Coordinated synthesis of aromatic amino acid derived pigments in yeast via global transcriptional engineering.

Background: Rational metabolic pathway engineering is capable of boosting upstream flux towards downstream synthesis of target products, such as aromatic amino acid derivatives. However, coordinated synthesis of multiple downstream derivatives faces difficulty of combinatorial optimization of cellular metabolism.

Results: We developed a strategy combining metabolic engineering optimization with the global transcriptional regulation of transcription factors (TFs) Spt15p and Gcn4p to optimize the synthesis of aromatic amino acid derivatives in yeast. It is verified that the special mutants of these TFs can respectively improve the biosynthesis of betaxanthin, a tyrosine derived edible pigment. Comparative transcriptome analysis shows that significant transcriptional tuning occurs in glycolysis, pentose phosphate pathway, aromatic amino acid synthesis pathways, etc. In addition, global transcriptional engineering is proved to enhance the coordinated biosynthesis of both tyrosine derived pigment betaxanthin and tryptophan derived pigment violacein by more than 50%. Finally, we obtain an optimized production of 208 mg/L betaxanthin in yeast cells by flask fermentation.

Conclusions: Our strategy supplies an effective way to optimize the coordinated synthesis of two structurally divergent pigments downstream of the common aromatic amino acid pathway.