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Cordyceps, Caterpillar Fungus · 2026 · Research Article

Medium relevance

An Acetyl-CoA-Gated Metabolic Checkpoint Links Precursor Supply to Cordycepin Biosynthesis in Cordyceps militaris.

Ophiocordyceps sinensis

Energy & fatigueMetabolic healthRespiratory
SpeciesCordyceps, Caterpillar Fungus
JournalCurrent issues in molecular biology
Year2026

Key points

  • The growth-specialized metabolism trade-off limits fungal natural product production
  • Here, we investigated cordycepin overproduction in Cordyceps militaris high-yield GYS60 and low-yield GYS80 via comparative proteomics, Post-Translational Modification (PTM) mapping, and metabolomics
  • We identified an acetyl-CoA-gated checkpoint centered on O-methyltransferase CCM_06472, whose activity is modulated by Lys123 acetylation and Ser34 phosphorylation in a manner consistent with activation and inhibition
  • GYS60 hyperactivates the tricarboxylic acid (TCA) cycle and β-oxidation to generate a 4.1-fold acetyl-CoA surplus, 62% of which is channeled into cordycepin synthesis
  • A single K123Q acetylation-mimetic mutation boosted cordycepin titers by >4-fold in wild-type strains
  • This acetyl-CoA checkpoint reveals PTM-gated flux allocation as a key regulatory mechanism, providing a minimal-intervention strategy for engineering fungal cell factories

Metadata-grounded summary

Citation abstract

The growth-specialized metabolism trade-off limits fungal natural product production. Here, we investigated cordycepin overproduction in Cordyceps militaris high-yield GYS60 and low-yield GYS80 via comparative proteomics, Post-Translational Modification (PTM) mapping, and metabolomics. We identified an acetyl-CoA-gated checkpoint centered on O-methyltransferase CCM_06472, whose activity is modulated by Lys123 acetylation and Ser34 phosphorylation in a manner consistent with activation and inhibition. GYS60 hyperactivates the tricarboxylic acid (TCA) cycle and β-oxidation to generate a 4.1-fold acetyl-CoA surplus, 62% of which is channeled into cordycepin synthesis. A single K123Q acetylation-mimetic mutation boosted cordycepin titers by >4-fold in wild-type strains. This acetyl-CoA checkpoint reveals PTM-gated flux allocation as a key regulatory mechanism, providing a minimal-intervention strategy for engineering fungal cell factories.

Citation

Zhang H, Yang D, Yang G, Luo S, Lu P, Xie G, et al. (2026). An Acetyl-CoA-Gated Metabolic Checkpoint Links Precursor Supply to Cordycepin Biosynthesis in Cordyceps militaris. Current issues in molecular biology https://doi.org/10.3390/cimb48040370 PMID: 42042030

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