Lakhasly

Nutritional control of metabolite production Fermented products that are used in our daily life are either primary or secondary metabolites produced during the trophophase and idiophase of the microbial growth, respectively.Carbon Source Action Metabolites Producer References Simple carbon Glycerol Interfering Actinomycin D Streptomyces parvullus Foster and Katz, 1981

		Erythromycins	Saccharopolyspora erythraea	Sanchez et al., 2010

		Cephalosporin	Cephalosporium acremonium	Sanchez and Demain, 2002

	Non-interfering	Simocyclinones	Streptomyces antibioticusTu 6040	Theobald et al., 2000

Monosaccharide Glucose Interfering Actinomycin Streptomyces sp. Gallo and Katz, 1972

		Cephalosporin	Cephalosporium acremonium	Sanchez and Demain, 2002

		Erythromycins	Saccharopolyspora erythraea	Sanchez et al., 2010

		Penicillin	Streptomyces chrysogenum	Sanchez and Demain, 2002

		Streptomycin	Streptomyces griseus	Sanchez and Demain, 2002

	Non-interfering	Bacilysin	Bacillus subtilis	Ozcengiz et al., 1990

Fructose	Interfering	Penicillin	Penicillium chrysogenum	Sanchez and Demain, 2002

	Non-interfering	Actinomycin	Streptomyces antibioticus	Rokem et al., 2007

		Gentamycin	Micromonospora purpurea	Sanchez and Demain, 2002

Galactose	Interfering	Penicillin	Penicillium chrysogenum	Sanchez and Demain, 2002

	Non-interfering	Actinomycin	Streptomyces antibioticus	Rokem et al., 2007

		Cephalosporin	Cephalosporium acremonium	Sanchez and Demain, 2002

Disaccharide Maltose Interfering Bacilysin Bacillus subtilis Ozcengiz et al., 1990

	Non-interfering	Gentamycin	Micromonospora purpurea	Sanchez and Demain, 2002

Sucrose	Interfering	Erythromycins	Streptomyces erythreus	Rokem et al., 2007

		Penicillin	Penicillium chrysogenum	Sanchez and Demain, 2002

	Non-interfering	Cephalosporin	Cephalosporium acremonium	Sanchez and Demain, 2002

Lactose	Interfering	*

	Non-interfering	Erythromycins	Streptomyce serythreus	Rokem et al., 2007

		Penicillin	Penicillium chrysogenum	Rokem et al., 2007

Mannose	Interfering	Erythromycin	Streptomyce serythreus	Sanchez and Demain, 2002

		Streptomycin	Streptomyces griseus	Sanchez et al., 2010

	Non-interfering	Kanamycin	Streptomyces kanamyceticus	Sanchez and Demain, 2002

Complex Starch Interfering *

	Non-interfering	Kanamycin	Streptomyces kanamyceticus	Rokem et al., 2007

Open in a new tab * Not reported.Rokem et al., 2007; Vastrad and Neelagund, 2011

	Non-interfering	*

Nitrate	Interfering	Aflatoxin	Aspergillus parasiticus	Sanchez and Demain, 2002

	Non-interfering	Rifamycin	Amycolatoposis mediterranei	Sanchez and Demain, 2002

Organic Urea Interfering Alternariol Alternaria alternata Non-interfering *

Amino acids L-alanine Interfering Actinomycin Streptomyces antibioticus Rokem et al., 2007

		Bacilysin	Bacillus subtilis	Ozcengiz et al., 1990

	Non-interfering	*

L-arginine	Interfering	*

	Non interfering	Cephalosporin	Cephalosporium acremonium	Sanchez and Demain, 2002

		Gramicidin S	Bacillus brevis	Poirier and Demain, 1981

d,l-Aspartate	Interfering	Actinomycin D	Streptomyces parvullus	Foster and Katz, 1981

	Non-interfering	Streptothricin	Streptomyces rochei	Sanchez and Demain, 2002

Leucine	Interfering	Monascus pigment	Monascus spp.In order to standardize the production medium, the concept of medium optimization has emerged.Lin and Demain, 1994

	Non-interfering	Chloramphenicol	Streptomyces venezuelae,	Rokem et al., 2007

L-isoleucine	Interfering	Actinomycin D	Streptomyces parvullus	Foster and Katz, 1981

	Non-interfering	Spiramycin	Streptomyces ambofaciens	Lebrihi et al., 1992

DL- phalanine	Interfering	Actinomycin	Streptomyces antibioticus	Rokem et al., 2007

	Non-interfering	Chloramphenicol	Streptomyces venezuelae,	Rokem et al., 2007

L-proline	Interfering	Actinomycin D	Streptomyces parvullus	Foster and Katz, 1981

	Non-interfering	Streptomycin	Streptomyces griseus	Sanchez and Demain, 2002

Tryptophan	Interfering	Candicidin	Streptomyces griseus	Sanchez and Demain, 2002

	Non-interfering	Actinomycin	Streptomyces parvullus	Foster and Katz, 1981

Open in a new tab * Not reported.Nitrogen Source Action Metabolites Producer References Inorganic NH+4 Interfering Spiramycin Streptomyces ambofaciens Lebrihi et al., 1992

		Cephalosporin	Cephalosporium acremonium	Sanchez and Demain, 2002

		Erythromycin	Streptomyces erythreus	Rokem et al., 2007

		Streptomycin	Streptomyces griseus	Sanchez and Demain, 2002

		Tetracycline	Streptomyces spp.The production of specific metabolites in high titer could be possible by maintaining proper control and regulation at different levels via transport and metabolism of extra-cellular nutrients, precursor formation and accumulation of intermediates (Rokem et al., 2007).Fermentation processes, where the precursor(s) of the specific products are not added in the medium, carbon and nitrogen sources present in the medium during their metabolism may initiate the biosynthesis of precursors that regulate the metabolism and influence the end product synthesis (Elibol, 2004).Marwick et al. (1999), while studying antibiotics production from marine bacteria noticed that the gradually assimilating carbon sources, like, galactose generally enhances the production of secondary metabolites (antibiotics).Given this in view, nutrients type and their concentrations in the medium play an important role in commencing the production of primary and secondary metabolites as limited supply of an essential nutrient can restrict the growth of microbial cells or product formation.Singh et al. (2009) during the optimization of actinomycin V production by Streptomyces triostinicus found that biosynthesis of actinomycin V involves tryptophan pathway and addition of amino acid tryptophan to the medium enhances the production.Sanchez and Demain (2002) reported that various secondary metabolites' production such as, actinorhodin, cephalosporin, clavulanic acid, streptomycin, tetracycline, vancomycin etc.Table 1.Table 2.

Nutritional control of metabolite production
Fermented products that are used in our daily life are either primary or secondary metabolites produced during the trophophase and idiophase of the microbial growth, respectively. High productivity titer is the pre-requisite for the industrial production of any type of metabolite. The production of specific metabolites in high titer could be possible by maintaining proper control and regulation at different levels via transport and metabolism of extra-cellular nutrients, precursor formation and accumulation of intermediates (Rokem et al., 2007). Fermentation processes, where the precursor(s) of the specific products are not added in the medium, carbon and nitrogen sources present in the medium during their metabolism may initiate the biosynthesis of precursors that regulate the metabolism and influence the end product synthesis (Elibol, 2004). Given this in view, nutrients type and their concentrations in the medium play an important role in commencing the production of primary and secondary metabolites as limited supply of an essential nutrient can restrict the growth of microbial cells or product formation. Generally, carbon and nitrogen sources present in the medium can influence the metabolite production.
Carbon source
Carbon is the most important medium component, as it is an energy source for the microorganisms and plays an important role in the growth as well as in the production of primary and secondary metabolite. The rate at which the carbon source is metabolized can often influence the formation of biomass and/or the production of primary or secondary metabolites. Marwick et al. (1999), while studying antibiotics production from marine bacteria noticed that the gradually assimilating carbon sources, like, galactose generally enhances the production of secondary metabolites (antibiotics). A classic example for this is, penicillin production, where glucose is found to have repression effect. Later, it was found that lactose is a slowly assimilating carbon source and helped in the production of secondary metabolites (i.e., penicillin). Hence, in order to overcome the carbon catabolite repression phenomenon, the production process was established using lactose fermentation. Describing the role of each carbon in different fermentation processes, will increase the length of this manuscript. Hence we compiled a list, wherein we summarized some interfering and non-interfering carbon sources (Table 1).
Table 1.
Examples of some interfering and non-interfering carbon sources.
Carbon Source Action Metabolites Producer References
Simple carbon Glycerol Interfering Actinomycin D Streptomyces parvullus Foster and Katz, 1981

		Erythromycins	Saccharopolyspora erythraea	Sánchez et al., 2010



		Cephalosporin	Cephalosporium acremonium	Sanchez and Demain, 2002



	Non-interfering	Simocyclinones	Streptomyces antibioticusTü 6040	Theobald et al., 2000

Monosaccharide Glucose Interfering Actinomycin Streptomyces sp. Gallo and Katz, 1972

		Cephalosporin	Cephalosporium acremonium	Sanchez and Demain, 2002



		Erythromycins	Saccharopolyspora erythraea	Sánchez et al., 2010



		Penicillin	Streptomyces chrysogenum	Sanchez and Demain, 2002



		Streptomycin	Streptomyces griseus	Sanchez and Demain, 2002



	Non-interfering	Bacilysin	Bacillus subtilis	Ozcengiz et al., 1990



Fructose	Interfering	Penicillin	Penicillium chrysogenum	Sanchez and Demain, 2002



	Non-interfering	Actinomycin	Streptomyces antibioticus	Rokem et al., 2007



		Gentamycin	Micromonospora purpurea	Sanchez and Demain, 2002



Galactose	Interfering	Penicillin	Penicillium chrysogenum	Sanchez and Demain, 2002



	Non-interfering	Actinomycin	Streptomyces antibioticus	Rokem et al., 2007



		Cephalosporin	Cephalosporium acremonium	Sanchez and Demain, 2002

Disaccharide Maltose Interfering Bacilysin Bacillus subtilis Ozcengiz et al., 1990

	Non-interfering	Gentamycin	Micromonospora purpurea	Sanchez and Demain, 2002



Sucrose	Interfering	Erythromycins	Streptomyces erythreus	Rokem et al., 2007



		Penicillin	Penicillium chrysogenum	Sanchez and Demain, 2002



	Non-interfering	Cephalosporin	Cephalosporium acremonium	Sanchez and Demain, 2002



Lactose	Interfering	*



	Non-interfering	Erythromycins	Streptomyce serythreus	Rokem et al., 2007



		Penicillin	Penicillium chrysogenum	Rokem et al., 2007



Mannose	Interfering	Erythromycin	Streptomyce serythreus	Sanchez and Demain, 2002



		Streptomycin	Streptomyces griseus	Sánchez et al., 2010



	Non-interfering	Kanamycin	Streptomyces kanamyceticus	Sanchez and Demain, 2002

Complex Starch Interfering *

	Non-interfering	Kanamycin	Streptomyces kanamyceticus	Rokem et al., 2007

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*
Not reported.
Fermentation processes, where raw materials/medium components cover the significant portion of the product cost, selection of these things become an important task for the production companies. In addition to the rate of assimilation of carbon sources, the nature of carbon source also affects the type and amount of the product. An example of this is ethanol or single-cell protein production, where the raw materials contribute ~60–77% of the production cost; and the selling price of the product is determined largely by the cost of the carbon source. Methanol could be a very popular inexpensive carbon source for single-cell protein production, but being toxic to the cells even at low concentrations and low flash points, it can never be used in fermentation as media. Hence, not only the cost even the dynamics of the carbon source must be considered whether it plays a role as a substrate in fermentation process or not.
Nitrogen source
Like carbon, the selection of nitrogen source and its concentration in the media also play a crucial role in metabolite production. The microorganism can utilize both inorganic and/or organic sources of nitrogen. Use of specific amino acids can increase the productivity in some cases and conversely, unsuitable amino acids may inhibit the synthesis of secondary metabolites (Marwick et al., 1999). Singh et al. (2009) during the optimization of actinomycin V production by Streptomyces triostinicus found that biosynthesis of actinomycin V involves tryptophan pathway and addition of amino acid tryptophan to the medium enhances the production. On the contrary, the same amino acid showed inhibitory effect in the production of candicidin from Streptomyces griseus (Sanchez and Demain, 2002). Nevertheless, it is confirmed that nitrogen molecules have inhibitory effect on the metabolite production in some cases, whereas, some enhancer effects of nitrogen have also been reported (Table 2).
Table 2.
Examples of some interfering and non-interfering nitrogen sources.
Nitrogen Source Action Metabolites Producer References
Inorganic NH+4 Interfering Spiramycin Streptomyces ambofaciens Lebrihi et al., 1992

		Cephalosporin	Cephalosporium acremonium	Sanchez and Demain, 2002



		Erythromycin	Streptomyces erythreus	Rokem et al., 2007



		Streptomycin	Streptomyces griseus	Sanchez and Demain, 2002



		Tetracycline	Streptomyces spp.	Rokem et al., 2007; Vastrad and Neelagund, 2011



	Non-interfering	*



Nitrate	Interfering	Aflatoxin	Aspergillus parasiticus	Sanchez and Demain, 2002



	Non-interfering	Rifamycin	Amycolatoposis mediterranei	Sanchez and Demain, 2002

Organic Urea Interfering Alternariol Alternaría alternata
Non-interfering *

Amino acids L-alanine Interfering Actinomycin Streptomyces antibioticus Rokem et al., 2007

		Bacilysin	Bacillus subtilis	Ozcengiz et al., 1990



	Non-interfering	*



L-arginine	Interfering	*



	Non interfering	Cephalosporin	Cephalosporium acremonium	Sanchez and Demain, 2002



		Gramicidin S	Bacillus brevis	Poirier and Demain, 1981



d,l-Aspartate	Interfering	Actinomycin D	Streptomyces parvullus	Foster and Katz, 1981



	Non-interfering	Streptothricin	Streptomyces rochei	Sanchez and Demain, 2002



Leucine	Interfering	Monascus pigment	Monascus spp.	Lin and Demain, 1994



	Non-interfering	Chloramphenicol	Streptomyces venezuelae,	Rokem et al., 2007



L-isoleucine	Interfering	Actinomycin D	Streptomyces parvullus	Foster and Katz, 1981



	Non-interfering	Spiramycin	Streptomyces ambofaciens	Lebrihi et al., 1992



DL- phalanine	Interfering	Actinomycin	Streptomyces antibioticus	Rokem et al., 2007



	Non-interfering	Chloramphenicol	Streptomyces venezuelae,	Rokem et al., 2007



L-proline	Interfering	Actinomycin D	Streptomyces parvullus	Foster and Katz, 1981



	Non-interfering	Streptomycin	Streptomyces griseus	Sanchez and Demain, 2002



Tryptophan	Interfering	Candicidin	Streptomyces griseus	Sanchez and Demain, 2002



	Non-interfering	Actinomycin	Streptomyces parvullus	Foster and Katz, 1981

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*
Not reported.
Phosphate
Phosphate is another basic component which is required for the production of phospholipids present in the microbial cell membranes, and for the production of nucleic acids. The amount of phosphate which must be added in the fermentation medium depends upon the composition of the broth and the need of the organism, as well as according to the nature of the desired product. For instance, some cultures will not produce secondary metabolites in the presence of phosphate, e.g., phosphatase, phytases etc. Sanchez and Demain (2002) reported that various secondary metabolites' production such as, actinorhodin, cephalosporin, clavulanic acid, streptomycin, tetracycline, vancomycin etc. is highly influenced by inorganic phosphate concentration present in the production medium. In most cases, lower concentration of phosphate is required for the initiation of the metabolite (antibiotic) production and beyond a certain concentration it suppresses the secondary metabolism and ultimately inhibits the production of primary or secondary metabolite. High phosphate concentration was reported to inhibit the production of teicoplanin, a glycopeptide antibiotic (Rokem et al., 2007).
From the above description it is clear that changes in carbon or nitrogen sources of the production medium or variation from their optimum required concentration, may affect the nature of the end product or its productivity. Therefore, the production medium with all the required components in appropriate concentration is required for the production of desired metabolite at large scale. In order to standardize the production medium, the concept of medium optimization has emerged.