Regulation and biosynthesis of secondary metabolites

Čurdová, E.; Křemen, Alexandr; Ванек, З.; Hošťálek, Z.

doi:10.1007/bf02876940

Cited by 34 publications

(2 citation statements)

References 12 publications

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“…5H20, 0.001 g; ZnSO47H20, 0.01 g-, ferric ammonium citrate, 3.0 g; Betaine hydrochloride, 5.0 g; L-sodium glutamate, 20.0 g; glucose, 35.0 g; CaCO3, 3.0 g; methyloleate, 3.0 g; and K2HPO4, 2.3 g. Growth conditions and assay procedures were as previously described (Gray and Bhuwapathanapun, in press).…”

Section: Methodsmentioning

confidence: 99%

Metabolic regulation in tylosin-producing Streptomyces fradiae: regulatory role of adenylate nucleotide pool and enzymes involved in biosynthesis of tylonolide precursors

Vu-Trong¹,

Bhuwapathanapun²,

Gray³

1980

Antimicrob Agents Chemother

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The relationship was studied between the level of the intracellular adenylates and the biosynthesis of tylosin by Streptomyces fradiae NRRL 2702. The adenylate level was observed to be inversely related to the rate of tylosin biosynthesis and hence the final concentration of the antibiotic. The concentrations of the adenylates were maximal during the trophophase, dropped quickly before the onset of tylosin biosynthesis, and remained at low levels throughout the idiophase. The adenylate energy charge was almost constant throughout the fermentation and was in the range of 0.4 to 0.55. Glucose addition in the idiophase suppressed tylosin biosynthesis, accompanied by a rapid increase in the adenylate levels. The biosynthesis of tylosin resumed after a rapid drop in the adenosine triphosphate concentration. Two enzymes catalyzing the interconversion of propionyl-coenzyme A and methylmalonyl-coenzyme A were found in this organism: methylmalonyl-coenzyme A carboxyltransferase (EC 2.1.3.1) and propionyl-coenzyme A carboxylase (EC 6.4.1.3). The activity of the former was two orders of magnitude higher than that of the latter. The activities of both enzymes were affected by the increased glucose addition in the idiophase.Tylosin, a macrolide antibiotic synthesized by Streptomyces fradiae, was first described by McGuire et al. in 1961 (9). Later investigations showed that the organism coproduced four antibiotics with structures closely related to tylosin (6). Seno et al. (14) presented data showing that the major factors formed by S. fradiae were tylosin, macrocin, and relomycin (Fig. 1). These compounds occur in the terminal stages of tylosin biosynthesis, and a pathway relating the compounds has been proposed (14).In a previous study (P. P. Gray and S. Bhuwapathanapun, Biotechnol. Bioeng., in press), chemostat cultures were used to determine the relationship between the specific uptake rates of glucose, glycerol, phosphate, and sodium glutamate on the biosynthesis of tylosin and related compounds.In this study, shake flask cultures have been used to investigate the relationship between tylosin biosynthesis and the intracellular concentrations of adenosine triphosphate, diphosphate, and monophosphate (ATP, ADP, and AMP) and the adenylate energy charge in normal batch culture and after the addition of glucose to idiophase cultures. The 16-membered lactone ring of tylosin has been shown (11) to be derived from two acetates, five propionates, and one t Present address:

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Section: Methodsmentioning

confidence: 99%

Metabolic regulation in tylosin-producing Streptomyces fradiae: regulatory role of adenylate nucleotide pool and enzymes involved in biosynthesis of tylonolide precursors

Vu-Trong¹,

Bhuwapathanapun²,

Gray³

1980

Antimicrob Agents Chemother

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“…The biosynthesis of natural products produced by most actinomycetes is affected by phosphate concentrations in the medium ( Romero-Rodríguez et al., 2018 ; Martín et al., 2012 ; Solans et al., 2019 ). Initially, the phosphate effect was attributed to a decrease or inhibition of natural product production as a result of a phosphate increase in the culture medium ( Curdová et al., 1976 ). Further studies on phosphate metabolism-related genes identified several of these genes, such as alkaline phosphatase, polyphosphatase, and low- and high-affinity transporter genes, and the pho regulon ( Moura et al., 2001 ; Vuppada et al., 2018 ; Santos-Beneit et al., 2008 ; Martínez-Castro et al., 2018 ).…”

Section: Introductionmentioning

confidence: 99%

SenX3-RegX3, an Important Two-Component System, Regulates Strain Growth and Butenyl-spinosyn Biosynthesis in Saccharopolyspora pogona

Rang

Chen

et al. 2020

iScience

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Summary Butenyl-spinosyn produced by Saccharopolyspora pogona exhibits strong insecticidal activity and a broad pesticidal spectrum. Currently, important functional genes involved in butenyl-spinosyn biosynthesis remain unknown, which leads to difficulty in efficient understanding of its regulatory mechanism and improving its production by metabolic engineering. Here, we present data supporting a role of the SenX3-RegX3 system in regulating the butenyl-spinosyn biosynthesis. EMSAs and qRT-PCR demonstrated that RegX3 positively controls butenyl-spinosyn production in an indirect way. Integrated proteomic and metabolomic analysis, regX3 deletion not only strengthens the basal metabolic ability of S. pogona in the mid-growth phase but also promotes the flow of the acetyl-CoA produced via key metabolic pathways into the TCA cycle rather than the butenyl-spinosyn biosynthetic pathway, which ultimately leads to continued growth but reduced butenyl-spinosyn production. The strategy demonstrated here may be valuable for revealing the regulatory role of the SenX3-RegX3 system in the biosynthesis of other natural products.

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Continuous‐culture studies on the regulation of tylosin biosynthesis

Vu-Trong¹,

Gray²

1982

Biotech & Bioengineering

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The metabolic regulation of tylosin synthesis by Streptomyces fradiae NRRL 2702 was studied in batch and chemostat cultures using a soluble synthetic medium. In batch culture a medium which diminished the trophophase-idiophase kinetic pattern was used to assess the activities of the enzymes involved in tylosin synthesis. The enzymes methylmalonyl-coenzyme A carboxyltransferase (EC 2.1.3.1) and propionyl-coenzyme A carboxylase (EC 6.4.1.3) showed early enzymatic derepression, both enzymes reaching their highest specific activities after 72-96 fermentation. The activity of macrocin 3' -O-methyltransferase, the enzyme catalyzing the conversion of macrocin (tylosin C) to tylosin (tylosin A). also peaked at 72 h. The specific activities of the three enzymes showed close correlation with the q(tylosin) value. In chemostat cultures the activities of the enzymes and the intracellular level of the adenylate pool and energy charge were studied as a function of dilution rate. Under steady-state conditions, increases in the specific growth rate repressed the enzymes activities with a concomitant increase in the intracellular level of the adenylate pool, while the adenylate energy charge remained almost constant and in the range 0.5-0.52. The highest specific activities of the enzymes were observed when D = 0.008 h (-1). The specific rate of tylosin synthesis was inversely proportional to the specific growth rate and the intracellular level of adenylate pool. The pool of adenylate could be a nutritional parameter which had a considerable influence on the biosynthesis of tylosin.

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Regulation and biosynthesis of secondary metabolites

Cited by 34 publications

References 12 publications

Metabolic regulation in tylosin-producing Streptomyces fradiae: regulatory role of adenylate nucleotide pool and enzymes involved in biosynthesis of tylonolide precursors

Metabolic regulation in tylosin-producing Streptomyces fradiae: regulatory role of adenylate nucleotide pool and enzymes involved in biosynthesis of tylonolide precursors

SenX3-RegX3, an Important Two-Component System, Regulates Strain Growth and Butenyl-spinosyn Biosynthesis in Saccharopolyspora pogona

Continuous‐culture studies on the regulation of tylosin biosynthesis

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