An Acetyl-CoA-Gated metabolic checkpoint links precursor supply to cordycepin biosynthesis in cordyceps militaris

Zhang, H., Yang, D., Yang, G., Luo, S., Lu, P., Xie, G., Song, Y., Yang, J., Liu, L., Fan, H., Lao, W. and Vriesekoop, F. (2026) An Acetyl-CoA-Gated metabolic checkpoint links precursor supply to cordycepin biosynthesis in cordyceps militaris. Current Issues in Molecular Biology, 48 (4). ISSN 1467-3045

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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.

Item Type:	Article
Keywords:	cordycepin, Cordyceps militaris, proteomics, metabolic pathways, biosynthesis, secondary metabolites
Divisions:	Harper Food Innovation
Depositing User:	Mrs Rachael Giles
Date Deposited:	01 May 2026 14:07
Last Modified:	01 May 2026 14:07
URI:	https://hau.repository.guildhe.ac.uk/id/eprint/18357

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