Yang Xiaozhang, Huang Lianggang, Wang Kai, Li Yurong, Zhou Min, Pang Aiping, Liu Zhiqiang, Zheng Yuguo
National and Local Joint Engineering Research Center for Biomanufacturing of Choral Chemicals, Zhejiang University of Technology, Hangzhou, 310014 People's Republic of China.
Zhejiang Tiantai Pharmaceutical Co., Ltd., No.588, Fengze Road, Tiantai County, Taizhou City, 317200 Zhejiang People's Republic of China.
3 Biotech. 2025 Jun;15(6):158. doi: 10.1007/s13205-025-04331-4. Epub 2025 May 9.
Echinocandin B (ECB), a non-ribosomal lipopeptide synthesized by ascomycete fungi, serves as a first-line therapeutic agent for invasive fungal infections. While the biosynthetic gene clusters of ECB have been identified in several species, the regulatory mechanisms governing its intracellular biosynthesis remain poorly understood, hindering the development of efficient ECB-producing cell factories. To address this issue, we elucidated the mechanisms underlying echinocandin B (ECB) biosynthesis in ZJB16068 under fatty acid feeding conditions through genome and transcriptome sequencing. The genome of ZJB16068 was sequenced using Oxford Nanopore Technology, yielding a 32.67 Mbp assembly with 11 scaffolds and a GC content of 50.23%. A total of 10,505 protein-coding genes were annotated, revealing 66 secondary metabolite gene clusters. Comparative transcriptomics between ZJB16068 and the reference strain ZJB0817 identified 2,342 differentially expressed genes (DEGs) under fatty acid supplementation. The KEGG analysis of the top 20 DEGs highlighted predominant metabolic pathways, including translation, energy metabolism, cofactor supply and lipid metabolism. We found that the up-regulation of genes related to the fatty acid metabolic pathway, pantothenic acid and CoA synthesis pathway accelerated the synthesis of acetyl-CoA, and the down-regulation of TCA pathway contributed to the throttling of acetyl-CoA. In addition, the genes involved in oxidative phosphorylation are fully upregulated, providing sufficient ATP for ECB synthesis. These pathways synergistically enhance the synthesis of ECB. These findings highlight the critical role of acetyl-CoA synthesis and energy supply in ECB synthesis and provide potential direction for future metabolic engineering aiming at increasing ECB production.
The online version contains supplementary material available at 10.1007/s13205-025-04331-4.
棘白菌素B（ECB）是一种由子囊菌合成的非核糖体脂肽，是侵袭性真菌感染的一线治疗药物。虽然已在多个物种中鉴定出ECB的生物合成基因簇，但其细胞内生物合成的调控机制仍知之甚少，这阻碍了高效生产ECB的细胞工厂的开发。为了解决这个问题，我们通过基因组和转录组测序阐明了脂肪酸喂养条件下ZJB16068中棘白菌素B（ECB）生物合成的潜在机制。使用牛津纳米孔技术对ZJB16068的基因组进行测序，得到一个32.67 Mbp的组装体，有11个支架，GC含量为50.23%。共注释了10505个蛋白质编码基因，揭示了66个次级代谢产物基因簇。ZJB16068与参考菌株ZJB0817之间的比较转录组学确定了脂肪酸补充条件下2342个差异表达基因（DEG）。对前20个DEG的KEGG分析突出了主要代谢途径，包括翻译、能量代谢、辅因子供应和脂质代谢。我们发现，与脂肪酸代谢途径、泛酸和辅酶A合成途径相关的基因上调加速了乙酰辅酶A的合成，而三羧酸循环途径的下调有助于抑制乙酰辅酶A。此外，参与氧化磷酸化的基因完全上调，为ECB合成提供了足够的ATP。这些途径协同增强了ECB的合成。这些发现突出了乙酰辅酶A合成和能量供应在ECB合成中的关键作用，并为未来旨在提高ECB产量的代谢工程提供了潜在方向。
在线版本包含可在10.1007/s13205-025-04331-4获取的补充材料。
