Light-Exposed Metabolic Responses of Cordyceps militaris through Transcriptome-Integrated Genome-Scale Modeling

The genome-scale metabolic model (GSMM) of Cordyceps militaris provides a comprehensive
basis of carbon assimilation for cell growth and metabolite production. However, the model
with a simple mass balance concept shows limited capability to probe the metabolic responses of
C. militaris under light exposure. This study, therefore, employed the transcriptome-integrated
GSMM approach to extend the investigation of C. militaris’s metabolism under light conditions.
Through the gene inactivity moderated by metabolism and expression (GIMME) framework, the
iPS1474-tiGSMM model was furnished with the transcriptome data, thus providing a simulation
that described reasonably well the metabolic responses underlying the phenotypic observation
of C. militaris under the particular light conditions. The iPS1474-tiGSMM obviously showed
an improved prediction of metabolic fluxes in correlation with the expressed genes involved in
the cordycepin and carotenoid biosynthetic pathways under the sucrose culturing conditions.
Further analysis of reporter metabolites suggested that the central carbon, purine, and fatty
acid metabolisms towards carotenoid biosynthesis were the predominant metabolic processes
responsible in light conditions. This finding highlights the key responsive processes enabling
the acclimatization of C. militaris metabolism in varying light conditions. This study provides a
valuable perspective on manipulating metabolic genes and fluxes towards the target metabolite
production of C. militaris.