Inoculum size-dependent interactive regulation of metabolism and stress response of Saccharomyces cerevisiae revealed by comparative metabolomics

Ding, Ming-Zhu; Tian, Hong-Chi; Cheng, Jun; Yang, Yuan

doi:10.1016/j.jbiotec.2009.09.020

Cited by 48 publications

(24 citation statements)

References 32 publications

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“…4A and B suggest that 6-NDA could similarly inhibit the elongation of fatty acids longer than myristate in yeast cells, although the slight increase in palmitoleate (C 16:1 ) levels observed would appear to be somewhat counter to this notion. Palmitoleate, however, comprises the majority of unsaturated fatty acids found within cellular membranes of several yeast strains (including S288C) and likely plays a critical role in adaptation to stress (10,13,24). Therefore, the possibility cannot be discounted that regulatory pathways exist for the maintenance of adequate palmitoleate levels during stress exposure, thus compensating for the inhibitory effects of 6-NDA.…”

Section: Figmentioning

confidence: 99%

A Potent Plant-Derived Antifungal Acetylenic Acid Mediates Its Activity by Interfering with Fatty Acid Homeostasis

Tripathi

Feng

et al. 2012

Antimicrob Agents Chemother

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c 6-Nonadecynoic acid (6-NDA), a plant-derived acetylenic acid, exhibits strong inhibitory activity against the human fungal pathogens Candida albicans, Aspergillus fumigatus, and Trichophyton mentagrophytes. In the present study, transcriptional profiling coupled with mutant and biochemical analyses were conducted using the model yeast Saccharomyces cerevisiae to investigate its mechanism of action. 6-NDA elicited a transcriptome response indicative of fatty acid stress, altering the expression of genes that are required for yeast growth in the presence of oleate. Mutants of S. cerevisiae lacking transcription factors that regulate fatty acid ␤-oxidation showed increased sensitivity to 6-NDA. Fatty acid profile analysis indicated that 6-NDA inhibited the formation of fatty acids longer than 14 carbons in length. In addition, the growth inhibitory effect of 6-NDA was rescued in the presence of exogenously supplied oleate. To investigate the response of a pathogenic fungal species to 6-NDA, transcriptional profiling and biochemical analyses were also conducted in C. albicans. The transcriptional response and fatty acid profile of C. albicans were comparable to those obtained in S. cerevisiae, and the rescue of growth inhibition with exogenous oleate was also observed in C. albicans. In a fluconazole-resistant clinical isolate of C. albicans, a fungicidal effect was produced when fluconazole was combined with 6-NDA. In hyphal growth assays, 6-NDA inhibited the formation of long hyphal filaments in C. albicans. Collectively, our results indicate that the antifungal activity of 6-NDA is mediated by a disruption in fatty acid homeostasis and that 6-NDA has potential utility in the treatment of superficial Candida infections.

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Section: Figmentioning

confidence: 99%

A Potent Plant-Derived Antifungal Acetylenic Acid Mediates Its Activity by Interfering with Fatty Acid Homeostasis

Tripathi

Feng

et al. 2012

Antimicrob Agents Chemother

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“…It was also confirmed that the glutamate could be used for the biosynthesis of proline (Brandriss and Falvey 1992). Although the increase in the level of proline in S. cerevisiae was proposed to be a critical amino acid involved in stress responses resulting from a higher inoculation size (40 gL −1 , DCW) (Ding et al 2009a), the levels of glutamate and proline in S. lydicus under a high pitching ratio (30 %, v/v) were much lower than that under low pitching ratio (1 %, v/v) (Figs. 2 and 3).…”

Section: Discussionmentioning

confidence: 84%

“…In Streptomyces coelicolor, concordance analysis was applied to detect reliable changes for 97 putatively identified metabolics that are significantly concordant and reproducible across the time series (Jankevics et al 2011). Previous researches demonstrated that the pathway shifts and variations of metabolite levels in Saccharomyces cerevisiae responded the stresses triggered by high cell density (Cheng et al 2009;Ding et al 2009a). Comparative LC-MS analysis in S. lydicus under 10 % pitching ration was rapid, sensitive, and suitable for characterizing intermediates, metabolites, and pathways for elucidation of the metabolic alterations during strain improvement (Li et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Metabolic analysis reveals the amino acid responses of Streptomyces lydicus to pitching ratios during improving streptolydigin production

Cheng

Liang

Ding

et al. 2013

Appl Microbiol Biotechnol

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Pitching ratio has been reported to impact not only on the primary metabolism, but also the secondary metabolism. Comparative metabolomics was used to explore the metabolic responses of Streptomyces lydicus E9 to pitching ratios (1, 10, and 30%, v/v). We identified more than 120 metabolites involved in glycolysis, tricarboxylic acid cycle, and amino acid and secondary metabolism, of which there are significant differences in the quantified 32 metabolites under different pitching ratios by gas chromatography coupled to time-of-flight mass spectrometry. The intracellular levels of most amino acids (e.g., valine, alanine, and isoleucine) declined with the increases of pitching ratios. Especially, the relative abundances of glutamate and proline were not only decreased with the increases of pitching rations, but also had much low level at stages II and III, which might be related to the significant enhancement in streptolydigin of S. lydicus E9 under 30% high pitching ratio. Moreover, principal component analysis revealed that eight metabolites, including glucopyranoside, maltose, cAMP, glycine, proline, lysine, isoleucine, and valine, were considered as potential biomarkers to distinguish the influences of pitching ratios on streptolydigin production. Further investigations demonstrated that the additions of exogenous glutamate and proline (100 mgL⁻¹) enhanced significantly the accumulation of streptolydigin, indicating that glutamate was the synthetic precursor of streptolydigin, while proline in S. lydicus E9 was converted into glutamate and consequently improved streptolydigin biosynthesis. Therefore, these findings provide new insights into the amino acid responses of S. lydicus E9 to pitching ratios and provide potential strategies to improve streptolydigin production.

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“…For example, comparative metabolomics based on GC-MS was employed to investigate the external stress mechanism in Saccharomyces cerevisiae under high cell density culture [11]. In this study, metabolomics enables us to gain comprehensive insights into complex cellular metabolic mechanisms in the synthesis of rapamycin.…”

Section: Discussionmentioning

confidence: 99%

Comparative metabolic profiling reveals the key role of amino acids metabolism in the rapamycin overproduction by Streptomyces hygroscopicus

Wang

Liu

et al. 2015

Journal of Industrial Microbiology and Biotechnology

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Rapamycin is an important natural macrolide antibiotic with antifungal, immunosuppressive and anticancer activity produced by Streptomyces hygroscopicus. In this study, a mutant strain obtained by ultraviolet mutagenesis displayed higher rapamycin production capacity compared to the wild-type S. hygroscopicus ATCC 29253. To gain insights into the mechanism of rapamycin overproduction, comparative metabolic profiling between the wild-type and mutant strain was performed. A total of 86 metabolites were identified by gas chromatography-mass spectrometry. Pattern recognition methods, including principal component analysis, partial least squares and partial least squares discriminant analysis, were employed to determine the key biomarkers. The results showed that 22 potential biomarkers were closely associated with the increase of rapamycin production and the tremendous metabolic difference was observed between the two strains. Furthermore, metabolic pathway analysis revealed that amino acids metabolism played an important role in the synthesis of rapamycin, especially lysine, valine, tryptophan, isoleucine, glutamate, arginine and ornithine. The inadequate supply of amino acids, or namely "nitrogen starvation" occurred in the mutant strain. Subsequently, the exogenous addition of amino acids into the fermentation medium of the mutant strain confirmed the above conclusion, and rapamycin production of the mutant strain increased to 426.7 mg/L after adding lysine, approximately 5.8-fold of that in the wild-type strain. Finally, the results of real-time PCR and enzyme activity assays demonstrated that dihydrodipicolinate synthase involved with lysine metabolism played vital role in the biosynthesis of rapamycin. These findings will provide a theoretical basis for further improving production of rapamycin.

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Inoculum size-dependent interactive regulation of metabolism and stress response of Saccharomyces cerevisiae revealed by comparative metabolomics

Cited by 48 publications

References 32 publications

A Potent Plant-Derived Antifungal Acetylenic Acid Mediates Its Activity by Interfering with Fatty Acid Homeostasis

A Potent Plant-Derived Antifungal Acetylenic Acid Mediates Its Activity by Interfering with Fatty Acid Homeostasis

Metabolic analysis reveals the amino acid responses of Streptomyces lydicus to pitching ratios during improving streptolydigin production

Comparative metabolic profiling reveals the key role of amino acids metabolism in the rapamycin overproduction by Streptomyces hygroscopicus

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