enzymes that probably arose by the duplication and divergence of genes originally coding for primary metabolism. Most secondary metabolites are restricted to single major taxa on the universal phylogenetic tree and so probably originated only once. But different secondary metabolic pathways have originated from different ancestral enzymes at radically different times in evolution. Secondary metabolites are most abundantly produced by microorganisms in crowded habitats and by plants, fungi and sessile animals like sponges, where chemical defence and attack rather than physical escape or fighting are at a premium. The first secondary metabolites were probably antibiotics produced in microbial mats over 3500 million years ago. These first ecosystems probably consisted entirely of eubacteria: archaebacteria and eukaryotes arose much later. As a phylogenetic context for considering the earliest origins of antibiotics I summarize a cladistic analysis of the explosive eubacterial primary diversification. This suggests that the most primitive surviving cells are the photosynthetic heliobacteria. Study of these and of the nearly as primitive chloroflexibacteria, spirochaetes and deinobacteria may provide the best evidence on the origins of secondary and primary metabolism.

Anti-Bacterial Agents↗
PubMed2004

Crosstalk and differential response to abiotic and biotic stressors reflected at the transcriptional level of effector genes from secondary metabolism.

Plant secondary metabolism significantly contributes to defensive measures against adverse abiotic and biotic cues. To investigate stress-induced, transcriptional alterations of underlying effector gene families, which encode enzymes acting consecutively in secondary metabolism and defense reactions, a DNA array (MetArray) harboring gene-specific probes was established. It comprised complete sets of genes encoding 109 secondary product glycosyltransferases and 63 glutathione-utilizing enzymes along with 62 cytochrome P450 monooxygenases and 26 ABC transporters. Their transcriptome was monitored in different organs of unstressed plants and in shoots in response to herbicides, UV-B radiation, endogenous stress hormones, and pathogen infection. A principal component analysis based on the transcription of these effector gene families defined distinct responses and crosstalk. Methyl jasmonate and ethylene treatments were separated from a group combining reactions towards two sulfonylurea herbicides, salicylate and an avirulent strain of Pseudomonas syringae pv. tomato . The responses to the herbicide bromoxynil and UV-B radiation were distinct from both groups. In addition, these analyses pinpointed individual effector genes indicating their role in these stress responses. A small group of genes was diagnostic in differentiating the response to two herbicide classes used. Interestingly, a subset of genes induced by P. syringae was not responsive to the applied stress hormones. Small groups of comprehensively induced effector genes indicate common defense strategies. Furthermore, homologous members within branches of these effector gene families displayed differential expression patterns either in both organs or during stress responses arguing for their non-redundant functions.

Acetates↗
PubMed2002

Quantification of metabolic flux in plant secondary metabolism by a biogenetic organizational approach.

Metabolic engineering represents a promising approach to enhance the yield of valuable natural products from plants. A method to quantify flux through metabolite measurements is necessary for the analysis of native and modified pathways. Rather than focusing only on the accumulation of the final products, analyzing a wide range of secondary metabolites has significant advantages. We propose a model that organizes the flux analysis by grouping metabolites of similar biosynthetic origin. To this end, we have quantified temporal profiles of metabolites from several branches of the indole alkaloid pathway in Catharanthus roseus hairy root cultures. By analyzing these data, we are able to examine the distribution of flux around key branchpoints. Furthermore, this analysis provides crucial information such as an estimate of total flux to secondary metabolism.

Aspidosperma↗
PubMed2000

The evolution of secondary metabolism - a unifying model.

Why do microbes make secondary products? That question has been the subject of intense debate for many decades. There are two extreme opinions. Some argue that most secondary metabolites play no role in increasing the fitness of an organism. The opposite view, now widely held, is that every secondary metabolite is made because it possesses (or did possess at some stage in evolution) a biological activity that endows the producer with increased fitness. These opposing views can be reconciled by recognizing that, because of the principles governing molecular interactions, potent biological activity is a rare property for any molecule to possess. Consequently, in order for an organism to evolve the rare potent, biologically active molecule, a great many chemical structures have to be generated, most of which will possess no useful biological activity. Thus, the two sides of the debate about the role and evolution of secondary metabolism can be accommodated within the view that the possession of secondary metabolism can enhance fitness, but that many products of secondary metabolism will not enhance the fitness of the producer. It is proposed that secondary metabolism will have evolved such that traits that optimize the production and retention of chemical diversity at minimum cost will have been selected. Evidence exists for some of these predicted traits. Opportunities now exist to exploit these unique properties of secondary metabolism to enhance secondary product diversity and to devise new strategies for biotransformation and bioremediation.

Bacteria↗
PubMed2004

LaeA, a regulator of secondary metabolism in Aspergillus spp.

Secondary metabolites, or biochemical indicators of fungal development, are of intense interest to humankind due to their pharmaceutical and/or toxic properties. We present here a novel Aspergillus nuclear protein, LaeA, as a global regulator of secondary metabolism in this genus. Deletion of laeA (DeltalaeA) blocks the expression of metabolic gene clusters, including the sterigmatocystin (carcinogen), penicillin (antibiotic), and lovastatin (antihypercholesterolemic agent) gene clusters. Conversely, overexpression of laeA triggers increased penicillin and lovastatin gene transcription and subsequent product formation. laeA expression is negatively regulated by AflR, a sterigmatocystin Zn2Cys6 transcription factor, in a unique feedback loop, as well as by two signal transduction elements, protein kinase A and RasA. Although these last two proteins also negatively regulate sporulation, DeltalaeA strains show little difference in spore production compared to the wild type, indicating that the primary role of LaeA is to regulate metabolic gene clusters.

Amino Acid Sequence↗
PubMed2001

4'-phosphopantetheine transfer in primary and secondary metabolism of Bacillus subtilis.

4'-Phosphopantetheine transferases (PPTases) transfer the 4'-phosphopantetheine moiety of coenzyme A onto a conserved serine residue of acyl carrier proteins (ACPs) of fatty acid and polyketide synthases as well as peptidyl carrier proteins (PCPs) of nonribosomal peptide synthetases. This posttranslational modification converts ACPs and PCPs from their inactive apo into the active holo form. We have investigated the 4'-phosphopantetheinylation reaction in Bacillus subtilis, an organism containing in total 43 ACPs and PCPs but only two PPTases, the acyl carrier protein synthase AcpS of primary metabolism and Sfp, a PPTase of secondary metabolism associated with the nonribosomal peptide synthetase for the peptide antibiotic surfactin. We identified and cloned ydcB encoding AcpS from B. subtilis, which complemented an Escherichia coli acps disruption mutant. B. subtilis AcpS and its substrate ACP were biochemically characterized. AcpS also modified the d-alanyl carrier protein but failed to recognize PCP and an acyl carrier protein of secondary metabolism discovered in this study, designated AcpK, that was not identified by the Bacillus genome project. On the other hand, Sfp was able to modify in vitro all acyl carrier proteins tested. We thereby extend the reported broad specificity of this enzyme to the homologous ACP. This in vitro cross-interaction between primary and secondary metabolism was confirmed under physiological in vivo conditions by the construction of a ydcB deletion in a B. subtilis sfp(+) strain. The genes coding for Sfp and its homolog Gsp from Bacillus brevis could also complement the E. coli acps disruption. These results call into question the essential role of AcpS in strains that contain a Sfp-like PPTase and consequently the suitability of AcpS as a microbial target in such strains.

Amino Acid Sequence↗
PubMed2004

Responses of primary and secondary metabolism to sugar accumulation revealed by microarray expression analysis of the Arabidopsis mutant, pho3.

The Arabidopsis mutant pho3 accumulates sucrose and other carbohydrates to high levels, providing a means of investigating the genomic response to sucrose accumulation using microarray analysis. Wild-type and mutant plants were grown in soil to the mature rosette stage for the analysis of gene expression using the Affymetrix ATH1 chip, containing more than 22,500 probe sets. Small, but significant, decreases were observed in the expression of many genes encoding enzymes and regulatory proteins involved in primary carbon assimilation, suggesting that, in mature leaves of Arabidopsis, there is limited feedback regulation on gene expression by sugars. The study revealed a striking increase in the expression of the plastid glucose 6-phosphate/phosphate translocator, characteristically expressed only in heterotrophic tissues. This indicated a change in the nature of metabolite exchange between the plastid and the cytosol in the pho3 mutant. The expression of enzymes of starch synthesis also increased significantly. Very large increases were observed in the expression of transcription factors and enzymes involved in anthocyanin biosynthesis. This finding reinforces the emerging picture of an important role for primary metabolism in regulating secondary metabolism.

Arabidopsis↗
PubMed1979

Secondary metabolism as an expression of microbial growth and development.

A case is made out for regarding secondary metabolism as part of normal cell growth, related to its interactions with the environment. Secondary metabolism is widespread, especially in fungi and actinomycetes, and is not to be regarded as confined to the production of antibiotics and other special substances. It is part of the normal maturation process. Examples are given of the influence of secondary metabolism in ecological systems. It is also shown that cell productivity can be related to age structure. Secondary metabolism is thus linked with growth, although in many cases this may not be obvious in laboratory work. Initiation of production will arise from the system which regulates growth and differentiation. These processes are little understood at present, but it is clear that the factors involved differ in different instances and that they involve a very great variety of biochemical and physiological processes.

Actinomycetales↗
PubMed1995

A lacZ reporter fusion method for the genetic analysis of regulatory mutations in pathways of fungal secondary metabolism and its application to the Aspergillus nidulans penicillin pathway.

Secondary metabolism, usually superfluous under laboratory conditions, is intrinsically elusive to genetic analysis of its regulation. We describe here a method of analyzing regulatory mutations affecting expression of secondary metabolic genes, with an Aspergillus nidulans penicillin structural gene (ipnA [encoding isopenicillin N-synthase]) as a model. The method is based on a targeted double integration of a lacZ fusion reporter gene in a chromosome different from that containing the penicillin gene cluster. The trans-acting regulatory mutations simultaneously affect lacZ expression and penicillin biosynthesis. One of these mutations (npeE1) has been analyzed in detail. This mutation is recessive, prevents penicillin production and ipnA'::'lacZ expression, and results in very low levels of the ipnA message at certain times of growth. This indicates that npeE positively controls ipnA transcription. We also show that this tandem reporter fusion allows genetic analysis of npeE1 by using the sexual and parasexual cycles and that lacZ expression is an easily scorable phenotype. Haploidization analysis established that npeE is located in chromosome IV, but npeE1 does not show meiotic linkage to a number of known chromosome IV markers. This method might be of general applicability to genetic analysis of regulation of other fungal secondary metabolic pathways.

Aspergillus nidulans↗
PubMed1984

The role of secondary metabolism in the metabolic activation of 7,12-dimethylbenz[a]anthracene by rat liver microsomes.

The effect of induction by either phenobarbital (PB) or 3-methylcholanthrene (MC) on the kinetics of both primary and secondary metabolism of 7,12-dimethylbenz[a]anthracene (DMBA) have been studied. PB and MC induction stimulate the initial rate of total DMBA metabolism 4- and 8-fold, respectively. Individual metabolites exhibited distinct time courses dependent on the inducer. With both induced and uninduced microsomes, formation of DMBA 5,6-dihydrodiol exhibited a 2-5 min time lag before reaching a maximum rate while, in contrast, formation of 7-hydroxymethyl-12-methylbenz[a]anthracene (7HOMMBA) declined substantially from linearity at a very early point in the reaction. This was most apparent after 2 min and total levels decreased after 5 min. Regioselectivity for both DMBA and 7HOMMBA were measured based on the initial rates of mono-oxygenation derived from these kinetics. In each set of microsomes, prior 7-hydroxylation redirected metabolism towards DMBA 3,4-dihydrodiol formation and away from 5,6-dihydrodiol. Large differences were noted for the effectiveness and regioselectivity of secondary metabolism via 7HOMMBA. MC-induced liver microsomes exhibited a stronger preference for secondary metabolism of 7HOMMBA than PB-induced and control microsomes. In all cases, 7HOMMBA dihydrodiols, formed from DMBA, appeared in the same ratio as when formed directly from 7HOMMBA, suggesting formation from 7HOMMBA rather than from 7-hydroxylation of primary dihydrodiols. The extent of secondary metabolism of primary products was calculated as the difference between the calculated formation (determined from the appropriate regioselectivity and DMBA disappearance) and the quantitated level at a particular reaction time. However, for MC-induced microsomes, quantitation of 7HOMMBA mono-oxygenated metabolites accounted for less than 50% of the calculated 7HOMMBA secondary metabolism. This discrepancy results from selective further oxidation of 7HOMMBA phenols. For control and PB-induced liver microsomes, quantitation of identifiable 7HOMMBA mono-oxygenated metabolites agreed well with calculated secondary 7HOMMBA metabolism. Based on the results presented here, factors that favor hydroxylation of PAH prior to bay-region diol-epoxide formation are discussed.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1981

[Possibilities for direct manipulation of gene expression of microbial secondary metabolism].

The present review deals with some theoretical and applied aspects of directed manipulations of control mechanisms governing the expression of microbial secondary metabolism. In attempting to make broad generalizations, the production of secondary metabolites is discussed in terms of the cellular differentiation of relevant organisms. On the basis of the actual information about the regulation of microbial idiolite synthesis, some potential ways for the quantitative and the qualitative improvement of secondary metabolite production are discussed. A number of examples demonstrate the effectiveness of rational strategies of strain development, e. g., the removal of non-specific repressions of secondary metabolism by environmental factors, the excessive production of precursors due to altered control of intermediary metabolism, the increased resistance of producer organism against the autotoxicity of some idiolites, the deletion of alternative pathways of the primary and secondary metabolism, manipulations concerning the product spectrum, the deletion of feedback mechanisms, and elimination of degradating pathways in the secondary metabolism etc. The scope and limitations of rational strategies of strain improvement by genetic and physiologic manipulations are subjected to final discussion.

Anti-Bacterial Agents↗
PubMed2005

Regulation of secondary metabolism in filamentous fungi.

Fungal secondary metabolites are of intense interest to humankind due to their pharmaceutical (antibiotics) and/or toxic (mycotoxins) properties. In the past decade, tremendous progress has been made in understanding the genes that are associated with production of various fungal secondary metabolites. Moreover, the regulatory mechanisms controlling biosynthesis of diverse groups of secondary metabolites have been unveiled. In this review, we present the current understanding of the genetic regulation of secondary metabolism from clustering of biosynthetic genes to global regulators balancing growth, sporulation, and secondary metabolite production in selected fungi with emphasis on regulation of metabolites of agricultural concern. Particularly, the roles of G protein signaling components and developmental regulators in the mycotoxin sterigmatocystin biosynthesis in the model fungus Aspergillus nidulans are discussed in depth.

Fungi↗
PubMed1991

Molecular mechanisms of the A-factor-dependent control of secondary metabolism in Streptomyces.

A-factor, 2-isocapryloyl-(3R)-hydroxymethyl-gamma-butyrolactone, is a microbial hormone controlling secondary metabolism and morphogenesis of Streptomyces griseus. The A-factor-receptor protein present in the cytoplasm is a repressor-type regulator; it plays a role in repressing streptomycin production and sporulation while the binding of A-factor to the receptor protein releases its repression. Thus, secondary metabolism and sporulation of S. griseus involve a step of hormonal regulation by A-factor. The afsR gene codes for a global regulatory protein of 993 amino acids controlling positively secondary metabolic formation in Streptomyces coelicolor A3(2), probably at the transcriptional level. This protein comprises two domains, i.e., an ATP-binding domain at its NH2-terminal portion and a DNA-binding domain with a helix-turn-helix motif at its COOH-terminal portion. The AfsR protein is found to be phosphorylated. It is assumed that the extent of phosphorylation-dephosphorylation of the AfsR protein modulates the expression of genes responsible for secondary metabolic formation.

4-Butyrolactone↗
PubMed1991

Molecular mechanisms of the a-factor-dependent control of secondary metabolism in streptomyces.

A-factor, 2-isocapryloyl-(3 R)-hydroxymethyl-gamma-butyrolactone, is a microbial hormone controlling secondary metabolism and morphogenesis of STREPTOMYCES GRISEUS. The A-factor-receptor protein present in the cytoplasm is a repressor-type regulator; it plays a role in repressing streptomycin production and sporulation while the binding of A-factor to the receptor protein releases its repression. Thus, secondary metabolism and sporulation of S. GRISEUS involve a step of hormonal regulation by A-factor. The AFSR gene codes for a global regulatory protein of 993 amino acids controlling positively secondary metabolic formation in STREPTOMYCES COELICOLOR A3(2), probably at the transcriptional level. This protein comprises two domains, i.e., an ATP-binding domain at its NH (2)-terminal portion and a DNA-binding domain with a helix-turn-helix motif at its COOH-terminal portion. The AfsR protein is found to be phosphorylated. It is assumed that the extent of phosphorylation-dephosphorylation of the AfsR protein modulates the expression of genes responsible for secondary metabolic formation.

Journal Article↗
PubMed1999

Possible involvement of cAMP in aerial mycelium formation and secondary metabolism in Streptomyces griseus.

In Streptomyces griseus, A-factor (2-isocapryloyl-3R-hydroxymethyl-gamma-butyrolactone) triggers secondary metabolism and morphogenesis by binding a repressor protein (ArpA) and dissociating it from DNA. UV-mutagenesis of the A-factor-deficient mutant HH1 generated strain HO2, defective in the synthesis of ArpA and therefore able to form aerial mycelium, spores and streptomycin. Shotgun cloning of chromosomal DNA from wild-type S. griseus in strain HO2 yielded a gene that suppressed aerial mycelium formation and streptomycin production. Nucleotide sequencing and subcloning revealed that the gene encoded a eukaryotic-type adenylate cyclase (CyaA). In mutant HO2 production of cAMP was growth-dependent until the middle of the exponential growth stage; the production profile was the same as in the wild-type strain. However, the amount of cAMP produced was five times larger when mutant HO2 harboured cyaA on the high-copy-number plasmid pIJ486. Consistent with this, supplying cAMP exogenously at a high concentration to mutant HO2 suppressed formation of both aerial mycelium and streptomycin. On the other hand, some lower concentrations of cAMP stimulated or accelerated aerial mycelium formation. No effects of exogenous cAMP on morphogenesis and secondary metabolism were apparent in the wild-type strain. In addition, disruption of the chromosomal cyaA gene in the wild-type strain had almost no effect. Introducing cyaA cloned in either a low- or a high-copy-number plasmid suppressed morphogenesis and secondary metabolism not only in mutant HO2 but also in other arpA mutants, implying that the effects of cAMP became apparent in the arpA-defective background. When mutant HO2 carried cyaA on a plasmid, synthesis of the stringent response factor ppGpp was greatly reduced; this may account for the observed suppression by cAMP of morphogenesis and secondary metabolism. cAMP also affected protein tyrosine phosphorylation, as determined with antiphosphotyrosine antibody.

4-Butyrolactone↗