Metabolic Engineering for Gibberellic Acid Production in Fusarium fujikuroi: Advances and Perspectives
Gibberellic acids (GAs) are a class of tetracyclic diterpene carboxylic acid compounds produced by green plants, fungi, and bacteria, which have a wide range of applications in agricultural production and food ingredients processing. Owing to the continuously growing market demand, enhancing GA yield has become imperative. The biosynthesis of GAs is a multi-enzymatic synergistic process that can be enhanced through genetic and metabolic engineering strategies. In this review, we first summarize recent advances in GA production by Fusarium fujikuroi. We then highlight key metabolic engineering strategies, including biosynthetic pathway engineering, cluster-specific channeling of geranylgeranyl diphosphate biosynthesis, cofactor engineering, as well as regulatory mechanisms involving nitrogen modulation and histone modification. Finally, we discuss promising approaches for constructing high-efficiency microbial cell factories, such as implementation of the CRISPR/Cas9 system, the application of strong promoters, the development of target-specific technologies for small molecules, and the employment of genome-scale metabolic models. Recent metabolic engineering efforts have achieved GA3 titers of up to 3.16 g/L through multi-target nitrogen regulation strategies, highlighting the potential for further yield improvement.