VeA is involved in anti-tumor activity by regulating adenylosuccinate lyase to mediate the synthesis of Acadesine in endophytic Fusarium solani.

Abstract

Acadesine (AICAR) is a promising candidate for new drugs in Phase III clinical trials. The purpose of this study is to analyse the steps in the biosynthesis pathway of AICAR. Our previous study found that overexpression of veA, a gene encoding a global regulator, significantly increased AICAR production of endophytic Fusarium solani HB1-J1 and the anti-tumor activity of its extracts. Transcriptome and metabolome analysis of FsveA^OE14, a veA overexpressing F. solani strain, revealed a 10-step AICAR synthesis pathway, with adenylosuccinate lyase PurB as a key enzyme. Generally, overexpressing purB (the gene encoding adenylosuccinate lyase) enhances AICAR synthesis. However, in FsveA^OE14, despite down-regulation of purB, AICAR content increased, which is contradictory. Further studies revealed that expression levels of purB homologs gene, pro06469 and pro10879, were upregulated in FsveA^OE14. This suggests that although veA overexpression leads to purB down-regulation, their up-regulation may compensate for the reduction of purB, thus affecting AICAR synthesis. Additionally, compared to the wild type, overexpressing purB significantly enhances the inhibitory activity of the strain's extracts against the nonsmall-cell lung cancer cell line A549. Furthermore, it also increases the metabolic levels of other anti-tumor compounds, including 3-methyladenine, taurine, and others. These results indicate that VeA regulates AICAR biosynthesis via key enzymes like PurB, enhancing AICAR and other anti-tumor compound production, thus increasing the anti-tumor activity of F. solani extracts.