Uncovering global metabolic response to cordycepin production in Cordyceps militaris through transcriptome and genome-scale network-driven analysis

Abstract

The cellular metabolic adaptations of Cordyceps militaris have been progressively studied. In particular, the cordycepin pathway is of interest in medicinal applications. Even though the metabolic pathways for cordycepin production are known to be related to different carbon sources, the regulatory mechanisms at a systems level are poorly characterized. To explore the regulatory mechanisms, this study therefore aimed to investigate the global metabolic response to cordycepin production in C. militaris through transcriptome analysis and genome-scale network-driven analysis. Here, transcriptome analysis of 16,805 expressed genes in C. militaris strain TBRC6039 grown on different carbon sources was performed. Of these genes, 2,883 were significantly differentially expressed genes, uncovering sucrose- and glucose-mediated changes in the transcriptional regulation of central carbon metabolism in C. militaris, which was shown using the CmSNF1 mechanism as an example. After applying genome-scale metabolic network-driven analysis, reporter metabolites and key metabolic subnetworks involving adenosine, cordycepin and methionine were proposed through the up-regulation of cordycepin biosynthetic genes. Our findings suggest that the transcriptional regulation of these pathways is a ubiquitous feature in response to specific culture conditions during cordycepin overproduction.

Probing Carbon Utilization of Cordyceps militaris by Sugar Transportome and Protein Structural Analysis

“…However, there is not much to report regarding the polyol transport of the fungal group. Actually, this insect pathogenic fungus has capability in the production of mannitol which is a sugar alcohol with commercial interest in food products and also for medicinal uses [9]. It is noteworthy that further investigation in the functional role of the C. militaris genes coding for putative polyol transporters would be valuable for industrial viewpoints.…”

Transcriptome Analysis Reveals the Flexibility of Cordycepin Network in Cordyceps militaris Activated by L-Alanine Addition

“…High-throughput sequencing technologies have been used to discover the biosynthetic and metabolic pathway of cordycepin (Zheng et al, 2011;Yin et al, 2012;Raethong et al, 2018). As an isomer of 2 -deoxyadenosine, cordycepin was predicted to share a similar synthesis pathway of 2 -deoxyadenosine, but the relevant key enzyme was missing in the genome of C. militaris (Zheng et al, 2011).…”

“…A three-gene biosynthesis cluster was reported (Xia et al, 2017) to synthesize cordycepin from adenosine, and it revealed that cordycepin metabolism overlapped with parts of the purine pathway. Further transcriptome analysis of samples with three carbon sources (Raethong et al, 2018) had tried to draw a network between adenosine, methionine, and cordycepin. Unfortunately, it failed to provide further verification in a molecular level.…”

Metabolic Responses of Carotenoid and Cordycepin Biosynthetic Pathways in Cordyceps militaris under Light-Programming Exposure through Genome-Wide Transcriptional Analysis

“…C. militaris strain TBRC6039 was used in this study. Fungal cultures were grown in defined media, containing glucose or sucrose as carbon source, at static condition, 22 ± 2 °C, as detailed in the previous study [ 17 ]. For the carotenoid-producing condition, the fungal cultivation was conducted under the light-programming condition by switching the light (~1000 lux) and dark conditions at an interval of 12 h. All batch experiments were performed in three biological replicates.…”

“…To date, a genome-scale metabolic model has enabled the optimization of C. militaris cultivation to enhance growth and cordycepin production by rational design of culture medium composition [ 15 ]. Moreover, there are earlier studies documenting the carbon source utilization in C. militaris , in which glucose and sucrose were often used as preferred carbon sources for cell growth, cordycepin and carotenoid production [ 16 , 17 ]. To gain more insight into the key metabolites, it is worth addressing the metabolic network of biosynthetic pathways of cordycepin, and other metabolites in C. militaris (e.g., carotenoid), which would accelerate the progress in this fungal field in aspects of fundamental knowledge and biotechnological production of value-added metabolites.…”