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Overproduction Strategies for Microbial Secondary Metabolites: a Review

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Overproduction Strategies for Microbial Secondary Metabolites: a Review Review Article ISSN 2250-0480 Vol 3/Issue 1/Jan-Mar 2013 OVERPRODUCTION STRATEGIES FOR MICROBIAL SECONDARY METABOLITES: A REVIEW NAFISEH DAVATIA AND MOHAMMAD. B HABIBI NAJAFIB* aPh.D Student of Food Microbiology, Department of Food Science & Technology, Ferdowsi University of Mashhad, Mashhad, Iran bProfessor, Department of Food Science & Technology, Faculty of Agriculture, Ferdowsi University of Mashhad, P. O. Box 91775-1163, Mashhad, Iran ABSTRACT The formation of secondary metabolites is regulated by nutrients, growth rate, feedback control, enzyme inactivation, and enzyme induction. Regulation is influenced by unique low molecular mass compounds, transfer RNA, sigma factors and gene products formed during post-exponential development. The synthases of secondary metabolism are often coded by clustered genes on chromosomal DNA and infrequently on plasmid DNA. Strategies for overproduction of microbial products can be based on microbial response (Elicitors, quorum sensing), genetic engineering, metabolic engineering and ribosome engineering. Also molecular genetic improvement methods include amplification of SM biosynthetic genes, inactivation of competing pathways, disruption or amplification of regulatory genes, manipulation of secretory mechanisms, expression of a convenient heterologous protein, combinatorial biosynthesis. Key words: Secondary metabolites, Overproduction, Microbial, Strategies, Genetic. INTRODUCTION Secondary metabolites are organic compounds that metabolites, strategies for overproduction of such are not directly involved in the normal growth, metabolites with the aim of highlighting strategies development or reproduction of an organism (Anon, based on genetically modificationmethods. 2008). Secondary metabolites often play an important role in defense systems of different Regulation of secondary metabolites production organisms (Stamp N, 2003). Humans use secondary The formation of secondary metabolites is regulated metabolites as medicines, flavorings, and by nutrients, growth rate, feedback control, recreational drugs. Microbial secondary metabolites enzymeinactivation, and enzyme induction. include antibiotics, pigments, toxins, effectors of Regulation is influencedby unique low molecular ecological competition and symbiosis, pheromones, mass compounds, transfer RNA, sigmafactors and enzyme inhibitors, immune modulating agents, gene products formed during post- receptor antagonists and agonists, pesticides, exponentialdevelopment.Thesynthesis of secondary antitumor agentsand growth promoters of animals metabolites areoftencoded by clustered genes on and plants. They have a majoreffect on the health, chromosomal DNA and infrequently on plasmid nutrition and economics of our society. This paper DNA. Unlike primary metabolism, thepathways of discusses in detail the regulation of secondary secondary metabolism are still not understood to a L - 23 Life Science molecular biology Review Article ISSN 2250-0480 Vol 3/Issue 1/Jan-Mar 2013 great degree and thus provide opportunities for 1. STRATEGIES FOR OVER- basicinvestigations of enzymology, control and PRODUCTION OF MICROBIAL differentiation. Secondary metabolism is brought on by exhaustion of anutrient, biosynthesis or addition PRODUCTS of an inducer, and/or by a growth rate decrease. These events generate signals which affecta cascade 1.1. Microbial Response(Quorum Sensing, of regulatory events resulting in chemical Elicitation) differentiation (secondary metabolism) and 1.1.1. Elicitors morphologicaldifferentiation (morphogenesis1). The Environmental abiotic and biotic stress factors have signal is often a lowmolecular weight inducer which been proved to effect variety ofresponses in acts by negative control, i.e.by binding to and microbes. Elicitors, as stress factors, induce or inactivating a regulatory protein enhance the biosynthesis ofsecondary metabolites (repressorprotein/receptorprotein) which normally added to a biological system (Raina S et al, 2011). prevents secondary metabolism and morphogenesis They are classified into variousgroups based on during rapid growth andnutrient sufficiency. their nature and origin: physical or chemical, biotic Nutrient/growth rate/inducer signalspresumably or abiotic.Initial studies on elicitation of secondary activate a “master gene” which either acts at the metabolites werecarried out on plant cells and level of translation by encoding a rare tRNA, or by extended, over the years, to bacteria, animal cell encoding a positive transcription factor. Such cultures and filamentous fungi. Abiotic stress master genes control bothsecondary metabolism and (abiotic elicitors) imposed bypH improves pigment morphogenesis. At a second levelof regulatory production by Monascuspurpureus and antibiotic hierarchy genes could exist which control production by Streptomyces spp. onebranch of the cascade, i.e. either secondary Traditionallycarbohydrates have been used as metabolism ormorphogenesis but not both. In the carbon sources in fermentation processes. They havealso been used widely in small amounts (mg L- secondary metabolismbranch, genes at a third level 1 could control formation ofparticular groups of ) as elicitor molecules in bacterial andfungal secondary metabolites. At a fourth levelthere may fermentations for overproduction of commercially be genes which control smaller groups, and important secondarymetabolites.In one approach to finally,fifth level genes could control individual improve production, the effect of carbohydratebiotic biosynthetic pathways;these are usually positively elicitors(oligosaccharides, oligomannuronate, acting but some act negatively.There are also oligoguluronate and mannan- oligosaccharides) on several levels of hierarchy on the morphogenesis variety of fungal systems: branch. The second level could include genes which Penicilliumspp.,Ganodermaspp., Corylopsisspp. and controlaerial mycelium formation in filamentous bacterialcultures: Streptomyces spp., Bacillus spp. organisms plus allthe sporulation genes lower in the for production of antibiotics, enzymes, pigments cascade. Each third levellocus could control a and changes in morphology was investigated (Raina particular stage of sporulation. Some ofthese loci S et al, 2011). code for sigma factors. Feedback regulation also 1.1.2. Quorum Sensing isinvolved in secondary metabolite control (Demain Quorum sensing is the communication between AL, 1998). cells through the release of chemical signals when celldensity reaches a threshold concentration (critical mass. Under these conditions, they sense the presence of other microbes. This process, investigated for more than30 years, was first 1Morphogenesis (from the Greek morphê shape and genesis creation, discovered in Gram-negative bacteria, and then in literally, "beginning of the shape") is the biological process that causes an organism to develop its shape. It is one of three fundamental Gram-positivebacteria and dimorphic fungi (Raina aspects of developmental biology along with the control of cell S et al, 2011). The quorum sensing signals differ in growth and cellular differentiation(Anon, 2012). L - 24 Life Science molecular biology Review Article ISSN 2250-0480 Vol 3/Issue 1/Jan-Mar 2013 different microbialsystems; examples are acyl- receptor proteins which normally repress homoserine lactones, modified or unmodified chemicaland morphological differentiation peptides,complex γ -butyrolactone molecules and (secondary metabolism and differentiation intoaerial their derivatives. mycelia and spores respectively) but, when reacted A numberofphysiologicalactivities of microbes(e.g. with butanolide, can no longer function. symbiosis, competence, conjugation, sporulation, Homoserine lactones of Gram-negative bacteria biofilmformation, virulence, motility and the function athigh cell density and are structurally production of various secondary metabolites) are related to the butanolides. They turn on plantand regulated through the quorum-sensing.Thereis great animal virulence, light emission, plasmid transfer, potential for the use of this communication process and production of pigments, cyanide and β-lactam for industrial exploitation.Filamentous fungi are a antibiotics. They are made by enzymes homologous main microbial source for production of to Lux1, excreted by the cell, enter other cells at pharmaceutical andbiotechnological products. high density, bind to a Lux Rhomologue, the However, until recently, very little was reported in complex then binding to DNA upstream of genes theliterature regarding quorum sensing phenomena controlled by “quorum sensing”and turning on their in these fungi. Scientistsexplored, for thefirst time, expression. Quorum sensing also operates in the the possibility of overproduction of fungal case of thepeptide pheromones of the Gram-positive metabolites inresponse to the supplementation of bacteria. Here, secretion is accomplishedby an ATP liquid cultures by variety of quorum binding cassette (ABC transporter), the secreted sensingmolecules.Bacillus licheniformisis widely pheromone beingrecognized by a sensor component present in the environment. Its metabolic diversity of a two-component signal transduction system hasresulted in its use for production of enzymes, (Demain AL, 1998).The pheromone often induces antibiotics and fine chemicals. bacteriocin produced its own synthesis as well as those proteins by B. licheniformisis a polypeptide antibiotic active involvedin protein/peptide antibiotic (including against Gram positiveand some Gram-negative bacteriocins
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