MtfA, a C2H2 transcriptional regulator, negatively regulates PRPS2-mediated biosynthesis of the adenosine analogue acadesine in <i>Fusarium solani</i>

Endogenous AICAR (acadesine) demonstrates significant therapeutic potential as a phase III clinical agent for the treatment of adverse cardiovascular reactions to coronary artery bypass grafting and as a phase I/II clinical agent for chronic lymphocytic leukaemia. However, its biosynthetic mechanism remains poorly defined. Our previous study demonstrated that AICAR was significantly enriched in the <i>Fusarium solani</i> mutant <i>veA</i>^OE14, which overexpressed the global regulator VeA. We found that phosphoribosyl pyrophosphate synthase 2, viz., PRPS2 (PrsA) is regulated by VeA and involved in AICAR synthesis. Deletion of <i>PRPS2</i> resulted in a significant 17% (μg/mg) reduction in AICAR production in the strain (<i>p</i> &lt; 0.05), whereas its overexpression led to a statistically significant 1.2-fold increase in AICAR content (<i>p</i> &lt; 0.01). Furthermore, we characterised the transcription factor MtfA, which inhibits the expression of <i>PRPS2</i> gene and is negatively regulated by VeA. Further validation by yeast one-hybrid assay showed that MtfA directly regulated the <i>PRPS2</i> gene, while AICAR was significantly increased in the <i>mtfA</i> deletion mutant. The above results indicate that the global regulator VeA negatively regulates the transcription factor MtfA, which in turn targets negatively regulating transcriptional levels of PRPS2 to mediate AICAR biosynthesis in <i>F. solani</i>.